CGT Exome

Compatível com a maioria das plataformas e painéis de portares do mercado

Características:

Genes: 1576

Variantes: 30592

Numeros de doenças: >1600

Portadores estimados (%)*: 62.7%

Media estimada de mutações por indivíduo **: 2.28

Profundidade média: 100X

Testes complementares: HBA, F8, FMR1, SMN1, DMD, CYP21A2

Amostra: Sangue

Prazo: 25 dias úteis

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Versión: 1.0

GENE	DISEASE	TRANSCRIPT	MUTATIONS	DISEASE.DESCRIPTION	PRODUCTS
AAAS	Triple-A syndrome (achalasia-addisonianism-alacrimia) Triple-A syndrome (achalasia-addisonianism-alacrimia) Descrição da doença: The three specific features of triple-A syndrome are achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addisonism, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of addisonism include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of this syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two. Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. People with the syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).	NM_015665.5	c.1432C>T;c.1332-2A>T;c.1331+1G>A;c.1288C>T;c.1191 c.1432C>T;c.1332-2A>T;c.1331+1G>A;c.1288C>T;c.1191dupA;c.1159C>T;c.1144_1147delTCTG;c.1087+1G>A;c.1066_1067delCT;c.980dupT;c.938T>C;c.936-1G>C;c.934C>T;c.885G>A;c.787T>C;c.400-2A>G;c.310_317delTTTGAGTG;c.251G>A	The three specific features of triple-A syndrome are achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addisonism, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of addisonism include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of this syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two. Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. People with the syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).	Plus
AARS	Epileptic encephalopathy, early infantile, type 29 Epileptic encephalopathy, early infantile, type 29 Descrição da doença: Epileptic encephalopathy, early infantile, type 29 (EIEE29) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE29 patients manifest severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination.	NM_001605.2	c.986G>A;c.242A>C;c.211A>T c.986G>A;c.242A>C;c.211A>T	Epileptic encephalopathy, early infantile, type 29 (EIEE29) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE29 patients manifest severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination.	Plus
AARS2	Combined oxidative phosphorylation deficiency 8; Leukoencephalopathy, progressive, with ovarian failure Combined oxidative phosphorylation deficiency 8; Leukoencephalopathy, progressive, with ovarian failure Descrição da doença: Combined oxidative phosphorylation deficiency 8 (COXPD8) is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (Gotz et al., 2011). Mutation in the AARS2 gene can also cause progressive leukoencephalopathy with ovarian failure, an autosomal recessive neurodegenerative disorder characterized by loss of motor and cognitive skills, usually with onset in young adulthood. Some patients may have a history of delayed motor development or learning difficulties in early childhood. Neurologic decline is severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most patients lose speech and become wheelchair-bound or bedridden. Brain MRI shows progressive white matter signal abnormalities in the deep white matter. Affected females develop premature ovarian failure (summary by Dallabona et al., 2014).	NM_020745.3	c.2893G>A;c.2681C>A;c.2598+1G>T;c.2392C>T;c.2146-2 c.2893G>A;c.2681C>A;c.2598+1G>T;c.2392C>T;c.2146-2A>G;c.1774C>T;c.1561C>T;c.1213G>A;c.1008dupT;c.647dupG;c.595C>T;c.464T>G;c.149T>G	Combined oxidative phosphorylation deficiency 8 (COXPD8) is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (Gotz et al., 2011). Mutation in the AARS2 gene can also cause progressive leukoencephalopathy with ovarian failure, an autosomal recessive neurodegenerative disorder characterized by loss of motor and cognitive skills, usually with onset in young adulthood. Some patients may have a history of delayed motor development or learning difficulties in early childhood. Neurologic decline is severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most patients lose speech and become wheelchair-bound or bedridden. Brain MRI shows progressive white matter signal abnormalities in the deep white matter. Affected females develop premature ovarian failure (summary by Dallabona et al., 2014).	Plus
AASS	Hyperlysinemia, type 1 and type 2 Hyperlysinemia, type 1 and type 2 Descrição da doença: Hyperlysinemia, type 1 is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (Tondo et al., 2013; Houten et al., 2013).The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type 1, both enzymatic functions of AASS are defective; in hyperlysinemia type 2, also known as Saccharopinuria, some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1985).	NM_005763.3	c.2662+1_2662+5delGTAAGinsTT;c.1925C>G;c.1601_1609 c.2662+1_2662+5delGTAAGinsTT;c.1925C>G;c.1601_1609delGTAAACAAG;c.976_977delCA;c.194G>A	Hyperlysinemia, type 1 is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (Tondo et al., 2013; Houten et al., 2013).The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type 1, both enzymatic functions of AASS are defective; in hyperlysinemia type 2, also known as Saccharopinuria, some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1985).	Plus
ABAT	GABA-transaminase deficiency GABA-transaminase deficiency Descrição da doença: GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (Koenig et al., 2017).	NM_000663.4	c.275G>A;c.631C>T;c.659G>A;c.709G>A;c.1433T>C c.275G>A;c.631C>T;c.659G>A;c.709G>A;c.1433T>C	GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (Koenig et al., 2017).	Plus
ABCA1	Tangier disease Tangier disease Descrição da doença: Tangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).	NM_005502.3	c.6402-1G>T;c.6241C>T;c.6026T>C;c.3849_3852delCCCG c.6402-1G>T;c.6241C>T;c.6026T>C;c.3849_3852delCCCG;c.3738+1G>C;c.3343_3344delTC;c.3295G>T;c.2810C>T;c.2804A>G;c.2803A>C;c.2725delC;c.1824delG;c.1719C>A	Tangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).	Plus
ABCA12	Ichthyosis, congenital, autosomal recessive, type 4A; ICAR, type 4B (harlequin) Ichthyosis, congenital, autosomal recessive, type 4A; ICAR, type 4B (harlequin) Descrição da doença: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI 4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	NM_173076.2	c.7444C>T;c.7323delC;c.6610C>T;c.6353C>G;c.6234-1G c.7444C>T;c.7323delC;c.6610C>T;c.6353C>G;c.6234-1G>C;c.5787T>G;c.5414C>G;c.5381+1G>C;c.5231G>A;c.5128+2T>C;c.5012delA;c.4615G>A;c.4541G>A;c.4142G>A;c.4139A>G;c.4108G>T;c.3889C>T;c.3256A>T;c.2296C>T;c.2273dupT;c.2140C>T;c.2121+2T>G;c.1660C>T;c.1300C>T;c.859C>T;c.596G>A;c.178C>T	Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI 4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	Plus
ABCA3	Surfactant metabolism dysfunction, pulmonary, type 3 Surfactant metabolism dysfunction, pulmonary, type 3 Descrição da doença: Surfactant dysfunction is a lung disorder that causes breathing problems. This condition results from abnormalities in the composition or function of surfactant, a mixture of certain fats (called phospholipids) and proteins that lines the lung tissue and makes breathing easy. Without normal surfactant, the tissue surrounding the alveoli sticks together (because of a force called surface tension) after exhalation, causing the alveoli to collapse. As a result, filling the lungs with air on each breath becomes very difficult, and the delivery of oxygen to the body is impaired.The signs and symptoms of surfactant dysfunction can vary in severity. The most severe form of this condition causes respiratory distress syndrome in newborns. Affected babies have extreme difficulty breathing and are unable to get enough oxygen.	NM_001089.2	c.4909+1G>A;c.4772A>C;c.4658T>C;c.3426G>A;c.1702A> c.4909+1G>A;c.4772A>C;c.4658T>C;c.3426G>A;c.1702A>G;c.1609_1611+4delAAGGTGCinsCCA;c.875A>T	Surfactant dysfunction is a lung disorder that causes breathing problems. This condition results from abnormalities in the composition or function of surfactant, a mixture of certain fats (called phospholipids) and proteins that lines the lung tissue and makes breathing easy. Without normal surfactant, the tissue surrounding the alveoli sticks together (because of a force called surface tension) after exhalation, causing the alveoli to collapse. As a result, filling the lungs with air on each breath becomes very difficult, and the delivery of oxygen to the body is impaired.The signs and symptoms of surfactant dysfunction can vary in severity. The most severe form of this condition causes respiratory distress syndrome in newborns. Affected babies have extreme difficulty breathing and are unable to get enough oxygen.	Plus
ABCA4	Stargardt disease type 1; Cone-rod dystrophy type 3 Stargardt disease type 1; Cone-rod dystrophy type 3 Descrição da doença: Stargardt disease type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ABCA4 gene located on chromosomal region 1p22. The age of onset is infantile. This disease is characterized by progressive central vision loss, mild loss of color vision, delayed dark adaptation and macular atrophy with or without paramacular flecks and degeneration of the underlying retinal pigment ephitelium. The estimated prevalence is 1:8,000-10,000. Mutations in the ABCA4 gene account also for 30 to 60 percent of cases of cone-rod dystrophy that are inherited in an autosomal recessive pattern. The problems associated with this condition include a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision. These vision problems worsen over time.	NM_000350.2	c.6816+2T>A;c.6816+1G>A;c.6658C>T;c.6609C>A;c.6601 c.6816+2T>A;c.6816+1G>A;c.6658C>T;c.6609C>A;c.6601_6602delAG;c.6449G>A;c.6445C>T;c.6394G>T;c.6386+2C>G;c.6329G>A;c.6326T>C;c.6320G>A;c.6317G>A;c.6316C>T;c.6284A>T;c.6283-3_6283-2delCAinsAG;c.6230G>A;c.6229C>T;c.6184_6187delGTCT;c.6166A>T;c.6118C>T;c.6112C>T;c.6098T>C;c.6098T>G;c.6089G>A;c.6088C>T;c.6079C>T;c.6077T>C;c.5942C>G;c.5936C>T;c.5932A>G;c.5929G>A;c.5917delG;c.5912T>G;c.5909T>C;c.5899-1G>T;c.5899-2delA;c.5898+1G>A;c.5882G>A;c.5881G>A;c.5828T>C;c.5819T>C;c.5714+5G>A;c.5693G>A;c.5646G>A;c.5549T>C;c.5512delC;c.5513A>G;c.5512C>A;c.5512C>G;c.5461-10T>C;c.5391_5392delTG;c.5338C>G;c.5318C>T;c.5316G>A;c.5315G>A;c.5312+1G>A;c.5289delT;c.5196+2T>C;c.5196+1G>A;c.5189G>A;c.5175dupG;c.5161_5162delAC;c.5018+2T>A;c.5018+2T>C;c.4947delC;c.4919G>A;c.4918C>T;c.4793C>A;c.4773+3A>G;c.4685T>C;c.4640delA;c.4637T>G;c.4594G>A;c.4577C>T;c.4567C>T;c.4540-2A>G;c.4539+1G>T;c.4537delC;c.4537dupC;c.4469G>A;c.4462T>C;c.4457C>T;c.4429C>T;c.4363T>C;c.4354G>T;c.4352+1G>A;c.4297G>A;c.4254-1G>C;c.4253+4C>T;c.4234C>T;c.4222T>C;c.4195G>T;c.4139C>T;c.4129-1G>A;c.3970delG;c.3871C>T;c.3808G>T;c.3754G>T;c.3682G>T;c.3529_3532dupTGCA;c.3482G>A;c.3403C>T;c.3389T>C;c.3386G>T;c.3377T>C;c.3364G>A;c.3323G>T;c.3322C>T;c.3303G>A;c.3292C>T;c.3272G>A;c.3261A>C;c.3259G>T;c.3210_3211dupGT;c.3212C>T;c.3210_3211insGT;c.3139delG;c.3113C>T;c.3106G>A;c.3098delA;c.3093delA;c.3085C>T;c.3083C>T;c.3081T>G;c.3064G>A;c.3056C>T;c.3055A>G;c.3041T>G;c.2948C>T;c.2927delT;c.2894A>G;c.2888delG;c.2875A>T;c.2870A>G;c.2815G>T;c.2798A>T;c.2791G>A;c.2713delG;c.2692G>T;c.2690C>T;c.2616_2617delCT;c.2609C>T;c.2588G>C;c.2587+2T>C;c.2565G>A;c.2564G>A;c.2345G>A;c.2300T>A;c.2160+1G>T;c.2041C>T;c.1988G>A;c.1984dupG;c.1964T>G;c.1957C>T;c.1938-1G>A;c.1937+1G>A;c.1928T>G;c.1918C>G;c.1906C>T;c.1903C>T;c.1873C>T;c.1848delA;c.1834C>T;c.1807T>C;c.1805G>A;c.1804C>T;c.1771delT;c.1760+2T>G;c.1755delA;c.1715G>A;c.1630_1633dupGAAA;c.1622T>C;c.1584C>A;c.1557C>A;c.1497G>A;c.1357-2A>G;c.1339C>T;c.1317G>A;c.1293G>A;c.1253T>C;c.1239+1G>C;c.1225delA;c.1222C>T;c.1100-2A>T;c.1086T>A;c.1025_1038delACAATAACTATAAG;c.1018T>G;c.1015T>G;c.885delC;c.880C>T;c.850_857delATTCAAGA;c.853C>T;c.768G>T;c.763C>T;c.712C>T;c.688T>A;c.666_678delAAAGACGGTGCGC;c.664delG;c.656G>C;c.655A>T;c.634C>T;c.564delA;c.478G>T;c.454C>T;c.319C>T;c.302+1G>A;c.296dupA;c.287delA;c.286A>G;c.206G>A;c.203C>T;c.161G>A;c.160+2T>C;c.123G>A;c.122G>A;c.71G>A;c.67-1G>C;c.67-2A>G;c.52C>T;c.45G>A;c.1A>G	Stargardt disease type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ABCA4 gene located on chromosomal region 1p22. The age of onset is infantile. This disease is characterized by progressive central vision loss, mild loss of color vision, delayed dark adaptation and macular atrophy with or without paramacular flecks and degeneration of the underlying retinal pigment ephitelium. The estimated prevalence is 1:8,000-10,000. Mutations in the ABCA4 gene account also for 30 to 60 percent of cases of cone-rod dystrophy that are inherited in an autosomal recessive pattern. The problems associated with this condition include a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision. These vision problems worsen over time.	Plus
ABCB11	Cholestasis, benign recurrent intrahepatic, type 2; Cholestasis, progressive familial intrahepatic, type 2 Cholestasis, benign recurrent intrahepatic, type 2; Cholestasis, progressive familial intrahepatic, type 2 Descrição da doença: Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (van Mil et al., 2004). Mutation in the ABCB11 gene can also cause cholestasis, progressive familial intrahepatic, type 2, a severe form of liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.	NM_003742.2	c.3767dupC;c.3692G>A;c.3457C>T;c.3268C>T;c.3213+1d c.3767dupC;c.3692G>A;c.3457C>T;c.3268C>T;c.3213+1delG;c.3169C>T;c.3148C>T;c.2944G>A;c.2783_2787dupGAGAT;c.2782C>T;c.2380C>T;c.2296G>A;c.2178+1G>A;c.1966_1967delTT;c.1810-1G>A;c.1723C>T;c.1460G>A;c.1445A>G;c.1408C>T;c.1295G>C;c.1271delA;c.1069G>T;c.908+1delG;c.908+1G>A;c.890A>G;c.847G>T;c.409G>T;c.390-1G>T;c.379delA;c.167C>G;c.150+1G>A;c.22C>T	Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (van Mil et al., 2004). Mutation in the ABCB11 gene can also cause cholestasis, progressive familial intrahepatic, type 2, a severe form of liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.	Plus
ABCB4	Cholestasis, progressive familial intrahepatic, type 3 Cholestasis, progressive familial intrahepatic, type 3 Descrição da doença: Cholestasis, progressive familial intrahepatic, type 3 (PFIC3) is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (Pasmant et al., 2012).Mutation in the ABCB4 gene accounts for about 15% of ICP cases (Ziol et al., 2008).	NM_018849.2	c.3654+1G>T;c.3629C>G;c.3507+1G>A;c.3136C>T;c.3081 c.3654+1G>T;c.3629C>G;c.3507+1G>A;c.3136C>T;c.3081+1G>C;c.2869C>T;c.2833C>T;c.2626A>T;c.2473C>T;c.2211+1G>A;c.2177C>T;c.2169dupG;c.2002C>T;c.1712delT;c.1633C>G;c.1553delT;c.1501G>T;c.1328_1329delAGinsCAA;c.1207T>C;c.1144G>T;c.1015delT;c.1006-1G>T;c.1006-2A>C;c.932C>A;c.879delA;c.834-2A>G;c.526C>T;c.475C>T;c.430C>T;c.394_400delTATATAC;c.345-2A>G;c.139C>T	Cholestasis, progressive familial intrahepatic, type 3 (PFIC3) is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (Pasmant et al., 2012).Mutation in the ABCB4 gene accounts for about 15% of ICP cases (Ziol et al., 2008).	Plus
ABCB7	X-linked sideroblastic anemia and ataxia (XLSA/A) X-linked sideroblastic anemia and ataxia (XLSA/A) Descrição da doença: XLSA/A is caused by pathogenic variants in the ABCB7 gene located on chromosomal region Xq13.3. The age of onset is neonatal/infantile. XLSA/A is a rare condition characterized by a blood disorder called sideroblastic anemia and movement problems known as ataxia. This condition occurs only in males. People with X-linked sideroblastic anemia and ataxia have mature red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin. This disorder also leads to an abnormal accumulation of iron in red blood cells but does not cause a potentially dangerous buildup of iron in the body. The anemia is typically mild and usually does not cause any symptoms. The prevalence is very rare, estimated at <1:1,000,000.	NM_004299.4	c.1300G>A;c.1238T>C;c.1234G>C;c.1203T>G;c.627A>T c.1300G>A;c.1238T>C;c.1234G>C;c.1203T>G;c.627A>T	XLSA/A is caused by pathogenic variants in the ABCB7 gene located on chromosomal region Xq13.3. The age of onset is neonatal/infantile. XLSA/A is a rare condition characterized by a blood disorder called sideroblastic anemia and movement problems known as ataxia. This condition occurs only in males. People with X-linked sideroblastic anemia and ataxia have mature red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin. This disorder also leads to an abnormal accumulation of iron in red blood cells but does not cause a potentially dangerous buildup of iron in the body. The anemia is typically mild and usually does not cause any symptoms. The prevalence is very rare, estimated at <1:1,000,000.	Plus
ABCC6	Arterial calcification, generalized, of infancy, type 2 Arterial calcification, generalized, of infancy, type 2 Descrição da doença: Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (Rutsch et al., 2003; Cheng et al., 2005).	NM_001171.5	c.4448C>T;c.4441G>A;c.4434delA;c.4420A>T;c.4403+1G c.4448C>T;c.4441G>A;c.4434delA;c.4420A>T;c.4403+1G>T;c.4381C>T;c.4341G>A;c.4335delG;c.4318delA;c.4306_4312delACGGAGC;c.4271T>C;c.4254delG;c.4243_4244insAGAA;c.4220_4221insGAAA;c.4216C>A;c.4213G>A;c.4209-2A>C;c.4192C>T;c.4182delG;c.4104delC;c.4081G>A;c.4060G>C;c.4041G>C;c.4036C>T;c.4025T>C;c.4016G>A;c.4016G>T;c.4015C>T;c.4004T>A;c.4004T>C;c.3976G>T;c.3971G>A;c.3961G>A;c.3953C>G;c.3940C>T;c.3932G>A;c.3919T>C;c.3912delG;c.3907G>C;c.3904G>A;c.3902C>T;c.3895G>A;c.3892G>T;c.3876_3882+1delAGAGAAGG;c.3866_3869dupTCCA;c.3816_3828dupAAGATACCGACCT;c.3823C>T;c.3798delG;c.3790C>T;c.3787G>A;c.3777G>A;c.3775delT;c.3774dupC;c.3736-1G>A;c.3735G>T;c.3722G>A;c.3717T>G;c.3715T>C;c.3712G>C;c.3709C>T;c.3703C>T;c.3692_3693insTT;c.3668G>A;c.3662G>A;c.3661C>T;c.3633+1G>A;c.3608G>A;c.3544dupC;c.3507-1G>A;c.3506+2_3506+5delTAGG;c.3490C>T;c.3475A>G;c.3427C>T;c.3421C>T;c.3415G>A;c.3413G>A;c.3413G>C;c.3412C>T;c.3398G>C;c.3397G>T;c.3380T>C;c.3364delT;c.3362C>G;c.3362C>T;c.3341G>A;c.3341G>C;c.3340C>T;c.3208G>C;c.3207C>A;c.3188T>C;c.3188T>G;c.3168C>A;c.3145T>G;c.3088C>T;c.2974G>A;c.2974G>C;c.2943G>T;c.2891G>C;c.2855T>G;c.2831C>T;c.2820_2821insC;c.2814C>A;c.2814C>G;c.2784_2787delCAGG;c.2787+1G>T;c.2678C>G;c.2591-1G>T;c.2552T>C;c.2524C>T;c.2511C>A;c.2477T>C;c.2458G>C;c.2432C>G;c.2432C>T;c.2420G>A;c.2419C>G;c.2419C>T;c.2416-1_2416delGA;c.2387T>C;c.2383delG;c.2342C>T;c.2329G>A;c.2323delC;c.2304C>A;c.2297C>A;c.2294G>A;c.2293C>T;c.2279G>A;c.2278C>T;c.2263G>A;c.2252T>A;c.2248-2_2248-1delAG;c.2245C>T;c.2177T>C;c.2170_2173delAGAG;c.2162G>A;c.2126A>G;c.2125G>A;c.2125G>T;c.2097G>T;c.2093A>C;c.2030T>C;c.2018T>C;c.1999delG;c.1987G>A;c.1987G>T;c.1978delG;c.1944-1G>C;c.1857dupC;c.1798C>T;c.1781C>T;c.1780-2A>G;c.1734_1742delCAAGGCCCAinsG;c.1712_1713delTC;c.1703T>C;c.1685T>C;c.1674delC;c.1675G>T;c.1652T>C;c.1635+1G>T;c.1603T>C;c.1589T>C;c.1553G>A;c.1552C>T;c.1526C>G;c.1519delG;c.1519G>T;c.1505A>T;c.1484T>A;c.1465C>T;c.1460G>A;c.1388T>A;c.1363G>C;c.1318T>G;c.1256G>A;c.1244T>C;c.1194C>G;c.1192A>G;c.1176G>C;c.1171A>G;c.1144C>T;c.1132C>T;c.1091C>G;c.1087C>T;c.1064T>G;c.998+2_998+3delTG;c.998+2delT;c.962delG;c.960delC;c.951C>A;c.951C>G;c.938dupT;c.724G>T;c.713C>A;c.708_709dupCT;c.681C>G;c.601-2A>G;c.600+1G>A;c.595C>T;c.496C>T;c.450dupC;c.373G>T;c.196dupT;c.177_181delCCGGG;c.105delA;c.46C>T;c.37-1G>A	Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (Rutsch et al., 2003; Cheng et al., 2005).	Plus
ABCC8	Hyperinsulinemic hypoglycemia, type 1 (congenital hyperinsulinism); Permanent neonatal diabetes mellitus (PNDM) Hyperinsulinemic hypoglycemia, type 1 (congenital hyperinsulinism); Permanent neonatal diabetes mellitus (PNDM) Descrição da doença: Hyperinsulinemic hypoglycemia, also referred to as congenital hyperinsulinism or familial hyperinsulinism, is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). Furthermore, some mutations in the ABCC8 gene have been found to cause permanent neonatal diabetes mellitus (PNDM). PNDM is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins. Most clinical cases for the previous two phenotypes have autosomal recessive inheritance but dominant cases have been detected too. Remarkably, certain mutations in this gene can cause the dominant phenotypes noninsulin-dependent diabetes mellitus and hypoglycemia of infancy, leucine-sensitive.	NM_001287174.1	c.4631T>C;c.4618G>A;c.4567G>A;c.4556T>G;c.4548+2T> c.4631T>C;c.4618G>A;c.4567G>A;c.4556T>G;c.4548+2T>G;c.4519G>A;c.4481G>A;c.4480C>T;c.4477delG;c.4459_4460delAG;c.4454G>A;c.4454G>T;c.4453G>A;c.4435G>A;c.4415-2A>G;c.4414G>A;c.4379T>G;c.4371C>G;c.4356G>A;c.4325delC;c.4311-2A>G;c.4310G>A;c.4309C>T;c.4273A>G;c.4268C>G;c.4261C>T;c.4201G>A;c.4177T>G;c.4163_4165delTCT;c.4160_4162delCCT;c.4160C>T;c.4154_4155delAG;c.4149T>G;c.4139G>A;c.4139G>T;c.4138C>A;c.4138C>T;c.4123-1G>T;c.4122+1delG;c.4122+1G>A;c.4112C>T;c.4075_4076delAAinsT;c.4058G>A;c.4058G>C;c.4029_4030insC;c.4024C>T;c.3992-9G>A;c.3871-1G>A;c.3757-1G>A;c.3757-2A>G;c.3756+1G>A;c.3751C>T;c.3653+2T>A;c.3643C>T;c.3596C>T;c.3577delG;c.3560+1G>A;c.3560+1G>T;c.3557C>A;c.3548G>A;c.3547C>T;c.3545T>G;c.3528C>G;c.3520G>A;c.3512delT;c.3451_3452delGT;c.3403-1G>A;c.3402+1G>A;c.3127_3129delACCinsCAGCCAGGAACTG;c.3111G>A;c.3110G>A;c.2995C>T;c.2924-9G>A;c.2860C>T;c.2838_2841delGAGA;c.2800C>T;c.2698-1G>C;c.2698-2A>T;c.2697+1G>C;c.2686dupC;c.2559+1G>A;c.2509C>T;c.2298_2310delGAGAGGCCCCGTGinsAA;c.2295-1G>A;c.2258+2T>C;c.2222+1G>A;c.2222+1G>T;c.2202delA;c.2147G>T;c.2124_2127delGACT;c.2117-1G>A;c.2116+2T>C;c.2116+1G>A;c.2116+1G>T;c.2098_2099delAC;c.2041-1G>A;c.1879delC;c.1817+1G>T;c.1792C>T;c.1752delT;c.1732_1746dupGCCTCCCTCTCCCTC;c.1744C>G;c.1671+1G>C;c.1634delT;c.1630+1G>T;c.1616A>G;c.1606T>C;c.1603_1604insA;c.1562G>A;c.1536C>G;c.1532T>C;c.1468-2A>C;c.1467+2T>C;c.1467+1G>T;c.1347_1348delGA;c.1177-1G>A;c.1144G>A;c.1012-2A>G;c.823-1G>A;c.795dupG;c.742C>T;c.692G>A;c.683G>A;c.674T>C;c.638T>G;c.631C>A;c.627C>A;c.584dupA;c.579+2T>A;c.563A>G;c.560T>A;c.536_539delATGG;c.512dupT;c.415delC;c.413-2A>G;c.404T>C;c.394T>C;c.394T>G;c.331G>A;c.291-2A>G;c.290+2T>C;c.257T>C;c.257T>G;c.239T>G;c.221G>A;c.215A>G;c.149-1G>A;c.148+2T>G;c.134C>T;c.72C>A;c.62T>A	Hyperinsulinemic hypoglycemia, also referred to as congenital hyperinsulinism or familial hyperinsulinism, is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). Furthermore, some mutations in the ABCC8 gene have been found to cause permanent neonatal diabetes mellitus (PNDM). PNDM is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins. Most clinical cases for the previous two phenotypes have autosomal recessive inheritance but dominant cases have been detected too. Remarkably, certain mutations in this gene can cause the dominant phenotypes noninsulin-dependent diabetes mellitus and hypoglycemia of infancy, leucine-sensitive.	Plus
ABCD1	Adrenoleukodystrophy Adrenoleukodystrophy Descrição da doença: Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins.Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by Moser (1997). Moser et al. (2005) provided a clinical review of ALD.	NM_000033.3	c.253dupC;c.311G>A;c.320T>C;c.346G>A;c.421G>A;c.44 c.253dupC;c.311G>A;c.320T>C;c.346G>A;c.421G>A;c.442A>T;c.443A>G;c.454C>T;c.488G>A;c.520T>G;c.521A>G;c.529C>T;c.537_544dupCTACTACC;c.565C>T;c.614C>A;c.651G>C;c.761C>T;c.796G>A;c.838C>T;c.874_876delGAG;c.871G>A;c.886T>C;c.887A>G;c.1076_1077delAG;c.1082-1G>A;c.1096A>T;c.1126G>T;c.1166G>A;c.1252C>T;c.1270C>T;c.1288C>T;c.1366dupC;c.1390C>T;c.1396C>T;c.1415_1416delAG;c.1429G>T;c.1451C>G;c.1532G>A;c.1534G>A;c.1544C>T;c.1552delC;c.1552C>G;c.1552C>T;c.1553G>A;c.1586G>A;c.1628C>T;c.1634+1G>A;c.1635-2A>G;c.1660C>A;c.1661G>A;c.1679C>T;c.1771C>T;c.1772G>A;c.1780+2T>G;c.1781-1G>A;c.1802G>A;c.1817C>T;c.1825G>A;c.1826A>G;c.1849C>T;c.1850G>A;c.1865+1G>A;c.1866-10G>A;c.1866-1G>A;c.1866-1G>C;c.1876G>A;c.1895C>T;c.1978C>T;c.1992-2A>G;c.2006_2007delAC;c.2037G>A	Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins.Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by Moser (1997). Moser et al. (2005) provided a clinical review of ALD.	Plus
ABCD4	Methylmalonic aciduria and homocystinuria, cblJ type Methylmalonic aciduria and homocystinuria, cblJ type Descrição da doença: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (Coelho et al., 2012).	NM_005050.3	c.1746_1747insCT;c.1588C>T;c.956A>G;c.542+1G>T c.1746_1747insCT;c.1588C>T;c.956A>G;c.542+1G>T	Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (Coelho et al., 2012).	Plus
ABCG5	Sitosterolemia Sitosterolemia Descrição da doença: Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).	NM_022436.2	c.1336C>T;c.1256G>A;c.1256G>C;c.1222C>T;c.1166G>A; c.1336C>T;c.1256G>A;c.1256G>C;c.1222C>T;c.1166G>A;c.978delA;c.727C>T;c.403-1G>A;c.403-2A>G;c.229G>T;c.46C>T	Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).	Plus
ABCG8	Sitosterolemia Sitosterolemia Descrição da doença: Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).	NM_022437.2	c.64-2A>G;c.72_73delGGinsC;c.120C>A;c.320C>G;c.547 c.64-2A>G;c.72_73delGGinsC;c.120C>A;c.320C>G;c.547delC;c.965-1G>A;c.965-1G>C;c.1083G>A;c.1234C>T;c.1608G>A;c.1720G>A;c.1787T>G;c.1974C>G	Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).	Plus
ABHD12	PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract) PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract) Descrição da doença: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, also known as PHARC, is a slowly progressive neurologic disorder with a variable phenotype; clinical features include sensorineural hearing loss, visual problems related to cataracts, retinitis pigmentosa, pes cavus, ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features include hyporeflexia, hyperreflexia, extensor plantar responses.	NM_001042472.2;NM_015600.4	c.1189C>T;c.1054C>T;c.874C>T;c.846_852dupTAAGAGC;c c.1189C>T;c.1054C>T;c.874C>T;c.846_852dupTAAGAGC;c.620-2A>G;c.477G>A;c.447G>A;c.337_338delGAinsTTT;c.211_223delCGCCTGAGGAAGA;c.193C>T	Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, also known as PHARC, is a slowly progressive neurologic disorder with a variable phenotype; clinical features include sensorineural hearing loss, visual problems related to cataracts, retinitis pigmentosa, pes cavus, ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features include hyporeflexia, hyperreflexia, extensor plantar responses.	Plus
ABHD5	Chanarin-Dorfman syndrome Chanarin-Dorfman syndrome Descrição da doença: Chanarin-Dorfman syndrome is a condition in which fats (lipids) are stored abnormally in the body. Affected individuals cannot break down certain fats called triglycerides, and these fats accumulate in organs and tissues, including skin, liver, muscles, intestine, eyes, and ears. People with this condition also have dry, scaly skin (ichthyosis), which is usually present at birth. Additional features of this condition include an enlarged liver (hepatomegaly), clouding of the lens of the eyes (cataracts), difficulty with coordinating movements (ataxia), hearing loss, short stature, muscle weakness (myopathy), involuntary movement of the eyes (nystagmus), and mild intellectual disability. The signs and symptoms vary greatly among individuals with Chanarin-Dorfman syndrome. Some people may have ichthyosis only, while others may have problems affecting many areas of the body.	NM_016006.4	c.98C>G;c.340C>T;c.389A>C;c.594dupC;c.778G>A c.98C>G;c.340C>T;c.389A>C;c.594dupC;c.778G>A	Chanarin-Dorfman syndrome is a condition in which fats (lipids) are stored abnormally in the body. Affected individuals cannot break down certain fats called triglycerides, and these fats accumulate in organs and tissues, including skin, liver, muscles, intestine, eyes, and ears. People with this condition also have dry, scaly skin (ichthyosis), which is usually present at birth. Additional features of this condition include an enlarged liver (hepatomegaly), clouding of the lens of the eyes (cataracts), difficulty with coordinating movements (ataxia), hearing loss, short stature, muscle weakness (myopathy), involuntary movement of the eyes (nystagmus), and mild intellectual disability. The signs and symptoms vary greatly among individuals with Chanarin-Dorfman syndrome. Some people may have ichthyosis only, while others may have problems affecting many areas of the body.	Plus
ACAD8	Isobutyryl-CoA dehydrogenase deficiency Isobutyryl-CoA dehydrogenase deficiency Descrição da doença: Isobutyryl-CoA dehydrogenase (IBD) deficiency is a condition that disrupts the breakdown of certain proteins. People with IBD deficiency have inadequate levels of an enzyme that helps break down a particular amino acid called valine. Most people with IBD deficiency are asymptomatic. A few children with IBD deficiency have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also cause low numbers of red blood cells (anemia) and very low blood levels of carnitine, which is a natural substance that helps convert certain foods into energy.	NM_014384.2	c.3G>T;c.233T>C;c.400G>T;c.447_448dupCT;c.567+1G>A c.3G>T;c.233T>C;c.400G>T;c.447_448dupCT;c.567+1G>A;c.988C>T;c.1129G>A;c.1195+1G>C	Isobutyryl-CoA dehydrogenase (IBD) deficiency is a condition that disrupts the breakdown of certain proteins. People with IBD deficiency have inadequate levels of an enzyme that helps break down a particular amino acid called valine. Most people with IBD deficiency are asymptomatic. A few children with IBD deficiency have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also cause low numbers of red blood cells (anemia) and very low blood levels of carnitine, which is a natural substance that helps convert certain foods into energy.	Plus
ACAD9	Acyl-CoA dehydrogenase 9 deficiency (mitochondrial complex I deficiency, nuclear, type 20) Acyl-CoA dehydrogenase 9 deficiency (mitochondrial complex I deficiency, nuclear, type 20) Descrição da doença: Acyl-CoA dehydrogenase 9 deficiency, also known as mitochondrial complex I deficiency, nuclear, type 20, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAD9 gene located on chromosomal region 3q21.3. The age of onset is neonatal/infantile. This disease is a multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010).	NM_014049.4	c.23delT;c.130T>A;c.359delT;c.453+1G>A;c.509C>T;c. c.23delT;c.130T>A;c.359delT;c.453+1G>A;c.509C>T;c.514G>A;c.797G>A;c.976G>C;c.1030-1G>A;c.1240C>T;c.1249C>T;c.1594C>T;c.1687C>G;c.1693-2A>G;c.1715G>A	Acyl-CoA dehydrogenase 9 deficiency, also known as mitochondrial complex I deficiency, nuclear, type 20, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAD9 gene located on chromosomal region 3q21.3. The age of onset is neonatal/infantile. This disease is a multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010).	Plus
ACADM	Medium-chain acyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency Descrição da doença: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADM gene located on chromosomal region 1p31. Inherited deficiency of MCAD is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood sugar (hypoglycemia). Individuals with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death. The estimated prevalence is 1:4,900-1:27,000 in Caucasian populations and 1:14,600 in worldwide populations.	NM_001286043.1	c.30+2T>C;c.107_113dupGATTTAG;c.118+1G>T;c.157C>T; c.30+2T>C;c.107_113dupGATTTAG;c.118+1G>T;c.157C>T;c.173_174delAG;c.216+1G>T;c.216+2T>G;c.224delT;c.233T>C;c.244dupT;c.250C>T;c.253G>A;c.270_271delCA;c.286+2T>G;c.386-2A>G;c.386-1G>C;c.421_424delATTA;c.419T>C;c.446G>A;c.461C>T;c.486+1delG;c.486+1G>A;c.486+1G>T;c.525delG;c.530_533delAGTA;c.536delT;c.548_551delCTGA;c.546G>A;c.563T>C;c.676A>G;c.682G>A;c.699-18G>A;c.715C>T;c.716G>A;c.716G>T;c.797T>C;c.807+1G>A;c.807+2T>G;c.808-2A>C;c.808-1G>A;c.829T>C;c.833C>T;c.841A>G;c.896A>G;c.898G>A;c.916_928delGCAATGGGAGCTT;c.948+1G>A;c.949-2A>G;c.981_982delAG;c.980G>C;c.1012G>T;c.1025dupT;c.1083delG;c.1084A>G;c.1098_1110dupTAGAATGAGTTAC;c.1111_1112insTAGAATGAGTTAC;c.1111C>T;c.1144delC;c.1144C>T;c.1151C>T;c.1172delA;c.1201_1204delTTAG;c.1213dupG;c.1223T>C;c.1249G>T;c.1288dupT;c.1293+1G>A	Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADM gene located on chromosomal region 1p31. Inherited deficiency of MCAD is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood sugar (hypoglycemia). Individuals with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death. The estimated prevalence is 1:4,900-1:27,000 in Caucasian populations and 1:14,600 in worldwide populations.	Plus
ACADS	Short-chain acyl-CoA dehydrogenase deficiency Short-chain acyl-CoA dehydrogenase deficiency Descrição da doença: Short-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADS gene located on chromosomal region 12q24.31. The age of onset is infantile. This disease is characterized by seizures, developmental delay, failure to grow with poor feeding, and usually muscle weakness and hypotonia. The prevalence is <1:50,000.	NM_000017.3	c.125_135delTCCAGACATGC;c.136C>T;c.164C>T;c.211-1G c.125_135delTCCAGACATGC;c.136C>T;c.164C>T;c.211-1G>A;c.238delC;c.274G>T;c.310_312delGAG;c.315delC;c.319C>T;c.369C>G;c.409C>T;c.417G>A;c.417G>C;c.473-2A>G;c.527C>A;c.529T>C;c.561_568delCAATGCCT;c.593_594delTT;c.675dupG;c.682_683delGA;c.910dupC;c.974G>A;c.988C>T;c.1029+1G>A;c.1030-1G>A;c.1031delA;c.1084C>T;c.1086+1G>A;c.1086+1G>T;c.1095G>T;c.1138C>T;c.1147C>T;c.1164_1165delTG	Short-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADS gene located on chromosomal region 12q24.31. The age of onset is infantile. This disease is characterized by seizures, developmental delay, failure to grow with poor feeding, and usually muscle weakness and hypotonia. The prevalence is <1:50,000.	Plus
ACADSB	Short/branched-chain acyl-CoA dehydrogenase deficiency Short/branched-chain acyl-CoA dehydrogenase deficiency Descrição da doença: Short/branched-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADSB gene located on chromosomal region 10q26.3. The age of onset is neonatal/infantile. This disease is characterized by muscle hypotonia, cerebral palsy, developmental delay, lethargy, hypoglycemia, and metabolic acidosis. The prevalence is <1:1,000,000.	NM_001609.3	c.295C>T;c.303+1G>A;c.443C>T;c.621G>A;c.763C>T;c.1 c.295C>T;c.303+1G>A;c.443C>T;c.621G>A;c.763C>T;c.1194C>G;c.1228G>A	Short/branched-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADSB gene located on chromosomal region 10q26.3. The age of onset is neonatal/infantile. This disease is characterized by muscle hypotonia, cerebral palsy, developmental delay, lethargy, hypoglycemia, and metabolic acidosis. The prevalence is <1:1,000,000.	Plus
ACADVL	Very long-chain acyl-CoA dehydrogenase deficiency Very long-chain acyl-CoA dehydrogenase deficiency Descrição da doença: Very long-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADVL gene located on chromosomal region 17p13.1. The age of onset is neonatal/infantile. This disease is characterized by cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis. The prevalence is 1:100,000-9:100,000.	NM_001270447.1	c.132-2A>C;c.134C>A;c.174_178dupTGCCC;c.173delC;c. c.132-2A>C;c.134C>A;c.174_178dupTGCCC;c.173delC;c.207+1G>A;c.207+2T>C;c.261delA;c.279dupT;c.320_321delCA;c.325C>T;c.335delC;c.346+1G>T;c.346+2T>G;c.347-1G>A;c.367_368delCA;c.368_374delAGTTTCT;c.377_378delAA;c.385_394delGTGGAGCCTG;c.411+1G>C;c.412delG;c.457_459delGAG;c.467G>A;c.469C>T;c.502C>T;c.546+1G>C;c.547-1G>C;c.566_567delTC;c.589G>A;c.602T>C;c.622G>A;c.671_672delAC;c.672C>G;c.706G>A;c.713_716delGTCT;c.733G>A;c.754C>T;c.777_778delCT;c.822-2A>C;c.848C>T;c.868_871delGTTA;c.898_900delGAG;c.917T>C;c.938dupG;c.934G>A;c.950_953dupGGCC;c.956_957delCT;c.965_967delAGA;c.960delG;c.1001delT;c.1025C>A;c.1065delT;c.1065dupT;c.1146_1146+1delGGinsCAC;c.1146+1G>A;c.1146+1G>T;c.1146+2T>C;c.1165C>T;c.1166G>A;c.1175T>C;c.1182delG;c.1210_1212delGAG;c.1213A>C;c.1215G>C;c.1251+1G>A;c.1251+2T>C;c.1252-1G>A;c.1315G>A;c.1338+1G>A;c.1349G>A;c.1352delA;c.1385dupG;c.1391G>A;c.1402-2A>T;c.1418G>A;c.1424dupT;c.1426C>T;c.1427G>A;c.1436G>A;c.1441T>C;c.1444dupC;c.1445G>A;c.1458dupG;c.1457G>A;c.1474C>T;c.1475G>A;c.1503+2T>G;c.1537G>C;c.1573C>G;c.1601G>A;c.1601+1G>A;c.1601+2T>C;c.1662dupG;c.1675-2A>C;c.1675-1G>A;c.1748-6G>A;c.1799_1809delCCATGGTGGTG;c.1817C>G;c.1834delC;c.1839_1842delTGAG;c.1875_1876delCT;c.1906C>T;c.1912C>T;c.1951delC	Very long-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADVL gene located on chromosomal region 17p13.1. The age of onset is neonatal/infantile. This disease is characterized by cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis. The prevalence is 1:100,000-9:100,000.	Plus
ACAT1	Alpha-methylacetoacetic aciduria (3-ketothiolase deficiency) Alpha-methylacetoacetic aciduria (3-ketothiolase deficiency) Descrição da doença: Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone. This deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAT1 gene located on chromosomal region 11q22.3. The age of onset is neonatal/infantile. This disease is characterized by normal early development followed by a progressive loss of mental and motor skills. The prevalence is < 1:1,000,000.	NM_000019.3	c.2T>A;c.149delC;c.278A>G;c.412_419delCAAAGTCT;c.4 c.2T>A;c.149delC;c.278A>G;c.412_419delCAAAGTCT;c.433C>G;c.444_445delGG;c.455G>C;c.472A>G;c.473A>G;c.547G>A;c.622C>T;c.653C>T;c.730+2T>C;c.757G>A;c.814C>T;c.826+1G>T;c.890C>T;c.905delA;c.935T>C;c.997G>C;c.1006-2A>C;c.1006-1G>C;c.1035_1037delAGA;c.1083dupA;c.1136G>T;c.1138G>A;c.1160T>C;c.1163+2T>C	Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone. This deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAT1 gene located on chromosomal region 11q22.3. The age of onset is neonatal/infantile. This disease is characterized by normal early development followed by a progressive loss of mental and motor skills. The prevalence is < 1:1,000,000.	Plus
ACE	Renal tubular dysgenesis Renal tubular dysgenesis Descrição da doença: Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and the most common cause are pathogenic variants in the ACE (chromosomal region 17q23.3). The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	NM_000789.3	c.412C>T;c.798C>G;c.1319_1322delTGGA;c.1486C>T;c.1 c.412C>T;c.798C>G;c.1319_1322delTGGA;c.1486C>T;c.1511delC;c.1522C>T;c.1587-2A>G;c.2371C>T;c.2642-1G>A;c.3503+1G>C	Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and the most common cause are pathogenic variants in the ACE (chromosomal region 17q23.3). The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	Plus
ACO2	Infantile cerebellar-retinal degeneration Infantile cerebellar-retinal degeneration Descrição da doença: Infantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (Spiegel et al., 2012).	NM_001098.2	c.684+1G>T;c.776G>A;c.1819C>T;c.1981G>A;c.2208G>C; c.684+1G>T;c.776G>A;c.1819C>T;c.1981G>A;c.2208G>C;c.2328_2331delGGAA;c.2338_2339delCA	Infantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (Spiegel et al., 2012).	Plus
ACOX1	Peroxisomal acyl-CoA oxidase deficiency Peroxisomal acyl-CoA oxidase deficiency Descrição da doença: Peroxisomal acyl-CoA oxidase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACOX1 gene located on chromosomal region 17q25.1. The age of onset is neonatal/infantile. This disease is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy. The prevalence is < 1:1,000,000.	NM_004035.6	c.1851delT;c.926A>G;c.832A>G;c.591delG;c.532G>T;c. c.1851delT;c.926A>G;c.832A>G;c.591delG;c.532G>T;c.442C>T	Peroxisomal acyl-CoA oxidase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACOX1 gene located on chromosomal region 17q25.1. The age of onset is neonatal/infantile. This disease is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy. The prevalence is < 1:1,000,000.	Plus
ACP5	Spondyloenchondrodysplasia with immune dysregulation Spondyloenchondrodysplasia with immune dysregulation Descrição da doença: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family.	NM_001111034.2	c.816dupC;c.667C>T;c.602T>C;c.526C>T;c.325G>A;c.26 c.816dupC;c.667C>T;c.602T>C;c.526C>T;c.325G>A;c.266C>T;c.131C>T	Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family.	Plus
ACSF3	Combined malonic and methylmalonic aciduria Combined malonic and methylmalonic aciduria Descrição da doença: Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of malonic acid and methylmalonic acid in the body. The signs and symptoms of CMAMMA can begin in childhood. In some children, it causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.	NM_001127214.3	c.1028G>A;c.1073C>T;c.1378dupG;c.1446_1447delCA;c. c.1028G>A;c.1073C>T;c.1378dupG;c.1446_1447delCA;c.1502-2A>G;c.1567C>T;c.1608G>A;c.1672C>T	Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of malonic acid and methylmalonic acid in the body. The signs and symptoms of CMAMMA can begin in childhood. In some children, it causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.	Plus
ACSL4	Mental retardation, X-linked, type 63 Mental retardation, X-linked, type 63 Descrição da doença: Mental retardation, X-linked, type 63 (MRX63) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.	NM_001318509.1	c.1708C>A;c.1124C>T;c.968_969delAT c.1708C>A;c.1124C>T;c.968_969delAT	Mental retardation, X-linked, type 63 (MRX63) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.	Plus
ACTA1	Nemaline myopathy 3; Congenital fiber-type disproportion myopathy 1 Nemaline myopathy 3; Congenital fiber-type disproportion myopathy 1 Descrição da doença: Nemaline myopathy is a form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination ('nema' is Greek for 'thread'). The clinical phenotype is highly variable, with differing age at onset and severity. Muscle weakness typically involves proximal muscles, with involvement of the facial, bulbar, and respiratory muscles (Ilkovski et al., 2001). Attempts at classification of nemaline myopathies into clinical subtypes have been complicated by the overlap of clinical features and a continuous phenotypic spectrum of disease (North et al., 1997; Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs, 2001). In general, 2 clinical groups can be readily distinguished: 'typical' and 'severe.' Typical nemaline myopathy is the most common form, presenting as infantile hypotonia and muscle weakness. It is slowly progressive or nonprogressive, and most adults achieve ambulation. The severe form of the disorder is characterized by absence of spontaneous movement or respiration at birth, arthrogryposis, and death in the first months of life. Much less commonly, late-childhood or even adult-onset can occur. However, adult-onset nemaline myopathy is usually not familial and may represent a different disease (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001). Myopathy caused by mutations in the ACTA1 gene can show a range of clinical and pathologic phenotypes. Some patients have classic rods, whereas others may also show intranuclear rods, clumped filaments, cores, or fiber-type disproportion (255310), all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. The spectrum of clinical phenotypes caused by mutations in ACTA1 may result from different mutations, modifying factors affecting the severity of the disorder, variability in clinical care, or a combination of these factors (Nowak et al., 1999; Kaindl et al., 2004).	NM_001100.3	c.1075A>C;c.1074G>T;c.990+1G>T;c.809G>A;c.808G>C;c c.1075A>C;c.1074G>T;c.990+1G>T;c.809G>A;c.808G>C;c.682G>C;c.616+1G>A;c.553C>A;c.553C>T;c.541delG;c.493G>C;c.442G>A;c.435C>A;c.402G>A;c.350A>G;c.243G>A;c.217A>G;c.142G>A;c.133G>T;c.109G>T	Nemaline myopathy is a form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination ('nema' is Greek for 'thread'). The clinical phenotype is highly variable, with differing age at onset and severity. Muscle weakness typically involves proximal muscles, with involvement of the facial, bulbar, and respiratory muscles (Ilkovski et al., 2001). Attempts at classification of nemaline myopathies into clinical subtypes have been complicated by the overlap of clinical features and a continuous phenotypic spectrum of disease (North et al., 1997; Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs, 2001). In general, 2 clinical groups can be readily distinguished: 'typical' and 'severe.' Typical nemaline myopathy is the most common form, presenting as infantile hypotonia and muscle weakness. It is slowly progressive or nonprogressive, and most adults achieve ambulation. The severe form of the disorder is characterized by absence of spontaneous movement or respiration at birth, arthrogryposis, and death in the first months of life. Much less commonly, late-childhood or even adult-onset can occur. However, adult-onset nemaline myopathy is usually not familial and may represent a different disease (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001). Myopathy caused by mutations in the ACTA1 gene can show a range of clinical and pathologic phenotypes. Some patients have classic rods, whereas others may also show intranuclear rods, clumped filaments, cores, or fiber-type disproportion (255310), all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. The spectrum of clinical phenotypes caused by mutations in ACTA1 may result from different mutations, modifying factors affecting the severity of the disorder, variability in clinical care, or a combination of these factors (Nowak et al., 1999; Kaindl et al., 2004).	Plus
ACY1	Aminoacylase 1 deficiency Aminoacylase 1 deficiency Descrição da doença: Aminoacylase 1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (Ferri et al., 2014).	NM_000666.2	c.360-1G>A;c.589C>T;c.1001_1001+5delTGTGAG;c.1057C c.360-1G>A;c.589C>T;c.1001_1001+5delTGTGAG;c.1057C>T;c.1104_1105dupAC	Aminoacylase 1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (Ferri et al., 2014).	Plus
ADA	Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA) Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA) Descrição da doença: Severe combined immunodeficiency due to adenosine deaminase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADA gene located on chromosomal region 20q13.12. The age of onset is neonatal/infantile. This disease is characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections. The annual incidence is 1:200,000-1:1,000,000. The prevalence is 1:100,000-9:100,000.	NM_000022.3	c.1078+2T>A;c.986C>T;c.956_960delAAGAG;c.911T>G;c. c.1078+2T>A;c.986C>T;c.956_960delAAGAG;c.911T>G;c.890C>A;c.872C>G;c.872C>T;c.845+1G>C;c.736C>T;c.704G>A;c.703C>T;c.698C>T;c.646G>A;c.632G>A;c.603C>G;c.532delG;c.532dupG;c.478+1G>A;c.467G>A;c.466C>T;c.424C>T;c.396dupA;c.350G>A;c.320T>C;c.302G>A;c.221G>T;c.219-1G>A;c.219-2A>G;c.218+2T>G;c.218+1G>A;c.95+1G>A;c.58G>A;c.43C>G;c.33+1G>C;c.7C>T	Severe combined immunodeficiency due to adenosine deaminase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADA gene located on chromosomal region 20q13.12. The age of onset is neonatal/infantile. This disease is characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections. The annual incidence is 1:200,000-1:1,000,000. The prevalence is 1:100,000-9:100,000.	Plus
ADAM9	Cone-rod dystrophy 9 Cone-rod dystrophy 9 Descrição da doença: Cone-rod dystrophy 9 (CORD9) is an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors.	NM_003816.2	c.490C>T;c.766C>T;c.1130+1G>A c.490C>T;c.766C>T;c.1130+1G>A	Cone-rod dystrophy 9 (CORD9) is an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors.	Plus
ADAMTS10	Weill-Marchesani syndrome, type 1, recessive Weill-Marchesani syndrome, type 1, recessive Descrição da doença: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma, and, occasionally, heart defects (Dagoneau et al., 2004).	NM_030957.3	c.1190+1G>A;c.952C>T;c.810+1G>A;c.709C>T c.1190+1G>A;c.952C>T;c.810+1G>A;c.709C>T	Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma, and, occasionally, heart defects (Dagoneau et al., 2004).	Plus
ADAMTS13	Thrombotic thrombocytopenic purpura, familial (Schulman-Upshaw syndrome) Thrombotic thrombocytopenic purpura, familial (Schulman-Upshaw syndrome) Descrição da doença: The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh plasma infusion, and frequent relapses (Savasan et al., 2003; Kokame et al., 2002).Acquired TTP, which is usually sporadic, usually occurs in adults and is caused by an IgG inhibitor against the von Willebrand factor-cleaving protease.	NM_139025.4	c.286C>G;c.304C>T;c.331-1G>A;c.414+1G>A;c.587C>T;c c.286C>G;c.304C>T;c.331-1G>A;c.414+1G>A;c.587C>T;c.1345C>T;c.1585-1G>C;c.1783_1784delTT;c.3044+1G>A;c.3543delG;c.3638G>A;c.3770dupT;c.4143dupA	The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh plasma infusion, and frequent relapses (Savasan et al., 2003; Kokame et al., 2002).Acquired TTP, which is usually sporadic, usually occurs in adults and is caused by an IgG inhibitor against the von Willebrand factor-cleaving protease.	Plus
ADAMTS17	Weill-Marchesani syndrome, type 4, recessive Weill-Marchesani syndrome, type 4, recessive Descrição da doença: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (Shah et al., 2014).	NM_139057.3	c.2458dupG;c.1721+1G>A;c.873+1G>T;c.760C>T;c.652de c.2458dupG;c.1721+1G>A;c.873+1G>T;c.760C>T;c.652delG	Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (Shah et al., 2014).	Plus
ADAMTS18	Microcornea, myopic chorioretinal atrophy, and telecanthus Microcornea, myopic chorioretinal atrophy, and telecanthus Descrição da doença: Microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is a ocular syndrome characterized by microcornea and myopic chorioretinal atrophy. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. In addition to ocular findings, some patients have telecanthus and posteriorly rotated ears.	NM_199355.3	c.2065G>T;c.97C>T c.2065G>T;c.97C>T	Microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is a ocular syndrome characterized by microcornea and myopic chorioretinal atrophy. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. In addition to ocular findings, some patients have telecanthus and posteriorly rotated ears.	Plus
ADAMTS2	Ehlers-Danlos syndrome, dermatosparaxis type Ehlers-Danlos syndrome, dermatosparaxis type Descrição da doença: Ehlers-Danlos syndrome, dermatosparaxis type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTS2 gene located on chromosomal region 5q35.3. The age of onset is neonatal/infantile. This disease is characterized by extremely fragile tissues, hyperextensible skin and easy bruising. The prevalence is <1:1,000,000.	NM_014244.4	c.3070delA;c.2458-6_2458delGCACAGG;c.2384G>A;c.673 c.3070delA;c.2458-6_2458delGCACAGG;c.2384G>A;c.673C>T	Ehlers-Danlos syndrome, dermatosparaxis type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTS2 gene located on chromosomal region 5q35.3. The age of onset is neonatal/infantile. This disease is characterized by extremely fragile tissues, hyperextensible skin and easy bruising. The prevalence is <1:1,000,000.	Plus
ADAMTSL2	Geleophysic dysplasia type 1 Geleophysic dysplasia type 1 Descrição da doença: Geleophysic dysplasia type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTSL2 gene located on chromosomal region 9q34.2. The age of onset is infantile. This disease is characterized by extremely by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance. The prevalence is <1:1,000,000.	NM_001145320.1	c.234-2A>G;c.338G>A;c.340G>A;c.440C>T;c.661C>T c.234-2A>G;c.338G>A;c.340G>A;c.440C>T;c.661C>T	Geleophysic dysplasia type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTSL2 gene located on chromosomal region 9q34.2. The age of onset is infantile. This disease is characterized by extremely by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance. The prevalence is <1:1,000,000.	Plus
ADAMTSL4	Ectopia lentis et pupillae; Ectopia lentis, isolated Ectopia lentis et pupillae; Ectopia lentis, isolated Descrição da doença: Ectopia lentis et pupillae is a congenital hereditary disorder in which there is displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions (Cruysberg and Pinckers, 1995). Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disc, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy (Christensen et al., 2010). Autosomal recessive isolated ectopia lentis, type 2 (ECTO2) is also caused by mutation in the ADAMTSL4 gene. ECTOL2 is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).	NM_001288608.1	c.79-1G>A;c.239delC;c.421C>T;c.826_836delCGTGCATCC c.79-1G>A;c.239delC;c.421C>T;c.826_836delCGTGCATCCCC;c.1424_1425delTG;c.1854T>G;c.2077C>T;c.2339dupG;c.2444G>A	Ectopia lentis et pupillae is a congenital hereditary disorder in which there is displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions (Cruysberg and Pinckers, 1995). Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disc, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy (Christensen et al., 2010). Autosomal recessive isolated ectopia lentis, type 2 (ECTO2) is also caused by mutation in the ADAMTSL4 gene. ECTOL2 is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).	Plus
ADAR	Aicardi-Goutieres syndrome 6 Aicardi-Goutieres syndrome 6 Descrição da doença: Aicardi-Goutieres syndrome 6 is a form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.	NM_001111.4	c.3494T>C;c.3019G>A;c.2997G>T;c.2854A>T;c.2768T>C; c.3494T>C;c.3019G>A;c.2997G>T;c.2854A>T;c.2768T>C;c.2433_2434delAG;c.2130dupC;c.2077C>T;c.1675C>T;c.1630C>T;c.1493_1494delAG;c.1420C>T;c.1076_1080delAGCGA;c.941_942delCT;c.577C>G	Aicardi-Goutieres syndrome 6 is a form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.	Plus
ADGRG1	Polymicrogyria, bilateral frontoparietal Polymicrogyria, bilateral frontoparietal Descrição da doença: Polymicrogyria is a condition characterized by abnormal development of the brain before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small. The name of this condition literally means too many (poly-) small (micro-) folds (-gyria) in the surface of the brain. Bilateral forms of polymicrogyria tend to cause more severe neurological problems. Signs and symptoms of these conditions can include recurrent seizures (epilepsy), delayed development, crossed eyes, problems with speech and swallowing, and muscle weakness or paralysis. This condition causes severe intellectual disability, problems with movement, and seizures that are difficult or impossible to control with medication.	NM_001145771.2	c.10C>T;c.235C>T;c.286C>T;c.367C>T;c.620+1G>A;c.62 c.10C>T;c.235C>T;c.286C>T;c.367C>T;c.620+1G>A;c.621-1G>C;c.671delA;c.739_745delCAGGACC;c.944_945dupTT;c.1036T>A;c.1216delC;c.1426C>T;c.1508T>C;c.1533T>G;c.1970G>A	Polymicrogyria is a condition characterized by abnormal development of the brain before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small. The name of this condition literally means too many (poly-) small (micro-) folds (-gyria) in the surface of the brain. Bilateral forms of polymicrogyria tend to cause more severe neurological problems. Signs and symptoms of these conditions can include recurrent seizures (epilepsy), delayed development, crossed eyes, problems with speech and swallowing, and muscle weakness or paralysis. This condition causes severe intellectual disability, problems with movement, and seizures that are difficult or impossible to control with medication.	Plus
ADGRV1	Usher syndrome, type 2C Usher syndrome, type 2C Descrição da doença: Usher syndrome type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADGRV1 and PDZD7 genes located on chromosomal regions 5q14.3 and 10q24.32 respectively. The age of onset is infantile. This disease is characterized by the association of sensorineural prelingual deafness (usually congenital) with retinitis pigmentosa and progressive vision loss. The prevalence is 1/30,000.	NM_032119.3	c.956dupA;c.1608C>G;c.1701delC;c.2258_2270delAAGTG c.956dupA;c.1608C>G;c.1701delC;c.2258_2270delAAGTGCTGAAATC;c.2302G>T;c.2398C>T;c.2864C>A;c.2870dupA;c.4702delA;c.5357_5358delAA;c.5504_5507delTTCC;c.5643delG;c.5779_5783dupACGAG;c.6275-1G>A;c.6312dupT;c.6901C>T;c.7006C>T;c.7129C>T;c.7374_7375delTG;c.7406G>A;c.7606G>T;c.8204delA;c.8495C>A;c.8713_8716dupAACA;c.8737delG;c.8790delC;c.8807C>G;c.9877C>T;c.10060_10063delACAA;c.10213C>T;c.10736_10737delCC;c.11122-2A>G;c.11122-1G>C;c.11253C>G;c.11377G>T;c.11410C>T;c.12403+1G>T;c.12436C>T;c.12631C>T;c.12798T>A;c.12823C>T;c.14365C>T;c.14885G>A;c.14973-2A>G;c.14973-1G>C;c.14975C>G;c.15196_15199dupCAAA;c.15736C>T;c.17062C>T;c.17235T>G;c.17303_17315delGAGATTACATTCG;c.17314C>T;c.17662delT;c.17668_17669delAT;c.18131A>G	Usher syndrome type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADGRV1 and PDZD7 genes located on chromosomal regions 5q14.3 and 10q24.32 respectively. The age of onset is infantile. This disease is characterized by the association of sensorineural prelingual deafness (usually congenital) with retinitis pigmentosa and progressive vision loss. The prevalence is 1/30,000.	Plus
ADK	Hypermethioninemia due to adenosine kinase deficiency Hypermethioninemia due to adenosine kinase deficiency Descrição da doença: Hypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (Bjursell et al., 2011).	NM_006721.3	c.89G>A;c.704A>C;c.741T>A;c.953C>A c.89G>A;c.704A>C;c.741T>A;c.953C>A	Hypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (Bjursell et al., 2011).	Plus
ADSL	Adenylosuccinase deficiency Adenylosuccinase deficiency Descrição da doença: Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (Baresova et al., 2012).	NM_000026.3	c.253C>T;c.298C>G;c.340T>C;c.421C>T;c.550C>T;c.568 c.253C>T;c.298C>G;c.340T>C;c.421C>T;c.550C>T;c.568C>T;c.569G>A;c.736A>G;c.853C>T;c.907C>T;c.1009C>T;c.1123C>T;c.1187G>A;c.1277G>A;c.1312T>C;c.1339T>C;c.1349C>G	Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (Baresova et al., 2012).	Plus
AFF2	Mental retardation, X-linked, FRAXE type Mental retardation, X-linked, FRAXE type Descrição da doença: Mental retardation, X-linked, FRAXE type is a form of mild to moderate mental retardation associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (Bensaid et al., 2009). FRAXE is associated with a fragile site on chromosome Xq28 and is the cause of nonsyndromic X-linked mental retardation in 1 of 50,000 newborn males. The disorder can be caused either by silencing of the AFF2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (Stettner et al., 2011).	NM_002025.3	c.76A>T;c.3575delA c.76A>T;c.3575delA	Mental retardation, X-linked, FRAXE type is a form of mild to moderate mental retardation associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (Bensaid et al., 2009). FRAXE is associated with a fragile site on chromosome Xq28 and is the cause of nonsyndromic X-linked mental retardation in 1 of 50,000 newborn males. The disorder can be caused either by silencing of the AFF2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (Stettner et al., 2011).	Plus
AFG3L2	Spastic ataxia, type 5, autosomal recessive Spastic ataxia, type 5, autosomal recessive Descrição da doença: Spastic ataxia, type 5, autosomal recessive (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (Pierson et al., 2011).	NM_006796.2	c.2105G>A;c.2098G>A;c.2081C>A;c.2071G>A;c.2067_206 c.2105G>A;c.2098G>A;c.2081C>A;c.2071G>A;c.2067_2068delCA;c.2012G>A;c.2011G>A;c.1997T>C;c.1997T>G;c.1996A>G;c.1961C>T;c.1847A>G;c.1295A>C	Spastic ataxia, type 5, autosomal recessive (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (Pierson et al., 2011).	Plus
AGA	Aspartylglucosaminuria (glycosylasparaginase deficiency) Aspartylglucosaminuria (glycosylasparaginase deficiency) Descrição da doença: Aspartylglucosaminuria, also known as glycosylasparaginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGA gene located on chromosomal region 4q34.3. The age of onset is infantile. This disease is characterized by slowly developping mental retardation, beginning with clumsiness, late speech, and hyperkinesia, mild facial dysmorphism, and slight kyphoscoliosis.	NM_000027.3;NM_001171988.1	c.941-2A>G;c.940+1G>A;c.940+1G>T;c.916T>C;c.904G>A c.941-2A>G;c.940+1G>A;c.940+1G>T;c.916T>C;c.904G>A;c.800delT;c.800dupT;c.788delT;c.770C>T;c.755G>A;c.754G>C;c.698+1G>T;c.676+1G>A;c.623-2A>G;c.537C>A;c.508-2A>G;c.503G>A;c.490C>T;c.488G>C;c.473G>A;c.439T>C;c.404T>C;c.373_376delACAC;c.369_373delACACA;c.346C>T;c.336delT;c.333delT;c.319C>T;c.302C>T;c.299G>A;c.281+1G>T;c.214T>C;c.200_201delAG;c.192delT;c.192T>A;c.127+1G>A;c.102_108delGCCCTTT;c.101_107delGGCCCTT	Aspartylglucosaminuria, also known as glycosylasparaginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGA gene located on chromosomal region 4q34.3. The age of onset is infantile. This disease is characterized by slowly developping mental retardation, beginning with clumsiness, late speech, and hyperkinesia, mild facial dysmorphism, and slight kyphoscoliosis.	Plus
AGK	Cataract 38, autosomal recessive; Sengers syndrome Cataract 38, autosomal recessive; Sengers syndrome Descrição da doença: Cataract 38 is a disease charcaterized by an opacification of the crystalline lens of the eye becoming evident at birth. It frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. Mutation in the AGK gene can also cause Sengers syndrome, an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).	NM_018238.3	c.3G>C;c.102-1G>T;c.141+2T>C;c.297+2T>C;c.298-2A>G c.3G>C;c.102-1G>T;c.141+2T>C;c.297+2T>C;c.298-2A>G;c.306T>G;c.390+1G>A;c.390+1G>T;c.409C>T;c.424-3C>G;c.517C>T;c.672C>G;c.841C>T;c.975+1G>T;c.1047-2A>T	Cataract 38 is a disease charcaterized by an opacification of the crystalline lens of the eye becoming evident at birth. It frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. Mutation in the AGK gene can also cause Sengers syndrome, an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).	Plus
AGL	Glycogen storage disease, type 3 Glycogen storage disease, type 3 Descrição da doença: Glycogen storage disease (GSD), type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGL gene located on chromosomal region 1p21.2. The age of onset is infantile. This metabolic disorder is caused by deficiency of the glycogen debrancher enzyme and is associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and muscle (IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (Shen et al., 1996). These subtypes have been explained by differences in tissue expression of the deficient enzyme (Endo et al., 2006). In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively (Van Hoof and Hers, 1967; Ding et al., 1990). Clinically, patients with GSD type 3 present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with IIIa is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy (Shen et al., 1996).	NM_000028.2	c.22delC;c.22C>T;c.64delC;c.82+1G>A;c.94C>T;c.100C c.22delC;c.22C>T;c.64delC;c.82+1G>A;c.94C>T;c.100C>T;c.104T>G;c.118C>T;c.121G>T;c.140dupA;c.223_224delGA;c.251dupA;c.256C>T;c.276delG;c.289C>T;c.293+1delG;c.294-2A>T;c.294-1G>C;c.378T>A;c.437delG;c.442delA;c.460+1G>A;c.500dupG;c.535_538delTTAG;c.664+1G>A;c.664+3A>G;c.672dupT;c.753_756delCAGA;c.958+1G>A;c.1078C>T;c.1082+1G>C;c.1159C>T;c.1169_1172delACTA;c.1185+1G>A;c.1222C>T;c.1384delG;c.1391dupG;c.1400delC;c.1423+1G>T;c.1485delT;c.1533dupA;c.1536_1545delCACTGAAATA;c.1589C>G;c.1597_1598delCT;c.1612-1G>C;c.1735+1G>T;c.1782C>A;c.1783C>T;c.1999delC;c.2001+2T>C;c.2011_2012delGT;c.2039G>A;c.2120_2121delAA;c.2158-2A>G;c.2158-1G>A;c.2223_2224delGT;c.2278delA;c.2309-1G>A;c.2457_2460delACAA;c.2525delC;c.2538dupT;c.2717_2721delAGATC;c.2728C>T;c.2906_2907delAT;c.2929C>T;c.3204_3205delTA;c.3216_3217delGA;c.3235C>T;c.3297G>A;c.3363-1G>A;c.3439A>G;c.3443dupA;c.3444C>G;c.3554delC;c.3589-1G>A;c.3613C>T;c.3652C>T;c.3682C>T;c.3807dupT;c.3816_3817delAG;c.3836+1G>A;c.3911delA;c.3911dupA;c.3980G>A;c.4165_4166delCC;c.4175_4176delTT;c.4197delA;c.4221dupA;c.4260-1G>T;c.4322_4323dupAA;c.4323delA;c.4342G>C;c.4347+1G>A;c.4348G>T;c.4353G>T;c.4456delT;c.4459C>T;c.4481+1G>C;c.4481+2T>G;c.4529dupA	Glycogen storage disease (GSD), type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGL gene located on chromosomal region 1p21.2. The age of onset is infantile. This metabolic disorder is caused by deficiency of the glycogen debrancher enzyme and is associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and muscle (IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (Shen et al., 1996). These subtypes have been explained by differences in tissue expression of the deficient enzyme (Endo et al., 2006). In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively (Van Hoof and Hers, 1967; Ding et al., 1990). Clinically, patients with GSD type 3 present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with IIIa is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy (Shen et al., 1996).	Plus
AGPAT2	Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) Descrição da doença: Congenital generalized lipodystrophy type 1 (CGL1), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia (Garg, 2004).	NM_006412.3	c.683T>C;c.676C>T;c.662-2A>C;c.661+2T>G;c.643A>T;c c.683T>C;c.676C>T;c.662-2A>C;c.661+2T>G;c.643A>T;c.589-2A>G;c.570C>A;c.538delG;c.514G>A;c.503G>A;c.493-1G>C;c.492+1G>A;c.406G>A;c.377dupT;c.299G>A;c.282delC;c.202C>T;c.194G>A;c.183-2A>G;c.182+1G>A	Congenital generalized lipodystrophy type 1 (CGL1), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia (Garg, 2004).	Plus
AGPS	Rhizomelic chondrodysplasia punctata, type 3 Rhizomelic chondrodysplasia punctata, type 3 Descrição da doença: Rhizomelic chondrodysplasia punctata, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGPS gene located on chromosomal region 2q31.2. The age of onset is neonatal/infantile. This disease is characterized by shortness of the femur and humerus, vertebral disorders, cataract, cutaneous lesions and severe intellectual deficit. The prevalence is 1:100,000-9:100,000.	NM_003659.3	c.926C>T;c.1256G>A;c.1406T>C;c.1703C>T c.926C>T;c.1256G>A;c.1406T>C;c.1703C>T	Rhizomelic chondrodysplasia punctata, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGPS gene located on chromosomal region 2q31.2. The age of onset is neonatal/infantile. This disease is characterized by shortness of the femur and humerus, vertebral disorders, cataract, cutaneous lesions and severe intellectual deficit. The prevalence is 1:100,000-9:100,000.	Plus
AGRN	Myasthenic syndrome, congenital, type 8 Myasthenic syndrome, congenital, type 8 Descrição da doença: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 8, with pre- and postsynaptic defects (CMS8) is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (Maselli et al., 2012).	NM_001305275.1	c.1057C>T;c.1362dupC;c.4621C>T;c.5023G>A;c.5125G>C c.1057C>T;c.1362dupC;c.4621C>T;c.5023G>A;c.5125G>C;c.5179G>T	Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 8, with pre- and postsynaptic defects (CMS8) is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (Maselli et al., 2012).	Plus
AGT	Renal tubular dysgenesis Renal tubular dysgenesis Descrição da doença: Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	NM_000029.3	c.1290delT;c.1290dupT;c.1124G>A;c.1087C>T;c.856+1G c.1290delT;c.1290dupT;c.1124G>A;c.1087C>T;c.856+1G>T;c.604C>T	Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	Plus
AGTR1	Renal tubular dysgenesis Renal tubular dysgenesis Descrição da doença: Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	NM_004835.4	c.215dupT;c.259dupG;c.356G>A;c.481delC;c.481C>T c.215dupT;c.259dupG;c.356G>A;c.481delC;c.481C>T	Renal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.	Plus
AGXT	Hyperoxaluria, primary, type 1 Hyperoxaluria, primary, type 1 Descrição da doença: Primary hyperoxaluria, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGXT gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by variable clinical presentation, ranging from occasional symptomatic nephrolithiasis to nephrocalcinosis and end-stage renal disease with systemic involvement. The prevalence is 1:1,000,000-9:1,000,000.	NM_000030.2	c.2_3delTGinsAT;c.2T>C;c.3G>T;c.32_33delCC;c.33del c.2_3delTGinsAT;c.2T>C;c.3G>T;c.32_33delCC;c.33delC;c.33dupC;c.32C>G;c.74T>G;c.77T>C;c.83delC;c.106C>T;c.107G>A;c.116_117dupCA;c.126delG;c.126dupG;c.121G>A;c.122G>A;c.122G>T;c.125G>A;c.130C>T;c.139G>A;c.166-2A>G;c.166-1G>A;c.167T>A;c.187G>C;c.198C>G;c.205C>T;c.209C>A;c.215dupA;c.221_227dupTCACACT;c.242C>A;c.242C>T;c.244G>C;c.245G>A;c.248A>G;c.276delT;c.283_285dupGAG;c.283G>A;c.322T>C;c.327delG;c.323G>A;c.324G>T;c.326G>T;c.331C>T;c.332G>A;c.335C>A;c.349G>T;c.353G>A;c.358+1G>T;c.358+2T>G;c.364C>T;c.406_410dupCTGCA;c.409C>T;c.423G>T;c.423+1G>A;c.424-2A>G;c.445delG;c.447_454delGCTGCTGT;c.449T>C;c.454T>A;c.460delA;c.466G>A;c.473C>A;c.473C>T;c.481G>A;c.481G>C;c.481G>T;c.497T>C;c.508G>A;c.518G>A;c.519C>A;c.524+2T>A;c.525-1G>A;c.533G>A;c.547G>A;c.560C>T;c.570delG;c.568G>A;c.577delC;c.577dupC;c.583A>C;c.584T>G;c.596-2A>G;c.603C>A;c.605T>A;c.612C>A;c.613T>C;c.614C>A;c.614C>T;c.642_645delTCCA;c.646G>A;c.661T>C;c.673_676delAAGG;c.679_680+2delAAGT;c.680+1G>A;c.680+1G>C;c.680+2T>A;c.681-1G>T;c.697C>T;c.698G>A;c.698G>T;c.725dupT;c.727G>C;c.731T>C;c.737G>A;c.738G>A;c.744delC;c.752G>A;c.753G>A;c.757T>C;c.776+1G>A;c.776+1G>C;c.776+2T>G;c.777-2A>G;c.777-1G>C;c.798_802delCATCAinsACAATCTCAG;c.806T>C;c.823_824dupAG;c.822G>C;c.834delC;c.844C>T;c.846G>C;c.846+1G>A;c.846+1G>T;c.847-1G>C;c.851T>C;c.853G>T;c.891T>G;c.893T>C;c.907C>T;c.919delC;c.922C>T;c.942+1G>T;c.943-1G>A;c.943-1G>T;c.956C>T;c.959_960delCA;c.971_972delTG;c.976delG;c.996G>A;c.997A>T;c.1014C>G;c.1045G>A;c.1071+1G>A;c.1076T>C;c.1079G>A;c.1079G>C;c.1102G>A;c.1125_1126delCG;c.1151T>C	Primary hyperoxaluria, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGXT gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by variable clinical presentation, ranging from occasional symptomatic nephrolithiasis to nephrocalcinosis and end-stage renal disease with systemic involvement. The prevalence is 1:1,000,000-9:1,000,000.	Plus
AHCY	Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Descrição da doença: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase is a metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.	NM_001322086.1	c.434A>G;c.342G>A c.434A>G;c.342G>A	Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase is a metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.	Plus
AHI1	Joubert syndrome, type 3 Joubert syndrome, type 3 Descrição da doença: Joubert syndrome, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AHI1 gene located on chromosomal region 6q23.3. The age of onset is variable. This disease is characterized by the neurological features of Joubert syndrome (neonatal hypotonia, developmental delay, mild to severe intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus) associated with retinal dystrophy.	NM_001134830.1	c.3263_3264delGG;c.2609G>A;c.2598_2604delAGTGTAT;c c.3263_3264delGG;c.2609G>A;c.2598_2604delAGTGTAT;c.2569_2570insAG;c.2495T>G;c.2493-2A>G;c.2368_2369insT;c.2297G>A;c.2295dupA;c.2212C>T;c.2187_2196delGAGAGAAGAT;c.2174G>A;c.2172delA;c.2173T>C;c.2168G>A;c.2156A>G;c.2098_2099dupGT;c.2087A>G;c.2036+1G>T;c.2023G>A;c.2012C>T;c.1997A>T;c.1897_1898dupGG;c.1861G>T;c.1765C>T;c.1626+1G>A;c.1614delA;c.1516C>T;c.1484G>A;c.1303C>T;c.1267C>T;c.1260G>A;c.1205delC;c.1152-2A>G;c.1052G>T;c.1051C>T;c.985C>T;c.662C>G	Joubert syndrome, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AHI1 gene located on chromosomal region 6q23.3. The age of onset is variable. This disease is characterized by the neurological features of Joubert syndrome (neonatal hypotonia, developmental delay, mild to severe intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus) associated with retinal dystrophy.	Plus
AICDA	Immunodeficiency with hyper-IgM, type 2 Immunodeficiency with hyper-IgM, type 2 Descrição da doença: Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections.	NM_020661.2	c.452T>C;c.441C>A;c.415A>G;c.334C>T;c.317T>C;c.251 c.452T>C;c.441C>A;c.415A>G;c.334C>T;c.317T>C;c.251G>A;c.238T>C;c.203G>A;c.70C>T	Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections.	Plus
AIFM1	Cowchock syndrome; Deafness, X-linked, type 5 Cowchock syndrome; Deafness, X-linked, type 5 Descrição da doença: Cowchock syndrome (COWCK) is an X-linked recessive neuromuscular disorder characterized by early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated in some patients with sensorineural deafness and cognitive impairment (Rinaldi et al., 2012). Hemizygous mutations in AIFM1 gene are also associated with deafness, X-linked, type 5, a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (Zong et al., 2015).	NM_004208.3;NM_001130846.3	c.1492G>A;c.1478A>T;c.1436A>G;c.1352G>A;c.1265G>A; c.1492G>A;c.1478A>T;c.1436A>G;c.1352G>A;c.1265G>A;c.1264C>T;c.1078G>C;c.2T>C;c.778A>G	Cowchock syndrome (COWCK) is an X-linked recessive neuromuscular disorder characterized by early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated in some patients with sensorineural deafness and cognitive impairment (Rinaldi et al., 2012). Hemizygous mutations in AIFM1 gene are also associated with deafness, X-linked, type 5, a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (Zong et al., 2015).	Plus
AIMP1	Leukodystrophy, hypomyelinating, type 3 Leukodystrophy, hypomyelinating, type 3 Descrição da doença: Leukodystrophy, hypomyelinating, type 3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (Feinstein et al., 2010).The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401).	NM_001142416.1	c.187C>T;c.364_365delCA;c.406C>T;c.434_438delAGAAA c.187C>T;c.364_365delCA;c.406C>T;c.434_438delAGAAA	Leukodystrophy, hypomyelinating, type 3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (Feinstein et al., 2010).The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401).	Plus
AIPL1	Leber congenital amaurosis type 4 Leber congenital amaurosis type 4 Descrição da doença: Leber congenital amaurosis type 4 (LCA4) is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. Mutations in the AIPL1 gene may cause approximately 20% of recessive LCA. Other conditions caused by pathogenic variants in the AIPL1 gene are cone rod dystrophy and the less agressive form, juvenile retinitis pigmentosa. Cone-rod dystropy is characterized by decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness.	NM_014336.4	c.1053_1064delTGCAGAGCCACC;c.1010_1011delAG;c.834G c.1053_1064delTGCAGAGCCACC;c.1010_1011delAG;c.834G>A;c.715T>C;c.589G>C	Leber congenital amaurosis type 4 (LCA4) is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. Mutations in the AIPL1 gene may cause approximately 20% of recessive LCA. Other conditions caused by pathogenic variants in the AIPL1 gene are cone rod dystrophy and the less agressive form, juvenile retinitis pigmentosa. Cone-rod dystropy is characterized by decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness.	Plus
AIRE	Autoimmune polyendocrinopathy syndrome type 1 Autoimmune polyendocrinopathy syndrome type 1 Descrição da doença: Autoimmune polyendocrinopathy syndrome (APS) type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981).	NM_000383.3	c.62C>T;c.83T>C;c.132+1_132+3delGTGinsCT;c.157G>T; c.62C>T;c.83T>C;c.132+1_132+3delGTGinsCT;c.157G>T;c.199_202delCTGAinsTGG;c.205_208dupCAGG;c.232T>C;c.233G>A;c.239T>G;c.247A>G;c.254A>G;c.255C>A;c.260delT;c.274C>T;c.319_321delAGCinsTG;c.328delC;c.415C>T;c.457_458delAGinsC;c.463+2T>C;c.464-2A>T;c.469C>T;c.510_522dupAGAGCAGCAGCGC;c.517C>T;c.652+1G>T;c.652+2T>C;c.682G>T;c.769C>T;c.789delC;c.798+1G>A;c.798+1G>C;c.798+1G>T;c.809_810delAG;c.823delC;c.931delT;c.932G>A;c.958delC;c.967_979delCTGTCCCCTCCGC;c.977delC;c.1066dupC;c.1084delG;c.1095+1G>A;c.1096-1G>A;c.1103dupC;c.1116_1117delGG;c.1163_1164insA;c.1193delC;c.1249dupC;c.1265delC;c.1278+1delG;c.1279-2A>G;c.1365G>A;c.1513delG;c.1566+2T>A;c.1567-2A>G;c.1616C>T;c.1638A>T	Autoimmune polyendocrinopathy syndrome (APS) type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981).	Plus
AK1	Hemolytic anemia due to adenylate kinase deficiency Hemolytic anemia due to adenylate kinase deficiency Descrição da doença: Hemolytic anemia due to adenylate kinase deficiency is a rare hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by moderate to severe chronic nonspherocytic hemolytic anemia that may require regular blood transfusions and/or splenectomy and may be associated with psychomotor impairment.	NM_001318122.1	c.539A>G;c.367C>T;c.238G>A;c.187delG;c.166G>A c.539A>G;c.367C>T;c.238G>A;c.187delG;c.166G>A	Hemolytic anemia due to adenylate kinase deficiency is a rare hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by moderate to severe chronic nonspherocytic hemolytic anemia that may require regular blood transfusions and/or splenectomy and may be associated with psychomotor impairment.	Plus
AK2	Reticular dysgenesis Reticular dysgenesis Descrição da doença: Reticular dysgenesis (RDYS) is a fatal form of severe combined immunodeficiency, characterized by absence of granulocytes, almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immunity, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal.	NM_001625.3	c.556C>T;c.545C>A;c.523delC;c.494A>G;c.453delC;c.3 c.556C>T;c.545C>A;c.523delC;c.494A>G;c.453delC;c.307C>T;c.118delT;c.25G>T;c.1A>G	Reticular dysgenesis (RDYS) is a fatal form of severe combined immunodeficiency, characterized by absence of granulocytes, almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immunity, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal.	Plus
AKR1C2	46,XY disorder of sex development due to testicular 17,20-desmolase deficiency 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency Descrição da doença: 46,XY sex reversal 8 (SRXY8) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.	NM_001354.5	c.270T>G c.270T>G	46,XY sex reversal 8 (SRXY8) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.	Plus
AKR1D1	Bile acid synthesis defect, congenital, type 2 Bile acid synthesis defect, congenital, type 2 Descrição da doença: Congenital bile acid synthesis defect, type 2 (BAS defect type 2) is an anomaly of bile acid synthesis characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins.	NM_005989.3	c.93+1G>T;c.261+1G>T;c.316C>T;c.580-1G>A;c.583G>T; c.93+1G>T;c.261+1G>T;c.316C>T;c.580-1G>A;c.583G>T;c.593C>T	Congenital bile acid synthesis defect, type 2 (BAS defect type 2) is an anomaly of bile acid synthesis characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins.	Plus
ALAD	Porphyria, acute hepatic Porphyria, acute hepatic Descrição da doença: ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).	NM_001003945.2;NM_001317745.1	c.910G>A;c.907G>A;c.484G>A;c.63C>G c.910G>A;c.907G>A;c.484G>A;c.63C>G	ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).	Plus
ALAS2	X-linked sideroblastic anemia, type 1 (XLSA or SIDBA1) X-linked sideroblastic anemia, type 1 (XLSA or SIDBA1) Descrição da doença: X-linked sideroblastic anemia type 1 is caused by pathogenic variants in the ALAS2 gene, located on chromosomal region Xp11.21. This disease is characterized by clinical features of anemia and/or iron overload such as pallor, fatigue, weakness, and more rarely breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism.	NM_000032.4	c.1706_1709delAGTG;c.1702A>G;c.1699_1700delAT;c.16 c.1706_1709delAGTG;c.1702A>G;c.1699_1700delAT;c.1699A>G;c.1642C>T;c.1570C>G;c.1427T>A;c.1355G>A;c.1354C>T;c.1231C>T;c.1184G>A;c.1163C>G;c.1093T>C;c.895A>C;c.871G>A;c.606G>A;c.595T>C;c.514G>A;c.475G>A;c.475G>T	X-linked sideroblastic anemia type 1 is caused by pathogenic variants in the ALAS2 gene, located on chromosomal region Xp11.21. This disease is characterized by clinical features of anemia and/or iron overload such as pallor, fatigue, weakness, and more rarely breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism.	Plus
ALDH18A1	Spastic paraplegia, type 9B, autosomal recessive; De Barsy syndrome Spastic paraplegia, type 9B, autosomal recessive; De Barsy syndrome Descrição da doença: Spastic paraplegia, type 9B, autosomal recessive (SPG9B) is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (Coutelier et al., 2015). Mutation in the ALDH18A1 gene can cause cutis laxa, autosomal recessive, type IIIA (De Barsy syndrome), characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (Kivuva et al., 2008).	NM_001323413.1	c.2294G>A;c.2143G>C;c.2131delC;c.1994G>T;c.1923+1G c.2294G>A;c.2143G>C;c.2131delC;c.1994G>T;c.1923+1G>A;c.1910T>C;c.755G>A;c.754C>T;c.727G>C;c.413G>A;c.413G>T;c.412C>T;c.359T>C;c.332A>G	Spastic paraplegia, type 9B, autosomal recessive (SPG9B) is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (Coutelier et al., 2015). Mutation in the ALDH18A1 gene can cause cutis laxa, autosomal recessive, type IIIA (De Barsy syndrome), characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (Kivuva et al., 2008).	Plus
ALDH3A2	Sjogren-Larsson syndrome Sjogren-Larsson syndrome Descrição da doença: Sjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (FALDH) (Lossos et al., 2006).	NM_001031806.1	c.28C>T;c.73C>T;c.103C>T;c.153+2T>G;c.154_155delAG c.28C>T;c.73C>T;c.103C>T;c.153+2T>G;c.154_155delAG;c.191T>A;c.231delA;c.234G>A;c.281dupA;c.374_378delCCATC;c.386-2A>T;c.471+1delG;c.471+2T>G;c.472-2A>G;c.521delT;c.551C>T;c.574dupA;c.577delG;c.623T>C;c.641G>A;c.733G>A;c.769dupA;c.798+1delG;c.798+1_798+6delGTTTGT;c.798+1G>A;c.809delG;c.824_825delAG;c.835T>A;c.901_903delGCTinsCC;c.943C>T;c.979delG;c.1069A>T;c.1094C>T;c.1100delA;c.1108-2A>G;c.1108-1G>A;c.1108-1G>C;c.1108-1G>T;c.1157A>G;c.1202G>A;c.1207+1G>A;c.1212delC;c.1277T>G;c.1291_1292delAA;c.1297_1298delGA;c.1302dupT;c.1307_1311dupACAAA;c.1367T>A;c.1443+1G>A;c.*42-1G>T	Sjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (FALDH) (Lossos et al., 2006).	Plus
ALDH4A1	Hyperprolinemia, type 2 Hyperprolinemia, type 2 Descrição da doença: Hyperprolinemia type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH4A1 gene located on chromosomal region 1p36. The age of onset is variable. This disease is characterized by seizures, intellectual deficit and mild developmental delay.	NM_003748.3	c.1560dupT;c.1055C>T;c.866+1G>A;c.298-1G>C;c.21del c.1560dupT;c.1055C>T;c.866+1G>A;c.298-1G>C;c.21delG	Hyperprolinemia type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH4A1 gene located on chromosomal region 1p36. The age of onset is variable. This disease is characterized by seizures, intellectual deficit and mild developmental delay.	Plus
ALDH5A1	Succinic semialdehyde dehydrogenase deficiency Succinic semialdehyde dehydrogenase deficiency Descrição da doença: Succinic semialdehyde dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH451 gene located on chromosomal region 6p22. The age of onset is infantile. This disease is characterized by psychomotor retardation, delayed speech development, hypotonia and ataxia. It is a rare disease with around 350 cases reported.	NM_170740.1	c.278G>T;c.526G>A;c.610-2A>G;c.612G>A;c.842G>A;c.8 c.278G>T;c.526G>A;c.610-2A>G;c.612G>A;c.842G>A;c.858delT;c.1265G>A;c.1273C>T;c.1382+1G>A;c.1382+1G>T;c.1579C>T;c.1636G>A	Succinic semialdehyde dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH451 gene located on chromosomal region 6p22. The age of onset is infantile. This disease is characterized by psychomotor retardation, delayed speech development, hypotonia and ataxia. It is a rare disease with around 350 cases reported.	Plus
ALDH6A1	Methylmalonate semialdehyde dehydrogenase deficiency Methylmalonate semialdehyde dehydrogenase deficiency Descrição da doença: Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (Marcadier et al., 2013).	NM_005589.3	c.1336G>A;c.785C>A;c.514T>C;c.184C>T c.1336G>A;c.785C>A;c.514T>C;c.184C>T	Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (Marcadier et al., 2013).	Plus
ALDH7A1	Epilepsy, pyridoxine-dependent Epilepsy, pyridoxine-dependent Descrição da doença: Pyridoxine-dependent epilepsy, characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (Bennett et al., 2005).	NM_001182.4	c.1597delG;c.1566-1G>T;c.1565+1G>T;c.1513G>C;c.148 c.1597delG;c.1566-1G>T;c.1565+1G>T;c.1513G>C;c.1489+5G>A;c.1468delG;c.1317+2T>C;c.1281G>T;c.1279G>C;c.1224T>G;c.1200+1G>T;c.1093+1G>A;c.1004G>A;c.901_902delAA;c.902A>T;c.834G>A;c.826A>C;c.796C>T;c.664A>G;c.607T>G;c.596C>T;c.589C>T;c.584A>G;c.571A>G;c.545G>A;c.518-1G>C;c.503_506delTCTT;c.394-1G>C;c.328C>T;c.312+2T>A;c.312+1G>A;c.285_286insG;c.246+1G>A;c.177G>A	Pyridoxine-dependent epilepsy, characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (Bennett et al., 2005).	Plus
ALDOA	Glycogen storage disease type 12 Glycogen storage disease type 12 Descrição da doença: Glycogen storage disease type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOA gene located on chromosomal region 16p11.2. The age of onset is neonatal/infantile. This disease is characterized by myopathy with exercise intolerance and rhabdomyolysis associated with hemolytic anaemia.	NM_001243177.1	c.548A>G;c.781G>A c.548A>G;c.781G>A	Glycogen storage disease type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOA gene located on chromosomal region 16p11.2. The age of onset is neonatal/infantile. This disease is characterized by myopathy with exercise intolerance and rhabdomyolysis associated with hemolytic anaemia.	Plus
ALDOB	Fructose intolerance, hereditary Fructose intolerance, hereditary Descrição da doença: Hereditary fructose intolerance follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOB gene located on chromosomal region 9q21.3-q22.2. The age of onset is neonatal/infantile. This disease is characterized by severe abdominal pain, vomiting, and hypoglycemia following ingestion of fructose or other sugars metabolised through fructose-1-phosphate. The prevalence is 1:100,000-9:100,000.	NM_000035.3	c.1067C>A;c.1013C>T;c.1005C>G;c.940dupT;c.941G>A;c c.1067C>A;c.1013C>T;c.1005C>G;c.940dupT;c.941G>A;c.911G>A;c.888G>A;c.865delC;c.800-2A>C;c.720C>A;c.625-1G>A;c.625-2A>G;c.612T>A;c.546delA;c.524C>A;c.522C>G;c.448G>C;c.444G>A;c.442T>C;c.420delA;c.380-1G>A;c.380-2A>G;c.379+1G>A;c.360_363delCAAA;c.325-1G>A;c.324+2T>A;c.324+1G>A;c.178C>T;c.113-1_115delGGTA;c.112+1delG;c.10C>T;c.2T>C	Hereditary fructose intolerance follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOB gene located on chromosomal region 9q21.3-q22.2. The age of onset is neonatal/infantile. This disease is characterized by severe abdominal pain, vomiting, and hypoglycemia following ingestion of fructose or other sugars metabolised through fructose-1-phosphate. The prevalence is 1:100,000-9:100,000.	Plus
ALG1	Congenital disorder of glycosylation, type 1K Congenital disorder of glycosylation, type 1K Descrição da doença: Congenital disorder of glycosylation type 1K follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG1 gene located on chromosomal region 16p13.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay, seizures, microcephaly and coagulation anomalies. The prevalence is <1:1,000,000.	NM_019109.4	c.15C>A;c.149A>G;c.304C>T;c.434G>A;c.450C>G;c.773C c.15C>A;c.149A>G;c.304C>T;c.434G>A;c.450C>G;c.773C>T;c.823G>T;c.863-2A>G;c.901+1G>A;c.1079C>T;c.1129A>G;c.1187+1G>A;c.1187+3A>G;c.1188-2A>G;c.1188T>A;c.1250_1251insTG	Congenital disorder of glycosylation type 1K follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG1 gene located on chromosomal region 16p13.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay, seizures, microcephaly and coagulation anomalies. The prevalence is <1:1,000,000.	Plus
ALG11	Congenital disorder of glycosylation, type 1P Congenital disorder of glycosylation, type 1P Descrição da doença: Congenital disorder of glycosylation, type 1P (CDG1P) is a form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.	NM_001004127.2	c.953A>C;c.1123_1126delAACA;c.1142T>C;c.1402C>T c.953A>C;c.1123_1126delAACA;c.1142T>C;c.1402C>T	Congenital disorder of glycosylation, type 1P (CDG1P) is a form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.	Plus
ALG12	Congenital disorder of glycosylation, type 1G Congenital disorder of glycosylation, type 1G Descrição da doença: Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.	NM_024105.3	c.1242C>G;c.1001delA;c.930_931delAC;c.162+1G>T;c.1 c.1242C>G;c.1001delA;c.930_931delAC;c.162+1G>T;c.117delG	Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.	Plus
ALG13	Epileptic encephalopathy, early infantile, type 36 Epileptic encephalopathy, early infantile, type 36 Descrição da doença: Epileptic encephalopathy, early infantile, type 36 (EIEE36) is an X-linked dominant neurodevelopmental disorder characterized by onset of seizures in infancy followed by delayed psychomotor development. Some patients may have dysmorphic features. Only females with this specific phenotype have been reported (Dimassi et al., 2016).	NM_001099922.2	c.320A>G c.320A>G	Epileptic encephalopathy, early infantile, type 36 (EIEE36) is an X-linked dominant neurodevelopmental disorder characterized by onset of seizures in infancy followed by delayed psychomotor development. Some patients may have dysmorphic features. Only females with this specific phenotype have been reported (Dimassi et al., 2016).	Plus
ALG2	Myasthenic syndrome, congenital, type 14, with tubular aggregates Myasthenic syndrome, congenital, type 14, with tubular aggregates Descrição da doença: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 14 (CMS14) is a form of congenital myasthenic syndrome. Clinical features are easy fatigability and muscle weakness. CMS14 is an autosomal recessive form characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound.	NM_033087.3	c.1040delG;c.203T>G c.1040delG;c.203T>G	Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 14 (CMS14) is a form of congenital myasthenic syndrome. Clinical features are easy fatigability and muscle weakness. CMS14 is an autosomal recessive form characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound.	Plus
ALG6	Congenital disorder of glycosylation, type 1C Congenital disorder of glycosylation, type 1C Descrição da doença: Congenital disorder of glycosylation type 1C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG6 gene located on chromosomal region 1p31.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay and muscular hypotonia, and possible coagulation anomalies, hormonal abnormalities and seizures. The prevalence is <1:1,000,000.	NM_013339.3	c.171T>A;c.257+5G>A;c.316C>T;c.680G>A;c.680+2T>G;c c.171T>A;c.257+5G>A;c.316C>T;c.680G>A;c.680+2T>G;c.897_899delAAT;c.998C>T;c.1432T>C	Congenital disorder of glycosylation type 1C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG6 gene located on chromosomal region 1p31.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay and muscular hypotonia, and possible coagulation anomalies, hormonal abnormalities and seizures. The prevalence is <1:1,000,000.	Plus
ALG8	Congenital disorder of glycosylation, type 1H Congenital disorder of glycosylation, type 1H Descrição da doença: CDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.	NM_024079.4	c.1090C>T;c.413delC;c.396dupA;c.121C>T;c.96-2A>G c.1090C>T;c.413delC;c.396dupA;c.121C>T;c.96-2A>G	CDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.	Plus
ALG9	Congenital disorder of glycosylation, type 1L; Gillessen-Kaesbach-Nishimura syndrome Congenital disorder of glycosylation, type 1L; Gillessen-Kaesbach-Nishimura syndrome Descrição da doença: Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type 1. Homozygous mutation in the ALG9 gene can also cause Gillessen-Kaesbach-Nishimura syndrome (GIKANIS). GIKANIS is an autosomal recessive multiple congenital anomaly disorder characterized by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life. The disorder is at the severe end of the phenotypic spectrum of congenital disorders of glycosylation (summary by Tham et al., 2016).	NM_024740.2	c.1173+2T>A c.1173+2T>A	Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type 1. Homozygous mutation in the ALG9 gene can also cause Gillessen-Kaesbach-Nishimura syndrome (GIKANIS). GIKANIS is an autosomal recessive multiple congenital anomaly disorder characterized by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life. The disorder is at the severe end of the phenotypic spectrum of congenital disorders of glycosylation (summary by Tham et al., 2016).	Plus
ALMS1	Alström syndrome Alström syndrome Descrição da doença: Alström syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALMS1 gene located on chromosomal region 2p13.1. The age of onset is neonatal/infantile. This disease is characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy and progressive hepatic and renal dysfunction. The prevalence is 1:10,000-1:1,000,000.	NM_015120.4	c.355C>T;c.359_360delTA;c.427C>T;c.709G>T;c.925_92 c.355C>T;c.359_360delTA;c.427C>T;c.709G>T;c.925_926insT;c.1051C>T;c.1196_1202delCACAGGA;c.1229_1230delAT;c.1237+2T>C;c.1557delG;c.1607_1608delTC;c.1668delT;c.1729delA;c.1788_1795dupGGCTTTGA;c.1894C>T;c.2127_2131delAGTAC;c.2135_2136delCT;c.2173dupT;c.2218dupA;c.2290_2293delTCAC;c.2323C>T;c.2723C>G;c.2749dupT;c.2787dupA;c.2816T>A;c.3013dupA;c.3294_3295delAA;c.3334delG;c.3486_3495delTATACCTGAA;c.3684_3685delTG;c.3778G>T;c.3870_3871delGA;c.4150dupA;c.4246delC;c.4290_4293delCACA;c.4422delC;c.4642dupA;c.4911_4914delTAAA;c.5139T>G;c.5173dupC;c.5193_5194delTC;c.5412delC;c.5459delC;c.5584C>T;c.5619delA;c.5624dupT;c.5857delG;c.5883delA;c.5920delG;c.5975_5976delAA;c.6163_6164dupAT;c.6430C>T;c.6480_6483delAACT;c.6565_6568delTCAC;c.6567_6570dupACAT;c.6584delA;c.6794T>A;c.6834delT;c.6895delG;c.6954_6957delACAG;c.7241C>A;c.7298_7299delAG;c.7369_7370delGA;c.7370_7373delATAG;c.7385_7389dupAGGGT;c.7824delC;c.8002C>T;c.8130delT;c.8138_8145delCCATCACT;c.8149dupT;c.8158C>T;c.8346_8349delAGAA;c.8377C>T;c.8383C>T;c.8388dupA;c.8411dupC;c.8753_8756delCTTC;c.8787dupT;c.9148_9149delCT;c.9427dupA;c.9535C>T;c.9614_9618delCAGAA;c.9757_9758dupAC;c.9812_9825delGTAGTACCAAGATG;c.9894dupC;c.10128dupA;c.10284_10285delTA;c.10297delCinsGA;c.10477C>T;c.10543C>T;c.10769delC;c.10784_10785delTG;c.10794_10797delTGAA;c.10819C>T;c.10825_10826delAG;c.10879C>T;c.10939G>T;c.10986G>A;c.11080delA;c.11201C>A;c.11310_11313delAGAG;c.11379delT;c.11443C>T;c.11453dupA;c.11612_11613delCT;c.11613dupT;c.11645_11646insGTTA;c.11697delA;c.11711_11714delTTGG;c.11781G>A;c.11806dupA;c.11870-2A>T;c.11988G>A;c.12080_12083delTACT;c.12101_12102delCA;c.12299_12302delTCCT;c.12439C>T;c.12445C>T	Alström syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALMS1 gene located on chromosomal region 2p13.1. The age of onset is neonatal/infantile. This disease is characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy and progressive hepatic and renal dysfunction. The prevalence is 1:10,000-1:1,000,000.	Plus
ALOX12B	Ichthyosis, congenital, autosomal recessive, type 2 Ichthyosis, congenital, autosomal recessive, type 2 Descrição da doença: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	NM_001139.2	c.2036G>T;c.1734C>A;c.1642C>T;c.1579G>A;c.1562A>G; c.2036G>T;c.1734C>A;c.1642C>T;c.1579G>A;c.1562A>G;c.1389delT;c.1277T>C;c.1207C>T;c.1180G>A;c.1156C>T;c.530G>A;c.527+2T>G;c.353-2A>G;c.340C>T;c.252C>A;c.242delC;c.166C>T	Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	Plus
ALOXE3	Ichthyosis, congenital, autosomal recessive, type 3 Ichthyosis, congenital, autosomal recessive, type 3 Descrição da doença: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	NM_001165960.1	c.2285C>T;c.2182-2A>G;c.2026C>T;c.1894G>T;c.1582C> c.2285C>T;c.2182-2A>G;c.2026C>T;c.1894G>T;c.1582C>A;c.1238G>A;c.1238G>T;c.1096C>T;c.1027C>T;c.814C>T	Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	Plus
ALPL	Hypophosphatasia, childhood/infantile Hypophosphatasia, childhood/infantile Descrição da doença: Childhood-onset hypophosphatasia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALPL gene located on chromosomal region 1p36.12. The age of onset is infantile. This inborn error of metabolism is characterized clinically by defective bone mineralization ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood; biochemically is characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase.	NM_000478.5	c.18delA;c.46_49delAACT;c.61+2T>G;c.87G>A;c.88C>T; c.18delA;c.46_49delAACT;c.61+2T>G;c.87G>A;c.88C>T;c.98C>T;c.114delA;c.129delT;c.130C>T;c.211C>T;c.212G>C;c.215T>C;c.297+2T>A;c.323C>T;c.346G>A;c.392delG;c.400_401delACinsCA;c.407G>A;c.427delC;c.522delC;c.526G>A;c.535G>A;c.542C>T;c.550C>T;c.571G>A;c.620A>C;c.648+1G>A;c.662dupG;c.667C>T;c.668G>A;c.791A>G;c.809G>A;c.814C>T;c.815G>A;c.841delC;c.862+1G>A;c.871G>A;c.881A>C;c.891C>A;c.892G>A;c.903delG;c.928_929delTC;c.963delG;c.979T>C;c.997+2T>G;c.998-2A>G;c.1001G>A;c.1039C>T;c.1088_1091dupGCAG;c.1114_1115delCT;c.1133A>T;c.1144G>A;c.1171C>T;c.1181_1182delCT;c.1216_1219delGACA;c.1250A>G;c.1306T>C;c.1363G>A;c.1366G>A;c.1559delT	Childhood-onset hypophosphatasia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALPL gene located on chromosomal region 1p36.12. The age of onset is infantile. This inborn error of metabolism is characterized clinically by defective bone mineralization ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood; biochemically is characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase.	Plus
ALS2	Amyotrophic lateral sclerosis, type 2, juvenile; Primary lateral sclerosis, juvenile; Spastic paralysis, infantile onset ascending Amyotrophic lateral sclerosis, type 2, juvenile; Primary lateral sclerosis, juvenile; Spastic paralysis, infantile onset ascending Descrição da doença: Amyotrophic lateral sclerosis (ALS), type 2, juvenile is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. Mutations in the same gene cause juvenile primary lateral sclerosis (PLSJ) and infantile-onset ascending spastic paralysis (IAHSP). Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis, they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLSJ became clear and diagnostic criteria established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. A diagnosis of PLS is essentially one of exclusion (Sotaniemi and Myllyla, 1985; Younger et al., 1988; Yang et al., 2001). Infantile-onset ascending spastic paralysis is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by Wakil et al., 2014).	NM_020919.3	c.4897C>T;c.4721delT;c.4573dupG;c.3619delA;c.3415C c.4897C>T;c.4721delT;c.4573dupG;c.3619delA;c.3415C>T;c.3158G>A;c.2992C>T;c.2980-2A>G;c.2761C>T;c.2581-1G>C;c.2537_2538delAT;c.2143C>T;c.2002G>T;c.1999-2A>T;c.1921C>T;c.1867_1868delCT;c.1816-1G>A;c.1619G>A;c.1472-1G>T;c.1425_1428delAGAG;c.1427_1428delAG;c.1007_1008delTA;c.735_738delAGAA;c.553delA;c.535C>T;c.470G>A;c.138delA	Amyotrophic lateral sclerosis (ALS), type 2, juvenile is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. Mutations in the same gene cause juvenile primary lateral sclerosis (PLSJ) and infantile-onset ascending spastic paralysis (IAHSP). Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis, they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLSJ became clear and diagnostic criteria established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. A diagnosis of PLS is essentially one of exclusion (Sotaniemi and Myllyla, 1985; Younger et al., 1988; Yang et al., 2001). Infantile-onset ascending spastic paralysis is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by Wakil et al., 2014).	Plus
ALX1	Frontonasal dysplasia, type 3 Frontonasal dysplasia, type 3 Descrição da doença: Frontonasal dysplasia, type 3 is the most severe form of frontonasal dysplasia, an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. At least three mutations in the ALX1 gene have been found to cause frontonasal dysplasia.	NM_006982.2	c.531+1G>A c.531+1G>A	Frontonasal dysplasia, type 3 is the most severe form of frontonasal dysplasia, an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. At least three mutations in the ALX1 gene have been found to cause frontonasal dysplasia.	Plus
ALX3	Frontonasal dysplasia, type 1 Frontonasal dysplasia, type 1 Descrição da doença: The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.	NM_006492.2	c.608A>G;c.578_581delCTGA;c.547C>T;c.543T>A c.608A>G;c.578_581delCTGA;c.547C>T;c.543T>A	The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.	Plus
ALX4	Frontonasal dysplasia, type 2 Frontonasal dysplasia, type 2 Descrição da doença: The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.	NM_021926.3	c.815G>C;c.793C>T;c.736C>T;c.673C>G;c.653G>A;c.620 c.815G>C;c.793C>T;c.736C>T;c.673C>G;c.653G>A;c.620C>A;c.504delT;c.503delC;c.385_394delTGCAAGACGC;c.291delG	The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.	Plus
AMACR	Bile acid synthesis defect, congenital, type 4; Alpha-methylacyl-CoA racemase deficiency Bile acid synthesis defect, congenital, type 4; Alpha-methylacyl-CoA racemase deficiency Descrição da doença: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (Smith et al., 2010). AMACR deficiency is caused by mutations in the AMACR gene. AMACR gene mutations that result in a lack of functional AMACR enzyme have also been identified in infants with a life-threatening disorder called congenital bile acid synthesis defect type 4. Babies with this disorder have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to an enlarged liver (hepatomegaly) and irreversible liver disease (cirrhosis) in the first few months of life. Some researchers consider congenital bile acid synthesis defect type 4 and AMACR deficiency (see above) to be variations of the same disorder. Because most individuals with congenital bile acid synthesis defect type 4 do not survive infancy, it is unclear whether they would have later developed the neurological symptoms seen in adults with AMACR deficiency.	NM_001167595.1	c.320T>C;c.154T>C c.320T>C;c.154T>C	Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (Smith et al., 2010). AMACR deficiency is caused by mutations in the AMACR gene. AMACR gene mutations that result in a lack of functional AMACR enzyme have also been identified in infants with a life-threatening disorder called congenital bile acid synthesis defect type 4. Babies with this disorder have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to an enlarged liver (hepatomegaly) and irreversible liver disease (cirrhosis) in the first few months of life. Some researchers consider congenital bile acid synthesis defect type 4 and AMACR deficiency (see above) to be variations of the same disorder. Because most individuals with congenital bile acid synthesis defect type 4 do not survive infancy, it is unclear whether they would have later developed the neurological symptoms seen in adults with AMACR deficiency.	Plus
AMELX	Amelogenesis imperfecta, type 1E Amelogenesis imperfecta, type 1E Descrição da doença: Amelogenesis imperfecta, type 1E is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).	NM_182680.1	c.155delC;c.420delC;c.473delC;c.541delC;c.571G>T c.155delC;c.420delC;c.473delC;c.541delC;c.571G>T	Amelogenesis imperfecta, type 1E is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).	Plus
AMER1	Osteopathia striata with cranial sclerosis Osteopathia striata with cranial sclerosis Descrição da doença: Osteopathia striata with cranial sclerosis is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae (Jenkins et al., 2009). In males, the disorder is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. Osteosclerosis in the cranial and facial bones leads to disfigurement and to disability due to pressure on cranial nerves, e.g., deafness. Osteopathia striata is a frequent feature of focal dermal hypoplasia (FDH; 305600).Although early reports of familial cases of this disorder appeared to suggest autosomal dominant inheritance (see, e.g., Horan and Beighton, 1978; Konig et al., 1996), reappraisal of the literature (Behninger and Rott, 2000; Rott et al., 2003) and the finding of a molecular basis for the disorder by Jenkins et al. (2009) confirms that the inheritance pattern is X-linked dominant. Affected males who survive have a more severe phenotype than affected females, and sporadic male cases may result from somatic mosaicism (Behninger and Rott, 2000).	NM_152424.3	c.1267delC;c.1072C>T;c.1057C>T;c.811C>T;c.780dupA; c.1267delC;c.1072C>T;c.1057C>T;c.811C>T;c.780dupA;c.671delC;c.655delG;c.429T>A	Osteopathia striata with cranial sclerosis is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae (Jenkins et al., 2009). In males, the disorder is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. Osteosclerosis in the cranial and facial bones leads to disfigurement and to disability due to pressure on cranial nerves, e.g., deafness. Osteopathia striata is a frequent feature of focal dermal hypoplasia (FDH; 305600).Although early reports of familial cases of this disorder appeared to suggest autosomal dominant inheritance (see, e.g., Horan and Beighton, 1978; Konig et al., 1996), reappraisal of the literature (Behninger and Rott, 2000; Rott et al., 2003) and the finding of a molecular basis for the disorder by Jenkins et al. (2009) confirms that the inheritance pattern is X-linked dominant. Affected males who survive have a more severe phenotype than affected females, and sporadic male cases may result from somatic mosaicism (Behninger and Rott, 2000).	Plus
AMH	Persistent Mullerian duct syndrome, type 1 Persistent Mullerian duct syndrome, type 1 Descrição da doença: The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (Knebelmann et al., 1991).	NM_000479.4	c.208dupC;c.571C>T c.208dupC;c.571C>T	The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (Knebelmann et al., 1991).	Plus
AMN	Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome) Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome) Descrição da doença: Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.	NM_030943.3	c.14delG;c.43+1G>T;c.208-2A>G;c.208-1G>C;c.295+1de c.14delG;c.43+1G>T;c.208-2A>G;c.208-1G>C;c.295+1delG;c.468dupT;c.663G>A;c.742C>T;c.760+1G>A;c.844-1G>C;c.974_977dupCCCG;c.1253dupA;c.1314_1315delCA	Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.	Plus
AMPD1	Myopathy due to myoadenylate deaminase deficiency Myopathy due to myoadenylate deaminase deficiency Descrição da doença: Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).	NM_000036.2	c.1373G>A;c.1261C>T;c.567G>T c.1373G>A;c.1261C>T;c.567G>T	Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).	Plus
AMT	Glycine encephalopathy Glycine encephalopathy Descrição da doença: Glycine encephalopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AMT and GLDC genes located on chromosomal regions 3p21.31 and 9p24.1 respectively. The age of onset is neonatal/infantile. This disease is characterized by lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. The prevalence is 1:1,000,000-9:1,000,000.	NM_000481.3	c.1033+2T>C;c.982_983delGCinsT;c.982delG;c.959G>A; c.1033+2T>C;c.982_983delGCinsT;c.982delG;c.959G>A;c.878-1G>A;c.870G>A;c.849dupT;c.826G>C;c.806G>A;c.696+2T>A;c.696+1G>A;c.674A>G;c.574C>T;c.535delC;c.496C>T;c.471+2T>C;c.434A>T;c.348_349delGT;c.259-1G>C;c.230C>T;c.164G>A;c.144_148delAATGG;c.148delG;c.125A>G;c.61delG;c.59delC;c.16delA	Glycine encephalopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AMT and GLDC genes located on chromosomal regions 3p21.31 and 9p24.1 respectively. The age of onset is neonatal/infantile. This disease is characterized by lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. The prevalence is 1:1,000,000-9:1,000,000.	Plus
ANGPTL3	Hypobetalipoproteinemia, familial, type 2 Hypobetalipoproteinemia, familial, type 2 Descrição da doença: Hypobetalipoproteinemia, familial, type 2 is defined as permanently low levels, below the 5th percentile of sex- and age-matched individuals in the population, of apolipoprotein B (apoB), total cholesterol, and low-density lipoprotein (LDL) cholesterol; the lipid profile in FHBL2 includes low HDL cholesterol as well. HBL can result from environmental factors such as a strict vegetarian diet, or can be secondary to certain diseases such as intestinal fat malabsorption, chronic pancreatitis, severe liver disease, malnutrition, or hyperthyroidism. Heritable primary causes of HBL include chylomicron retention disease (CMRD; 246700), abetalipoproteinemia (200100), and familial hypobetalipoproteinemia (FHBL) (Martin-Campos et al., 2012).	NM_014495.3	c.55delA;c.1198+1G>T c.55delA;c.1198+1G>T	Hypobetalipoproteinemia, familial, type 2 is defined as permanently low levels, below the 5th percentile of sex- and age-matched individuals in the population, of apolipoprotein B (apoB), total cholesterol, and low-density lipoprotein (LDL) cholesterol; the lipid profile in FHBL2 includes low HDL cholesterol as well. HBL can result from environmental factors such as a strict vegetarian diet, or can be secondary to certain diseases such as intestinal fat malabsorption, chronic pancreatitis, severe liver disease, malnutrition, or hyperthyroidism. Heritable primary causes of HBL include chylomicron retention disease (CMRD; 246700), abetalipoproteinemia (200100), and familial hypobetalipoproteinemia (FHBL) (Martin-Campos et al., 2012).	Plus
ANO10	Spinocerebellar ataxia, autosomal recessive, type 10 Spinocerebellar ataxia, autosomal recessive, type 10 Descrição da doença: Spinocerebellar ataxia, autosomal recessive, type 10 is an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging (Vermeer et al., 2010). Some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment (Balreira et al., 2014).	NM_018075.3	c.1797+1G>A;c.1604delT;c.1476+1G>T;c.1150_1151delT c.1797+1G>A;c.1604delT;c.1476+1G>T;c.1150_1151delTT;c.1144G>T;c.473-2A>G;c.337+1G>A;c.289delA;c.132dupA;c.124A>T;c.96delA	Spinocerebellar ataxia, autosomal recessive, type 10 is an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging (Vermeer et al., 2010). Some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment (Balreira et al., 2014).	Plus
ANO5	Limb-girdle muscular dystrophy, type 12 (LGMD R12) Limb-girdle muscular dystrophy, type 12 (LGMD R12) Descrição da doença: Limb-girdle muscular dystrophy type 12 (LGMDR12, formerly LGMD2L) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ANO5 gene located on chromosomal region 11p14.3. This disease is characterized by weakness and wasting restricted to the limb musculature. Most often is characterized by an adult onset (but ranging from 11 to 51 years) of mainly proximal lower limb weakness, with difficulties standing on tiptoes being one of the initial signs. Proximal upper limb and distal lower limb weakness is also common, as well as atrophy of the quadriceps (most commonly), biceps brachii, and lower leg muscles. Calf hypertrophy has also been reported in some cases. LGMDR12 progresses slowly, with most patients remaining ambulatory until late adulthood. The estimated prevalence is <1:1,000,000.	NM_213599.2	c.108_109delGA;c.148C>T;c.169C>T;c.172C>T;c.191dup c.108_109delGA;c.148C>T;c.169C>T;c.172C>T;c.191dupA;c.201_205delCAAAG;c.206_207delAT;c.220C>T;c.242A>G;c.364-2A>G;c.412G>T;c.649-2A>G;c.692G>T;c.762+1G>A;c.835C>T;c.889G>T;c.989dupT;c.1013+1G>T;c.1088G>A;c.1120-1G>A;c.1207C>T;c.1210C>T;c.1213C>T;c.1261C>T;c.1295C>G;c.1406G>A;c.1407+5G>A;c.1520delT;c.1538C>T;c.1627dupA;c.1639C>T;c.1664G>T;c.1709C>G;c.1733T>C;c.1767C>A;c.1887delA;c.1898+1G>A;c.1914G>A;c.1955A>G;c.1960C>T;c.1992dupT;c.2004delG;c.2018A>G;c.2172_2178delTCATAGC;c.2176dupA;c.2235+1G>A;c.2311_2312delCA;c.2345C>G;c.2446G>T;c.2470delC;c.2521C>G	Limb-girdle muscular dystrophy type 12 (LGMDR12, formerly LGMD2L) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ANO5 gene located on chromosomal region 11p14.3. This disease is characterized by weakness and wasting restricted to the limb musculature. Most often is characterized by an adult onset (but ranging from 11 to 51 years) of mainly proximal lower limb weakness, with difficulties standing on tiptoes being one of the initial signs. Proximal upper limb and distal lower limb weakness is also common, as well as atrophy of the quadriceps (most commonly), biceps brachii, and lower leg muscles. Calf hypertrophy has also been reported in some cases. LGMDR12 progresses slowly, with most patients remaining ambulatory until late adulthood. The estimated prevalence is <1:1,000,000.	Plus
ANOS1	Hypogonadotropic hypogonadism, type 1, with or without anosmia (Kallmann syndrome 1) Hypogonadotropic hypogonadism, type 1, with or without anosmia (Kallmann syndrome 1) Descrição da doença: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.	NM_000216.3	c.1891C>T;c.1887_1888delTT;c.1615G>T;c.1449+2delT; c.1891C>T;c.1887_1888delTT;c.1615G>T;c.1449+2delT;c.1369C>T;c.1270C>T;c.1267C>T;c.1062+1G>T;c.784C>T;c.774G>A;c.769C>T;c.711G>A;c.580G>T	Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.	Plus
ANTXR1	GAPO syndrome GAPO syndrome Descrição da doença: The GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) noted that optic atrophy is not a consistent feature of this disorder.	NM_032208.2	c.262C>T;c.505C>T;c.1221dupT c.262C>T;c.505C>T;c.1221dupT	The GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) noted that optic atrophy is not a consistent feature of this disorder.	Plus
ANTXR2	Hyaline fibromatosis syndrome Hyaline fibromatosis syndrome Descrição da doença: Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (Denadai et al., 2012).	NM_001145794.1	c.1305delC;c.1074delT;c.1073dupC;c.658G>T;c.566T>C c.1305delC;c.1074delT;c.1073dupC;c.658G>T;c.566T>C;c.314G>A;c.134T>C;c.134T>G	Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (Denadai et al., 2012).	Plus
AP1S1	MEDNIK syndrome MEDNIK syndrome Descrição da doença: MEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (Montpetit et al., 2008).	NM_001283.3	c.183-2A>G;c.364dupG c.183-2A>G;c.364dupG	MEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (Montpetit et al., 2008).	Plus
AP1S2	Mental retardation, X-linked, syndromic, type 5 (Pettigrew syndrome) Mental retardation, X-linked, syndromic, type 5 (Pettigrew syndrome) Descrição da doença: Mental retardation, X-linked, syndromic, type 5, also known as Pettigrew syndrome, is characterized by mental retardation and highly variable additional features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain, both between and within families (Cacciagli et al., 2014).	NM_001272071.1	c.426+1G>T;c.226G>T;c.180-5_180-2delTACA;c.154C>T; c.426+1G>T;c.226G>T;c.180-5_180-2delTACA;c.154C>T;c.106C>T;c.92delC;c.40C>T	Mental retardation, X-linked, syndromic, type 5, also known as Pettigrew syndrome, is characterized by mental retardation and highly variable additional features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain, both between and within families (Cacciagli et al., 2014).	Plus
AP3B1	Hermansky-Pudlak syndrome, type 2 Hermansky-Pudlak syndrome, type 2 Descrição da doença: Hermansky-Pudlak syndrome, type 2 (HPS2) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (Jung et al., 2006).	NM_003664.4	c.1975G>T;c.1839_1842delTAGA;c.1754delT;c.1525C>T; c.1975G>T;c.1839_1842delTAGA;c.1754delT;c.1525C>T;c.904A>T;c.716G>A;c.177delA	Hermansky-Pudlak syndrome, type 2 (HPS2) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (Jung et al., 2006).	Plus
AP3B2	Epileptic encephalopathy, early infantile, type 48 Epileptic encephalopathy, early infantile, type 48 Descrição da doença: Epileptic encephalopathy, early infantile, type 48 (EIEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech, poor, if any, motor development, and onset of seizures in the first year of life. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (Assoum et al., 2016).	NM_001278512.1	c.3235_3238delACTG;c.2579_2582delTCAC;c.1837delG;c c.3235_3238delACTG;c.2579_2582delTCAC;c.1837delG;c.1110+1G>C;c.199C>T	Epileptic encephalopathy, early infantile, type 48 (EIEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech, poor, if any, motor development, and onset of seizures in the first year of life. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (Assoum et al., 2016).	Plus
AP4B1	Spastic paraplegia, type 47, autosomal recessive Spastic paraplegia, type 47, autosomal recessive Descrição da doença: Spastic paraplegia, type 47, autosomal recessive is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011).	NM_001253852.2	c.1345A>T;c.1282G>T;c.1216C>T;c.1177C>T;c.1160_116 c.1345A>T;c.1282G>T;c.1216C>T;c.1177C>T;c.1160_1161delCA;c.530_531insA;c.313delG;c.311_312delTGinsC;c.114-2A>C	Spastic paraplegia, type 47, autosomal recessive is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011).	Plus
AP4M1	Spastic paraplegia, type 50, autosomal recessive Spastic paraplegia, type 50, autosomal recessive Descrição da doença: Spastic paraplegia, type 50, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Verkerk et al., 2009).	NM_004722.3	c.58+2T>G;c.330C>G;c.802C>T;c.842_843delTG;c.916C> c.58+2T>G;c.330C>G;c.802C>T;c.842_843delTG;c.916C>T;c.923C>G;c.952C>T;c.1012C>T;c.1321C>T	Spastic paraplegia, type 50, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Verkerk et al., 2009).	Plus
AP4S1	Spastic paraplegia, type 52, autosomal recessive Spastic paraplegia, type 52, autosomal recessive Descrição da doença: Spastic paraplegia, type 52, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011). Some patients may have seizures (Hardies et al., 2015).	NM_007077.4	c.43C>T;c.124C>T;c.138+3_138+6delAAGT;c.138+2T>G;c c.43C>T;c.124C>T;c.138+3_138+6delAAGT;c.138+2T>G;c.229G>T;c.294+1G>C;c.294+1G>T	Spastic paraplegia, type 52, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011). Some patients may have seizures (Hardies et al., 2015).	Plus
AP5Z1	Spastic paraplegia, type 48, autosomal recessive Spastic paraplegia, type 48, autosomal recessive Descrição da doença: Spastic paraplegia, type 48, autosomal recessive is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (Hirst et al., 2015).	NM_014855.2	c.355_358dupCTCT;c.412C>T;c.1322G>A;c.1413_1426del c.355_358dupCTCT;c.412C>T;c.1322G>A;c.1413_1426delGGACCTGCCCTGCT;c.1732C>T	Spastic paraplegia, type 48, autosomal recessive is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (Hirst et al., 2015).	Plus
APOC2	Hyperlipoproteinemia, type 1B Hyperlipoproteinemia, type 1B Descrição da doença: Hyperlipoproteinemia 1B (HLPP1B) is an autosomal recessive trait characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis.	NM_000483.4	c.1A>G;c.142T>C;c.177C>A;c.177C>G;c.196_197delGC;c c.1A>G;c.142T>C;c.177C>A;c.177C>G;c.196_197delGC;c.255C>A	Hyperlipoproteinemia 1B (HLPP1B) is an autosomal recessive trait characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis.	Plus
APOE	Sea-blue histiocyte disease Sea-blue histiocyte disease Descrição da doença: Sea-blue histiocyte disease is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.	NM_001302688.1	c.315-2A>G;c.538C>A;c.539G>T;c.568A>C;c.568A>G;c.7 c.315-2A>G;c.538C>A;c.539G>T;c.568A>C;c.568A>G;c.761G>A	Sea-blue histiocyte disease is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.	Plus
APRT	Adenine phosphoribosyltransferase deficiency Adenine phosphoribosyltransferase deficiency Descrição da doença: Adenine phosphoribosyltransferase deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic (Sahota et al., 2001).Two types of APRT deficiency have been described based on the level of residual enzyme activity in in vitro studies of erythrocytes. Type I deficiency is characterized by complete enzyme deficiency in intact cells and in cell lysates, whereas type II deficiency is characterized by complete enzyme deficiency in intact cells, but only a partial deficiency in cell lysates. Type II alleles show reduced affinity for phosphoribosyl pyrophosphate (PRPP) compared to wildtype. In both types, APRT activity is not functional in vivo. Type II deficiency is most common among Japanese. Heterozygotes of either type do not appear to have any clinical or biochemical abnormalities (Sahota et al., 2001).	NM_000485.2	c.542G>C;c.448G>T;c.407T>C;c.329T>C;c.294G>A;c.258 c.542G>C;c.448G>T;c.407T>C;c.329T>C;c.294G>A;c.258_261dupCCGA;c.194A>T	Adenine phosphoribosyltransferase deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic (Sahota et al., 2001).Two types of APRT deficiency have been described based on the level of residual enzyme activity in in vitro studies of erythrocytes. Type I deficiency is characterized by complete enzyme deficiency in intact cells and in cell lysates, whereas type II deficiency is characterized by complete enzyme deficiency in intact cells, but only a partial deficiency in cell lysates. Type II alleles show reduced affinity for phosphoribosyl pyrophosphate (PRPP) compared to wildtype. In both types, APRT activity is not functional in vivo. Type II deficiency is most common among Japanese. Heterozygotes of either type do not appear to have any clinical or biochemical abnormalities (Sahota et al., 2001).	Plus
APTX	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Descrição da doença: Ataxia, early-onset, with oculomotor apraxia and hipoalbuminemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the APTX gene located on chromosomal region 9p13.1. Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive, progressive, cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia. The prevalence is unknown.	NM_001195248.1	c.917-1G>A;c.917-2A>G;c.883delT;c.879G>A;c.877T>C; c.917-1G>A;c.917-2A>G;c.883delT;c.879G>A;c.877T>C;c.830T>G;c.739A>T;c.731dupT;c.710T>C;c.709C>T;c.659C>T;c.644A>G;c.362delC;c.209delT;c.176-2A>G;c.166C>T	Ataxia, early-onset, with oculomotor apraxia and hipoalbuminemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the APTX gene located on chromosomal region 9p13.1. Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive, progressive, cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia. The prevalence is unknown.	Plus
AQP2	Diabetes insipidus, nephrogenic, type 2 Diabetes insipidus, nephrogenic, type 2 Descrição da doença: Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form, type I (304800), which is caused by mutation in the gene encoding the vasopressin V2 receptor (AVPR2; 300538). The remaining 10% of patients have the autosomal form, type II, caused by mutation in the AQP2 gene (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (CDI; 125700) is caused by mutation in the gene encoding arginine vasopressin, located on 20p13.	NM_000486.5	c.64C>G;c.170A>C;c.190G>A;c.203A>G;c.211G>A;c.277C c.64C>G;c.170A>C;c.190G>A;c.203A>G;c.211G>A;c.277C>T;c.299G>T;c.369delC;c.374C>T;c.377C>T;c.439G>A;c.523G>A;c.543C>G;c.559C>T;c.560G>A;c.568G>A;c.646T>C;c.721delG;c.727delG	Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form, type I (304800), which is caused by mutation in the gene encoding the vasopressin V2 receptor (AVPR2; 300538). The remaining 10% of patients have the autosomal form, type II, caused by mutation in the AQP2 gene (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (CDI; 125700) is caused by mutation in the gene encoding arginine vasopressin, located on 20p13.	Plus
AR	Androgen insensitivity syndrome, complete Androgen insensitivity syndrome, complete Descrição da doença: The complete androgen insensitivity syndrome (CAIS) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the AR gene located on chromosomal region Xq12. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male 46,XY karyotype. There is unresponsiveness to age-appropriate levels of androgens. There is also a partial androgen insensitivity syndrome (PAIS; OMIM 312300) caused by mutations in the AR gene, called Reifenstein syndrome, which results in hypospadias and micropenis with gynecomastia. Note: A specific type of mutation in the AR gene (a CAG repeat expansion) also cause a rare condition known as Spinal and bulbar muscular atrophy or Kennedy disease; this mutation is not tested by this carrier test.	NM_000044.3	c.178C>T;c.217C>T;c.268C>T;c.340C>T;c.393C>A;c.521 c.178C>T;c.217C>T;c.268C>T;c.340C>T;c.393C>A;c.521T>G;c.796dupG;c.865G>T;c.1185C>A;c.1720G>C;c.1732G>A;c.1739G>A;c.1739G>T;c.1748T>A;c.1768+2T>C;c.1771A>T;c.1789G>A;c.1804T>G;c.1822C>T;c.1823G>A;c.1826G>A;c.1847G>A;c.1886-1G>A;c.1888delC;c.1888C>T;c.1952delG;c.2033T>C;c.2069A>C;c.2103G>T;c.2104C>T;c.2105T>A;c.2117A>G;c.2123T>G;c.2137C>A;c.2137C>T;c.2157G>A;c.2164G>A;c.2191G>A;c.2222C>G;c.2231G>A;c.2231G>T;c.2248A>G;c.2257C>T;c.2258G>A;c.2258G>T;c.2281_2287delAGGATGCinsTTCGCCCCTGA;c.2291A>G;c.2296G>A;c.2297C>A;c.2301delT;c.2314A>C;c.2318+1G>C;c.2323C>T;c.2324G>A;c.2343G>A;c.2343G>T;c.2359C>T;c.2362A>G;c.2391G>A;c.2395C>G;c.2420G>A;c.2423T>C;c.2437C>T;c.2438T>C;c.2450-1G>A;c.2504A>G;c.2521C>T;c.2522G>A;c.2562_2563delAA;c.2566C>T;c.2567G>A;c.2567G>T;c.2571C>G;c.2596T>C;c.2599G>A;c.2599G>T;c.2610T>G;c.2613delG;c.2623C>T;c.2632A>G;c.2650A>T;c.2668G>A;c.2668G>C;c.2708A>G	The complete androgen insensitivity syndrome (CAIS) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the AR gene located on chromosomal region Xq12. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male 46,XY karyotype. There is unresponsiveness to age-appropriate levels of androgens. There is also a partial androgen insensitivity syndrome (PAIS; OMIM 312300) caused by mutations in the AR gene, called Reifenstein syndrome, which results in hypospadias and micropenis with gynecomastia. Note: A specific type of mutation in the AR gene (a CAG repeat expansion) also cause a rare condition known as Spinal and bulbar muscular atrophy or Kennedy disease; this mutation is not tested by this carrier test.	Plus
ARFGEF2	Periventricular heterotopia with microcephaly Periventricular heterotopia with microcephaly Descrição da doença: Periventricular heterotopia with microcephaly is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. Periventricular heterotopia with microcephaly is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with Periventricular heterotopia with microcephaly.	NM_006420.2	c.656dupC;c.1958+1G>A;c.3169C>T c.656dupC;c.1958+1G>A;c.3169C>T	Periventricular heterotopia with microcephaly is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. Periventricular heterotopia with microcephaly is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with Periventricular heterotopia with microcephaly.	Plus
ARG1	Argininemia (arginase deficiency) Argininemia (arginase deficiency) Descrição da doença: Argininemia, also known as arginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARG1 gene located on chromosomal region 6q23. The age of onset is neonatal/infantile. This disease is characterized by variable degrees of hyperammonemia, developing from about 3 years of age, and leading to progressive loss of developmental milestones and spasticity in the absence of treatment. The prevalence is 1:350,000-1:1,000,000.	NM_001244438.1	c.2T>C;c.32T>C;c.57+1G>A;c.58-2A>C;c.61C>T;c.129de c.2T>C;c.32T>C;c.57+1G>A;c.58-2A>C;c.61C>T;c.129delA;c.130+1G>T;c.296dupG;c.389G>A;c.437G>T;c.490-2A>G;c.490-1G>C;c.717delT;c.727G>A;c.727G>C;c.811G>T;c.868delC;c.895C>T	Argininemia, also known as arginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARG1 gene located on chromosomal region 6q23. The age of onset is neonatal/infantile. This disease is characterized by variable degrees of hyperammonemia, developing from about 3 years of age, and leading to progressive loss of developmental milestones and spasticity in the absence of treatment. The prevalence is 1:350,000-1:1,000,000.	Plus
ARHGEF9	Epileptic encephalopathy, early infantile, type 8 Epileptic encephalopathy, early infantile, type 8 Descrição da doença: Epileptic encephalopathy, early infantile, type 8 (EIEE8) is a disorder characterized by hyperekplexia and early infantile epileptic encephalopathy. Neurologic features include exaggerated startle response, seizures, impaired psychomotor development, and mental retardation. Seizures can be provoked by tactile stimulation or extreme emotion.	NM_015185.2;NM_001173479.1	c.901C>T;c.899G>A;c.865C>T;c.561+1G>A;c.4C>T c.901C>T;c.899G>A;c.865C>T;c.561+1G>A;c.4C>T	Epileptic encephalopathy, early infantile, type 8 (EIEE8) is a disorder characterized by hyperekplexia and early infantile epileptic encephalopathy. Neurologic features include exaggerated startle response, seizures, impaired psychomotor development, and mental retardation. Seizures can be provoked by tactile stimulation or extreme emotion.	Plus
ARL13B	Joubert syndrome type 8 Joubert syndrome type 8 Descrição da doença: Joubert syndrome type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL13B gene located on chromosomal region 3q11.1. The age of onset is neonatal/infantile. This disease is characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia and delay in achieving motor milestones. The prevalence is 1/80,000 to 1/100,000.	NM_001174150.1	c.65T>G;c.236G>A;c.246G>A;c.598C>T;c.1252C>T c.65T>G;c.236G>A;c.246G>A;c.598C>T;c.1252C>T	Joubert syndrome type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL13B gene located on chromosomal region 3q11.1. The age of onset is neonatal/infantile. This disease is characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia and delay in achieving motor milestones. The prevalence is 1/80,000 to 1/100,000.	Plus
ARL6	Bardet-Biedl syndrome, type 3 Bardet-Biedl syndrome, type 3 Descrição da doença: Bardet-Biedl syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL6 gene located on chromosomal region 3q11.2. The age of onset is early. A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease.	NM_001323513.1	c.4G>T;c.92C>G;c.92C>T;c.185+1G>C;c.266C>T;c.272T> c.4G>T;c.92C>G;c.92C>T;c.185+1G>C;c.266C>T;c.272T>C;c.281T>C;c.351_353delTATinsGAAAA;c.364C>T;c.506G>C;c.509T>G	Bardet-Biedl syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL6 gene located on chromosomal region 3q11.2. The age of onset is early. A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease.	Plus
ARSA	Metachromatic leukodystrophy Metachromatic leukodystrophy Descrição da doença: Metachromatic leukodystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSA gene located on chromosomal region 22q13.33. The age of onset is variable. This disease is characterized by hypotonia, walking difficulties, optic atrophy and motor regression preceding mental impairment in the late infantile form, arrested intellectual development, followed by motor regression, epileptic seizures and ataxia in the juvenile form, and motor or psychiatric disorders, but with slow progression in the adult form. The incidence is 0.5:5,000-1:50,000 and the prevalence is 1:10,000 -5/10,000.	NM_000487.5	c.1489_1492dupCCCC;c.1492dupC;c.1462C>T;c.1408_141 c.1489_1492dupCCCC;c.1492dupC;c.1462C>T;c.1408_1418delGCAGCTGTGAC;c.1401_1411delGTTAGACGCAG;c.1344dupC;c.1337delG;c.1283C>T;c.1279C>A;c.1274A>G;c.1264delC;c.1241delC;c.1232C>T;c.1210+1G>A;c.1210+1G>T;c.1175G>A;c.1174C>T;c.1150G>A;c.1136C>T;c.1125_1126delCT;c.1114C>T;c.1108-2A>G;c.1107+1delG;c.1036delG;c.1010A>T;c.991G>T;c.986C>T;c.980-2A>C;c.979_979+3delGGTC;c.979+1G>A;c.979G>A;c.960G>A;c.938G>A;c.937C>T;c.931G>A;c.929delG;c.905G>T;c.899T>C;c.891delC;c.890C>A;c.883G>A;c.877C>T;c.869G>A;c.868C>T;c.862A>C;c.854+1G>A;c.854+1G>T;c.827C>T;c.769G>C;c.763G>A;c.758dupT;c.746T>C;c.739G>A;c.737G>A;c.697C>A;c.674_675dupAT;c.641C>T;c.622delC;c.583delT;c.582delC;c.545delC;c.545C>G;c.542dupT;c.542T>G;c.526C>T;c.495_501delGCCGGCC;c.494dupC;c.474C>A;c.470C>G;c.467G>A;c.466-2A>G;c.465+2T>A;c.465+1G>A;c.421C>T;c.418delC;c.418dupC;c.410T>C;c.346C>T;c.304delC;c.302delG;c.302G>A;c.293C>T;c.263G>A;c.257G>A;c.256C>T;c.240dupC;c.229G>C;c.227_228insTA;c.225-2A>G;c.224+1G>A;c.211_212delTG;c.206_209delCTCT;c.195delC;c.185_186dupCA;c.109_116delGACCTGGG;c.98T>C;c.34delG	Metachromatic leukodystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSA gene located on chromosomal region 22q13.33. The age of onset is variable. This disease is characterized by hypotonia, walking difficulties, optic atrophy and motor regression preceding mental impairment in the late infantile form, arrested intellectual development, followed by motor regression, epileptic seizures and ataxia in the juvenile form, and motor or psychiatric disorders, but with slow progression in the adult form. The incidence is 0.5:5,000-1:50,000 and the prevalence is 1:10,000 -5/10,000.	Plus
ARSB	Mucopolysaccharidosis, type 6 (Maroteaux-Lamy syndrome) Mucopolysaccharidosis, type 6 (Maroteaux-Lamy syndrome) Descrição da doença: Mucopolysaccharidosis type 6, also known as Maroteaux-Lamy syndrome, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSB gene located on chromosomal region 5q14.1. The age of onset is infantile. This lysosomal storage disorder resulting from a deficiency of arylsulfatase B is characterized by educed pulmonary function, hepatosplenomegaly, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease and occasionally central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The prevalence is 1:250,000-1:600,000 newborns.	NM_000046.3	c.1577delC;c.1539C>G;c.1507C>T;c.1482delC;c.1475de c.1577delC;c.1539C>G;c.1507C>T;c.1482delC;c.1475delC;c.1438dupG;c.1394C>G;c.1391C>A;c.1366C>T;c.1350G>C;c.1336+2T>G;c.1279delA;c.1261G>T;c.1214G>A;c.1214-2A>G;c.1208delC;c.1208C>G;c.1197C>G;c.1178A>C;c.1161dupC;c.1143-1G>C;c.1143-8T>G;c.1142+2T>A;c.1142+2T>C;c.1142+1G>T;c.1130G>A;c.1059G>A;c.1036delG;c.979C>T;c.971G>T;c.966G>A;c.944G>A;c.943C>T;c.937C>G;c.936G>T;c.921delA;c.883_884dupTT;c.785dupA;c.765T>A;c.750_754delATACTinsCCTGAAGTCAAG;c.753C>G;c.743delC;c.659_660delTA;c.630_636delTTCAACA;c.629A>G;c.589C>T;c.574T>C;c.571C>T;c.533A>T;c.532C>G;c.498delT;c.479G>A;c.478C>T;c.454C>T;c.438G>A;c.430G>A;c.427delG;c.375dupT;c.349T>C;c.328C>T;c.253T>C;c.245delT;c.245T>G;c.237_243delGGTGCTC;c.238delG;c.208_215delCCGCACCT;c.215T>G;c.207_213dupGCCGCAC;c.116_123delCCGGGGCC	Mucopolysaccharidosis type 6, also known as Maroteaux-Lamy syndrome, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSB gene located on chromosomal region 5q14.1. The age of onset is infantile. This lysosomal storage disorder resulting from a deficiency of arylsulfatase B is characterized by educed pulmonary function, hepatosplenomegaly, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease and occasionally central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The prevalence is 1:250,000-1:600,000 newborns.	Plus
ARSE	Chondrodysplasia punctata, brachytelephalangic Chondrodysplasia punctata, brachytelephalangic Descrição da doença: X-linked chondrodysplasia punctata, brachytelephalangic follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ARSE gene located on chromosomal region Xp22.33. The age of onset is neonatal. This is a disorder of cartilage and bone development that occurs almost exclusively in males. Include short stature and unusually short fingertips and ends of the toes. This condition is also associated with distinctive facial features, particularly a flattened-appearing nose with crescent-shaped nostrils and a flat nasal bridge. People with X-linked chondrodysplasia punctata 1 typically have normal intelligence and a normal life expectancy. However, some affected individuals have had serious or life-threatening complications including abnormal thickening (stenosis) of the cartilage that makes up the airways, which restricts breathing. Also, abnormalities of spinal bones in the neck can lead to pinching (compression) of the spinal cord, which can cause pain, numbness, and weakness. Other, less common features of X-linked chondrodysplasia punctata 1 include delayed development, hearing loss, vision abnormalities, and heart defects. The prevalence is 1:500,000.	NM_001282628.1	c.1818G>A;c.1807C>T;c.1550G>A;c.1517C>T;c.1504delG c.1818G>A;c.1807C>T;c.1550G>A;c.1517C>T;c.1504delG;c.1462G>A;c.1375G>A;c.485G>T;c.424G>A;c.407G>A;c.407G>C;c.194T>G;c.99-1G>A	X-linked chondrodysplasia punctata, brachytelephalangic follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ARSE gene located on chromosomal region Xp22.33. The age of onset is neonatal. This is a disorder of cartilage and bone development that occurs almost exclusively in males. Include short stature and unusually short fingertips and ends of the toes. This condition is also associated with distinctive facial features, particularly a flattened-appearing nose with crescent-shaped nostrils and a flat nasal bridge. People with X-linked chondrodysplasia punctata 1 typically have normal intelligence and a normal life expectancy. However, some affected individuals have had serious or life-threatening complications including abnormal thickening (stenosis) of the cartilage that makes up the airways, which restricts breathing. Also, abnormalities of spinal bones in the neck can lead to pinching (compression) of the spinal cord, which can cause pain, numbness, and weakness. Other, less common features of X-linked chondrodysplasia punctata 1 include delayed development, hearing loss, vision abnormalities, and heart defects. The prevalence is 1:500,000.	Plus
ARX	Epileptic encephalopathy, early infantile, type 1; ARX-related developmental disorders Epileptic encephalopathy, early infantile, type 1; ARX-related developmental disorders Descrição da doença: Early infantile epileptic encephalopathy type 1 (EIEE1) follows an X-linked recessive pattern of inheritance and is caused by pathogenic variants in the ARX gene located on chromosomal region Xp21.3. The age of onset is early. This severe disease is characterized by the onset of tonic spasms within the first 3 months of life leading to psychomotor impairment and death. Particularly,it is characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, with high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of EIEE patients progress to 'West syndrome,' which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). EIEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1) to syndromic (Partington syndrome; 309510) and nonsyndromic (Mental retardation, X-linked type 29; 300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). The prevalence is <1:1,000,000.	NM_139058.2	c.1604T>A;c.1593_1599dupCATAGCC;c.1579_1582delAGAC c.1604T>A;c.1593_1599dupCATAGCC;c.1579_1582delAGAC;c.1414C>T;c.1372delG;c.1337dupC;c.1117C>T;c.1111C>T;c.1105G>T;c.1096delG;c.1058C>T;c.1028T>A;c.1002_1007delGTTCACinsTGTACCA;c.998C>A;c.998C>G;c.995G>A;c.995G>T;c.980_983delAACA;c.922G>T;c.790delC;c.617delG;c.81C>G;c.34G>T;c.30C>A	Early infantile epileptic encephalopathy type 1 (EIEE1) follows an X-linked recessive pattern of inheritance and is caused by pathogenic variants in the ARX gene located on chromosomal region Xp21.3. The age of onset is early. This severe disease is characterized by the onset of tonic spasms within the first 3 months of life leading to psychomotor impairment and death. Particularly,it is characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, with high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of EIEE patients progress to 'West syndrome,' which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). EIEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1) to syndromic (Partington syndrome; 309510) and nonsyndromic (Mental retardation, X-linked type 29; 300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). The prevalence is <1:1,000,000.	Plus
ASAH1	Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsy Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsy Descrição da doença: Farber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (Alves et al., 2013). Biallelic mutation in the ASAH1 gene can also cause spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME). Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (Zhou et al., 2012).	NM_004315.5	c.1006A>G;c.898G>T;c.713C>A;c.696+1G>C;c.592C>G;c. c.1006A>G;c.898G>T;c.713C>A;c.696+1G>C;c.592C>G;c.553T>C;c.461A>T;c.173C>T;c.155A>G	Farber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (Alves et al., 2013). Biallelic mutation in the ASAH1 gene can also cause spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME). Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (Zhou et al., 2012).	Plus
ASL	Argininosuccinic aciduria Argininosuccinic aciduria Descrição da doença: Argininosuccinic aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASL gene located on chromosomal region 7q11.21. The age of onset is infantile. This disease is characterized by severe hyperammonemic coma, hypotonia, growth failure, anorexia and chronic vomiting or behavioral disorders during childhood, and hyperammonemic coma or behavioral disorders that simulate psychiatric disorders later in life. The prevalence is 1:70,000 newborns.	NM_000048.3	c.13-1G>C;c.35G>A;c.175G>A;c.257A>C;c.283C>T;c.291 c.13-1G>C;c.35G>A;c.175G>A;c.257A>C;c.283C>T;c.291+1G>T;c.292delG;c.292G>T;c.299T>C;c.337C>T;c.346C>T;c.446+1G>A;c.446+2T>C;c.447-1G>A;c.461T>C;c.524+2T>G;c.525-2A>T;c.532G>A;c.539T>G;c.544C>T;c.545G>A;c.575_580dupAGCGGA;c.578G>A;c.602+1G>A;c.637C>T;c.649C>T;c.735G>A;c.762C>A;c.765dupG;c.857A>G;c.889C>T;c.918+5G>A;c.973_976delTTAC;c.978G>C;c.1045_1057delGTCATCTCTACGC;c.1060C>T;c.1122dupC;c.1135C>T;c.1144-2A>G;c.1153C>T;c.1249_1250+12delAGGTACGGCCCATC;c.1255_1256delCT;c.1360C>T;c.1369dupG	Argininosuccinic aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASL gene located on chromosomal region 7q11.21. The age of onset is infantile. This disease is characterized by severe hyperammonemic coma, hypotonia, growth failure, anorexia and chronic vomiting or behavioral disorders during childhood, and hyperammonemic coma or behavioral disorders that simulate psychiatric disorders later in life. The prevalence is 1:70,000 newborns.	Plus
ASNS	Asparagine synthetase deficiency Asparagine synthetase deficiency Descrição da doença: Asparagine synthetase deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (Ruzzo et al., 2013).	NM_001673.4	c.1648C>T;c.1192dupT;c.1030+1G>A;c.601delA;c.187C> c.1648C>T;c.1192dupT;c.1030+1G>A;c.601delA;c.187C>T;c.146G>A;c.17C>A	Asparagine synthetase deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (Ruzzo et al., 2013).	Plus
ASPA	Canavan disease Canavan disease Descrição da doença: Canavan disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPA gene located on chromosomal region 17p13.3. The age of onset is neonatal/infantile. This disease is characterized by a variable spectrum between severe forms with leukodystrophy, macrocephaly and severe developmental delay, and a very rare mild/juvenile form characterized by mild developmental delay. The prevalence is 1:6,400- 1:13,500 in Askenazis Jewis.	NM_000049.2	c.2T>C;c.32delT;c.79G>A;c.212G>A;c.236+1G>A;c.237- c.2T>C;c.32delT;c.79G>A;c.212G>A;c.236+1G>A;c.237-2A>T;c.237-1G>A;c.237-1G>T;c.244dupA;c.244_245delAT;c.245delT;c.340G>T;c.382delC;c.433-2A>G;c.514_515dupAA;c.527-2A>C;c.631G>T;c.634+1G>T;c.640G>T;c.650_651delCC;c.654C>A;c.679_682delGAGA;c.697delC;c.693C>A;c.770C>G;c.827_828delGT;c.854A>C;c.859G>A;c.876_879delAGAA;c.914C>A;c.924delT	Canavan disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPA gene located on chromosomal region 17p13.3. The age of onset is neonatal/infantile. This disease is characterized by a variable spectrum between severe forms with leukodystrophy, macrocephaly and severe developmental delay, and a very rare mild/juvenile form characterized by mild developmental delay. The prevalence is 1:6,400- 1:13,500 in Askenazis Jewis.	Plus
ASPM	Primary microcephaly type 5, autosomal recessive Primary microcephaly type 5, autosomal recessive Descrição da doença: Primary autosomal recessive microcephaly type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPM gene located on chromosomal region 1q31. The age of onset is neonatal/infantile. This disease is characterized by a reduction in head circumference at birth, mild to moderate non-progressive intellectual impairment and delay in early motor milestones, speech delay and hyperactive behavior are common. The annual incidence is 1:1,000,000.	NM_018136.4	c.10168C>T;c.10060C>T;c.10059C>A;c.9984+1G>T;c.996 c.10168C>T;c.10060C>T;c.10059C>A;c.9984+1G>T;c.9961C>T;c.9910C>T;c.9841A>T;c.9789T>A;c.9754delA;c.9747_9748delCT;c.9730C>T;c.9697C>T;c.9686_9690delTTAAA;c.9685delA;c.9677dupG;c.9595A>T;c.9557C>G;c.9507delG;c.9492T>G;c.9454C>T;c.9337delG;c.9319C>T;c.9309_9310delAG;c.9238A>T;c.9190C>T;c.9178C>T;c.8988-1G>C;c.8987+1G>A;c.8903G>A;c.8844delC;c.8829G>A;c.8711_8712delAA;c.8704C>T;c.8668C>T;c.8599delC;c.8508_8509delGA;c.8506_8507delCA;c.8378delT;c.8273T>A;c.8266C>T;c.8230dupA;c.8191_8192delGA;c.8133_8136delGAAA;c.8131_8132delAA;c.8124T>G;c.8043dupA;c.8017C>T;c.7894C>T;c.7860_7861delGA;c.7857dupA;c.7825C>T;c.7783_7786delAAAG;c.7782_7783delGA;c.7761T>G;c.7665delA;c.7612C>T;c.7573_7574delGA;c.7491_7495delTATTA;c.7324C>T;c.7308dupT;c.7296dupA;c.7160_7161delCT;c.7125_7128dupACTG;c.6916_6919delTTAC;c.6852_6855delTCTC;c.6732delA;c.6651_6654delAACA;c.6568C>T;c.6337_6338delAT;c.6232C>T;c.6189T>G;c.6183_6184delGA;c.6082C>T;c.6073delG;c.5681_5685delTTAGA;c.5532T>G;c.5467C>T;c.5439_5440delAG;c.5233C>T;c.5196T>A;c.5149delA;c.5136C>A;c.5101_5102insG;c.5064delT;c.4858_4859delAT;c.4795C>T;c.4732C>T;c.4728_4729delAG;c.4720C>T;c.4583delA;c.4422G>A;c.4363G>T;c.4195dupA;c.4074G>A;c.3979C>T;c.3978G>A;c.3960_3961insA;c.3945_3946delAG;c.3853_3854delGA;c.3830G>A;c.3811C>T;c.3796G>T;c.3741+1G>A;c.3710C>G;c.3663delG;c.3527C>G;c.3506_3507delTG;c.3477_3481delCGCTA;c.3428dupT;c.3327T>G;c.3188T>G;c.3082+1G>C;c.3082G>A;c.3055C>T;c.2968delG;c.2967G>A;c.2938C>T;c.2936dupT;c.2922T>A;c.2791C>T;c.2770G>T;c.2488-1G>C;c.2419+2T>C;c.2409G>A;c.2389C>T;c.2120T>A;c.2085G>A;c.1990C>T;c.1959_1962delCAAA;c.1729_1730delAG;c.1726_1729delAAGA;c.1726_1727delAA;c.1674T>A;c.1671_1672delTT;c.1631_1635delATCTT;c.1590delA;c.1406_1413delATCCTAAA;c.1366G>T;c.1353dupT;c.1260_1266delTCAAGTC;c.1154_1155delAG;c.1138C>T;c.1002delA;c.803_804delAA;c.719_720delCT;c.637delA;c.577C>T;c.440delA;c.349C>T;c.297+1G>C;c.117_118delGT;c.77delG	Primary autosomal recessive microcephaly type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPM gene located on chromosomal region 1q31. The age of onset is neonatal/infantile. This disease is characterized by a reduction in head circumference at birth, mild to moderate non-progressive intellectual impairment and delay in early motor milestones, speech delay and hyperactive behavior are common. The annual incidence is 1:1,000,000.	Plus
ASS1	Citrullinemia, type 1 Citrullinemia, type 1 Descrição da doença: Citrullinemia, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASS1 gene located on chromosomal region 9q34.1. The age of onset is variable. This disease is characterized by hyperammonemia, progressive lethargy, poor feeding and vomiting in the neonatal form and by variable hyperammonemia in the later-onset form. The prevalence is 1:100,000-9:100,000.	NM_000050.4	c.-4C>T;c.40G>A;c.175-1G>A;c.226delG;c.256C>T;c.25 c.-4C>T;c.40G>A;c.175-1G>A;c.226delG;c.256C>T;c.257G>A;c.291C>A;c.349G>A;c.412C>T;c.420+1G>A;c.421-2A>G;c.450_451delCT;c.470G>A;c.496-2A>G;c.535T>C;c.539G>A;c.566+1G>T;c.567-1G>T;c.571G>A;c.688+1_688+5delGTATG;c.689G>C;c.773+1G>A;c.787G>A;c.793C>T;c.794G>A;c.805G>A;c.814C>T;c.823G>T;c.835C>T;c.836G>A;c.838+1G>T;c.847G>A;c.851C>T;c.892delG;c.910C>T;c.919C>T;c.931C>T;c.951delT;c.970G>A;c.970+1G>A;c.971-1G>A;c.978delG;c.1030C>T;c.1064delA;c.1069C>T;c.1085G>T;c.1087C>T;c.1088G>A;c.1127+1G>A;c.1138C>T;c.1139delA;c.1168G>A;c.1194-1G>C	Citrullinemia, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASS1 gene located on chromosomal region 9q34.1. The age of onset is variable. This disease is characterized by hyperammonemia, progressive lethargy, poor feeding and vomiting in the neonatal form and by variable hyperammonemia in the later-onset form. The prevalence is 1:100,000-9:100,000.	Plus
ATF6	Achromatopsia 7 Achromatopsia 7 Descrição da doença: Achromatopsia 7 is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (Kohl et al., 2015).	NM_007348.3	c.353delC;c.355dupG;c.417dupT;c.797dupC;c.1110dupA c.353delC;c.355dupG;c.417dupT;c.797dupC;c.1110dupA;c.1533+1G>C	Achromatopsia 7 is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (Kohl et al., 2015).	Plus
ATIC	AICA-ribosiduria due to ATIC deficiency AICA-ribosiduria due to ATIC deficiency Descrição da doença: AICA-ribosiduria due to ATIC deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATIC gene located on chromosomal region 2q35. The age of onset is neonatal/infantile. This disease is characterized by profound intellectual deficit, epilepsy, dysmorphic features of the knees, elbows, and shoulders and congenital blindness. The prevalence is <1:1,000,000.	NM_004044.6	c.1277A>G c.1277A>G	AICA-ribosiduria due to ATIC deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATIC gene located on chromosomal region 2q35. The age of onset is neonatal/infantile. This disease is characterized by profound intellectual deficit, epilepsy, dysmorphic features of the knees, elbows, and shoulders and congenital blindness. The prevalence is <1:1,000,000.	Plus
ATM	Ataxia-telangiectasia Ataxia-telangiectasia Descrição da doença: Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.	NM_000051.3	c.1A>G;c.2T>C;c.3G>A;c.8delT;c.15dupT;c.43delC;c.6 c.1A>G;c.2T>C;c.3G>A;c.8delT;c.15dupT;c.43delC;c.67C>T;c.72+1G>A;c.73-1G>A;c.103C>T;c.119_122delTTAA;c.138_141delTTCA;c.140C>G;c.151C>T;c.154G>T;c.157A>T;c.170G>A;c.185+1G>A;c.205C>T;c.217_218delGA;c.237delA;c.283C>T;c.289delA;c.299T>A;c.331+1G>A;c.331+2T>G;c.331+5G>A;c.364_368delAATTA;c.362T>A;c.368delA;c.378delT;c.381delA;c.387delA;c.392C>A;c.392C>G;c.432dupA;c.450_453delTTCT;c.471T>A;c.478_482delTCTCA;c.484C>T;c.496G>T;c.496+1G>A;c.496+5G>A;c.497-1G>C;c.513C>G;c.538C>T;c.549_550delTA;c.557T>G;c.561_562delGGinsT;c.564delT;c.588delA;c.597T>A;c.601C>T;c.606_609delTGAC;c.640delT;c.642delC;c.652C>T;c.662+1G>A;c.663-2A>G;c.664C>T;c.680delC;c.680C>G;c.689delA;c.710delC;c.717_720delCCTC;c.741dupT;c.742C>T;c.748C>T;c.756_757delTG;c.785T>A;c.790delT;c.802C>T;c.824delT;c.829G>T;c.850C>T;c.875C>T;c.877A>T;c.967A>G;c.977_978delTA;c.992delA;c.1003G>T;c.1017delT;c.1027_1030delGAAA;c.1053dupT;c.1058_1059delGT;c.1063C>T;c.1065+1G>C;c.1065+1G>T;c.1066-1G>A;c.1066-1G>T;c.1093G>T;c.1109dupA;c.1110C>G;c.1120C>T;c.1126_1127delGA;c.1126G>T;c.1139_1142dupACAG;c.1158delG;c.1179_1180delGG;c.1178G>A;c.1192delG;c.1208C>A;c.1212_1213delGA;c.1215delT;c.1221dupT;c.1235+1delG;c.1235G>A;c.1235+1G>A;c.1285_1288delAACT;c.1284_1291delTAACTGTG;c.1290_1291delTG;c.1305delA;c.1329delA;c.1333delC;c.1339C>T;c.1348delG;c.1348G>T;c.1355delC;c.1368dupA;c.1369C>T;c.1394_1395delGT;c.1396C>T;c.1402_1403delAA;c.1424C>G;c.1435_1436delGA;c.1439_1448delTATTAAAACT;c.1442T>G;c.1446delA;c.1463G>A;c.1495C>T;c.1501C>T;c.1514_1515delTT;c.1524delT;c.1537C>T;c.1547T>A;c.1547T>C;c.1547T>G;c.1564_1565delGA;c.1573A>T;c.1597_1600dupAGAC;c.1607+1G>T;c.1608-1G>A;c.1608-1G>C;c.1655delC;c.1658delG;c.1660delA;c.1692T>A;c.1697_1706delTAAATAGAAG;c.1737G>A;c.1740_1741delCT;c.1741_1742delTT;c.1753_1756delTTAG;c.1768G>T;c.1856delA;c.1880dupT;c.1898+1G>A;c.1898+1G>T;c.1898+2T>G;c.1899-1G>A;c.1915_1916insT;c.1920_1923delAGAA;c.1918A>T;c.1924G>T;c.1931C>A;c.1939G>T;c.1960C>T;c.2023C>T;c.2050C>T;c.2080_2081delCT;c.2098C>T;c.2113delT;c.2115C>G;c.2119_2123delTCTGA;c.2124+1G>T;c.2125-2A>C;c.2125-1G>A;c.2125delA;c.2129delC;c.2135C>G;c.2165dupT;c.2167_2173delGTGGGTG;c.2193C>A;c.2250+1G>A;c.2250+2T>C;c.2251-10T>G;c.2251-1G>C;c.2272G>T;c.2284_2285delCT;c.2286_2287delGT;c.2295delT;c.2308G>T;c.2376+1G>A;c.2376+1G>C;c.2376+1G>T;c.2377-2A>G;c.2413C>T;c.2426C>A;c.2465T>A;c.2466+1delG;c.2466+1G>A;c.2466+2T>A;c.2466+2T>G;c.2467-2A>C;c.2467-2A>T;c.2467-1G>A;c.2483delA;c.2494dupC;c.2497G>T;c.2500G>T;c.2502dupA;c.2521delG;c.2542G>T;c.2548G>T;c.2554C>T;c.2564dupT;c.2572_2575delTTTA;c.2583C>A;c.2606_2607delCA;c.2620G>T;c.2638+1delG;c.2638+2T>C;c.2654_2656delTAGinsAA;c.2654T>G;c.2662G>T;c.2672C>G;c.2677C>T;c.2693T>G;c.2720_2723delGTGT;c.2727delT;c.2730_2731insAG;c.2734C>T;c.2754delT;c.2775delG;c.2789T>G;c.2806_2809dupCTAG;c.2838+1G>T;c.2839-3_2839delTAGTinsGATACTA;c.2839-2A>G;c.2849T>G;c.2880delC;c.2877C>G;c.2882delT;c.2897_2899delTTCinsGCCAA;c.2902G>T;c.2912_2916delAACCA;c.2921+1G>A;c.2921+1G>C;c.2921+1G>T;c.2922-1G>T;c.2965delA;c.2985_2988delTCAT;c.2999dupA;c.3025G>T;c.3038dupA;c.3043C>T;c.3049C>T;c.3068delG;c.3077G>A;c.3077+1G>A;c.3078-1G>A;c.3078G>A;c.3085dupA;c.3102T>G;c.3154-2A>G;c.3154-1G>A;c.3167C>A;c.3206delC;c.3214G>T;c.3218dupT;c.3231dupT;c.3242_3245delATCA;c.3245_3247delATCinsTGAT;c.3252_3259delAGTTCGCA;c.3279_3282delCAAT;c.3279_3280insT;c.3284G>A;c.3284+1G>A;c.3284+1G>C;c.3292delC;c.3304G>T;c.3315dupC;c.3320_3323delTACT;c.3320T>A;c.3335dupC;c.3340A>T;c.3351_3354delAACA;c.3349C>T;c.3369delA;c.3372C>G;c.3381_3384delTCAG;c.3382C>T;c.3388G>T;c.3402+2T>C;c.3403-1G>A;c.3435_3436delTGinsA;c.3436G>T;c.3450_3454delAAAAT;c.3451A>T;c.3510dupA;c.3511C>T;c.3526delC;c.3532A>T;c.3539_3540delTG;c.3541A>T;c.3576G>A;c.3576+1G>A;c.3576+1G>T;c.3577-1G>C;c.3602_3603delTT;c.3603delT;c.3617_3621delTAGAAinsG;c.3619G>T;c.3626_3627delTT;c.3627delT;c.3631delG;c.3663G>A;c.3673C>T;c.3693_3697delATCTT;c.3704delC;c.3712_3716delTTATT;c.3747-2A>G;c.3747-1G>A;c.3747-1G>C;c.3754_3756delTATinsCA;c.3756T>A;c.3760delG;c.3780dupG;c.3802delG;c.3836G>A;c.3841delA;c.3848T>C;c.3850delA;c.3852delA;c.3865A>T;c.3880dupA;c.3894dupT;c.3895delG;c.3931C>T;c.3939_3940delGA;c.3935dupG;c.3980T>G;c.3990delA;c.3993+1G>A;c.3993+1G>T;c.3994-2A>C;c.3994-2A>G;c.3994-1G>T;c.4019_4029delTACCAGAGATT;c.4036G>T;c.4052delT;c.4052T>A;c.4081C>T;c.4084_4085delAG;c.4098_4099delTG;c.4104_4105delTT;c.4106C>A;c.4109+1G>T;c.4110-1G>A;c.4143dupT;c.4148C>A;c.4198A>T;c.4227delC;c.4236+1G>T;c.4246C>T;c.4303A>T;c.4318A>T;c.4330_4333delCTGTinsTAAAATAAA;c.4332_4337delGTTTGTinsTAAAA;c.4344dupA;c.4358_4359delTA;c.4359_4363delAAAAA;c.4370T>G;c.4373delG;c.4394T>C;c.4396C>T;c.4405delA;c.4415T>A;c.4416delG;c.4436+1G>T;c.4436+2T>C;c.4437-1G>A;c.4437-1G>C;c.4451delT;c.4493T>G;c.4507C>T;c.4587T>G;c.4588G>T;c.4609C>T;c.4611+1G>A;c.4612-2A>C;c.4612-1G>A;c.4625dupT;c.4632_4635delCTTA;c.4642_4645delGATA;c.4661delA;c.4664delT;c.4683_4689delTTTAGAT;c.4695delT;c.4732C>T;c.4735C>T;c.4741dupA;c.4774G>T;c.4776+1G>T;c.4776+2T>A;c.4776+2T>C;c.4800_4803delAAGT;c.4804_4805delGT;c.4844delA;c.4842_4843insCT;c.4852C>T;c.4879C>T;c.4906C>T;c.4909+1G>A;c.4909+1G>T;c.4910-2A>T;c.4910-1G>T;c.4938delA;c.4957C>T;c.5005+1G>T;c.5065C>T;c.5178-1G>A;c.5188C>T;c.5192C>G;c.5201_5202insAT;c.5203dupA;c.5209_5210delTT;c.5249G>A;c.5290delC;c.5309C>G;c.5318delA;c.5319+1G>A;c.5319+1G>T;c.5319+2T>C;c.5320-4_5323delCTAGTTTT;c.5320-5_5320-2delTCTA;c.5326G>T;c.5351delA;c.5396delG;c.5405dupA;c.5414G>A;c.5416delA;c.5433T>A;c.5441dupT;c.5443delG;c.5460dupA;c.5496+1G>A;c.5496+1G>T;c.5497-2A>C;c.5497-2A>G;c.5497-1G>A;c.5515C>T;c.5516dupA;c.5549delT;c.5549T>A;c.5554dupC;c.5554C>T;c.5573G>A;c.5623C>T;c.5631_5635delCTCGCinsA;c.5644C>T;c.5653dupA;c.5681_5682delAG;c.5692C>T;c.5697C>A;c.5712dupA;c.5762+1G>A;c.5762+1G>T;c.5763-2A>C;c.5763-2A>G;c.5763-2A>T;c.5765delC;c.5771C>A;c.5784dupT;c.5791delGinsCCT;c.5798G>A;c.5870_5871delAT;c.5893_5897delAAAAG;c.5890A>T;c.5894_5900dupAAAGTAT;c.5908C>T;c.5910delA;c.5919-2A>C;c.5919-2A>G;c.5932G>T;c.5935G>T;c.5944C>T;c.5948dupA;c.5959dupT;c.5971G>T;c.5979_5983delTAAAG;c.5982delA;c.6002T>G;c.6015dupC;c.6027C>G;c.6040G>T;c.6047A>G;c.6049dupA;c.6059delG;c.6080delT;c.6082C>T;c.6095G>A;c.6095+1G>A;c.6095+2T>C;c.6096-2A>G;c.6100C>T;c.6115G>A;c.6115G>T;c.6133delG;c.6154G>A;c.6181C>T;c.6198+1G>A;c.6198+2T>C;c.6199-2A>T;c.6200C>A;c.6222C>A;c.6228delT;c.6239_6240delAT;c.6238T>G;c.6272G>A;c.6289G>T;c.6311G>A;c.6312G>A;c.6326G>A;c.6327G>A;c.6347+1G>A;c.6348-2A>G;c.6348-1G>A;c.6373delC;c.6397C>T;c.6403_6404insCT;c.6404_6405insTT;c.6404dupT;c.6415_6416delGA;c.6433_6445delGAAAGTCTCAAAT;c.6435_6436delAA;c.6436dupA;c.6444dupA;c.6452+1G>T;c.6453-1G>C;c.6482_6483dupGC;c.6490G>T;c.6498_6499delGT;c.6572+1G>A;c.6573-2A>G;c.6586A>T;c.6615G>A;c.6628delC;c.6650_6657delTTAGTTTT;c.6657delT;c.6658C>T;c.6667delA;c.6673dupG;c.6679C>T;c.6725delC;c.6729_6730delAA;c.6752_6755dupTCAC;c.6754delA;c.6776_6777delCT;c.6850delG;c.6866_6867delCT;c.6867dupT;c.6908dupA;c.6913C>T;c.6916_6917delAG;c.6920_6923delTTGC;c.6975+1G>T;c.6976-2A>C;c.6976-2A>G;c.7000_7003delTACA;c.6997dupA;c.7010_7011delGT;c.7032G>A;c.7088delA;c.7089+1G>A;c.7089+1G>T;c.7089+2T>G;c.7091delC;c.7096G>T;c.7141_7151delAATGGAAAAAT;c.7166C>G;c.7181C>T;c.7189C>T;c.7220C>A;c.7240C>T;c.7262_7263delAA;c.7271T>G;c.7279_7284delCTTAGG;c.7293_7294delAA;c.7299_7302delGACA;c.7408T>G;c.7449G>A;c.7456C>T;c.7465_7466delTC;c.7517_7520delGAGA;c.7542T>G;c.7563C>G;c.7570G>C;c.7629_7629+4delTGTAA;c.7629+1G>A;c.7629+2T>C;c.7630-2A>C;c.7630-2A>G;c.7638_7646delTAGAATTTC;c.7665delCinsGTGA;c.7671_7674delGTTT;c.7699_7702delAACA;c.7701_7702delCA;c.7705_7706delGA;c.7708G>T;c.7767delA;c.7768C>T;c.7777C>T;c.7788+1G>T;c.7789-3T>G;c.7792C>T;c.7796delC;c.7838_7839dupGA;c.7875_7876delTGinsGC;c.7880delA;c.7913G>A;c.7921C>T;c.7926A>C;c.7927+1G>C;c.7928-2A>G;c.7928-2A>T;c.7928-1G>A;c.7929delA;c.7951C>T;c.7967T>C;c.7985T>A;c.7988_7991delTTGT;c.7998dupT;c.8010+1delG;c.8011-1G>C;c.8011-1G>T;c.8048_8049delTA;c.8098A>T;c.8103_8104delAA;c.8122G>A;c.8140C>T;c.8146G>T;c.8147T>C;c.8149A>T;c.8152-2A>G;c.8152-1G>A;c.8185C>T;c.8204_8205dupGT;c.8206_8207dupAA;c.8213T>G;c.8218C>T;c.8251_8254delACTA;c.8264_8268delATAAG;c.8265T>G;c.8266A>T;c.8268+1G>T;c.8283_8284delTC;c.8287C>T;c.8288delG;c.8292_8293delTG;c.8293G>A;c.8305_8317delTGGTGCACAGGAA;c.8307G>A;c.8319_8323dupTGTCC;c.8321_8322delTCinsA;c.8325delC;c.8367delAinsTT;c.8371_8374delTACA;c.8373C>A;c.8395_8404delTTTCAGTGCC;c.8397delT;c.8403C>A;c.8418+5_8418+8delGTGA;c.8418+1G>A;c.8418+2T>C;c.8419-2A>G;c.8419-1G>C;c.8419G>T;c.8432delA;c.8432dupA;c.8431A>T;c.8435_8436delCT;c.8440delG;c.8473C>T;c.8476_8477dupAA;c.8480T>G;c.8484delA;c.8494C>T;c.8495G>C;c.8505C>A;c.8514dupA;c.8535G>A;c.8545C>T;c.8546G>C;c.8549T>A;c.8564delG;c.8565_8566delTGinsAA;c.8584+1G>A;c.8584+2T>C;c.8624dupA;c.8641C>T;c.8655dupT;c.8671+1G>T;c.8671+2T>C;c.8672-1G>C;c.8672-1G>T;c.8711A>G;c.8725A>T;c.8737G>T;c.8766dupT;c.8786+1G>A;c.8786+1G>C;c.8786+1G>T;c.8786+2T>A;c.8793T>A;c.8802delC;c.8814_8824delGAGAAACTCTC;c.8818_8821dupAACT;c.8823_8824delTC;c.8833_8834delCT;c.8835_8836delGT;c.8850+1G>A;c.8850+2T>C;c.8851-2A>G;c.8851-1G>T;c.8873_8874delTT;c.8876_8879delACTG;c.8879G>A;c.8880G>A;c.8903T>A;c.8911C>T;c.8942delA;c.8977C>T;c.8987+1G>C;c.8988-2A>C;c.8988-2A>G;c.8988-1G>A;c.8988-1G>C;c.8998C>T;c.9001_9002delAG;c.9019G>T;c.9021dupA;c.9022C>T;c.9023G>A;c.9047_9057delAACTGAAAGGA;c.9064dupG	Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.	Plus
ATOH7	Persistent hyperplastic primary vitreous, autosomal recessive Persistent hyperplastic primary vitreous, autosomal recessive Descrição da doença: Persistent hyperplastic primary vitreous (PHPV), also termed 'persistent fetal vasculature,' is a developmental malformation of the eye in which the primary vitreous fails to regress in utero, resulting in the presence of a retrolental fibrovascular membrane with persistence of the posterior portion of the tunica vasculosa lentis and hyaloid artery. This abnormality is usually unilateral and associated with microphthalmia, cataract, glaucoma, and congenital retinal nonattachment (Haddad et al., 1978; Khaliq et al., 2001; Prasov et al., 2012).PHPV shares phenotypic overlap with Norrie disease (310600).	NM_145178.3	c.146A>T c.146A>T	Persistent hyperplastic primary vitreous (PHPV), also termed 'persistent fetal vasculature,' is a developmental malformation of the eye in which the primary vitreous fails to regress in utero, resulting in the presence of a retrolental fibrovascular membrane with persistence of the posterior portion of the tunica vasculosa lentis and hyaloid artery. This abnormality is usually unilateral and associated with microphthalmia, cataract, glaucoma, and congenital retinal nonattachment (Haddad et al., 1978; Khaliq et al., 2001; Prasov et al., 2012).PHPV shares phenotypic overlap with Norrie disease (310600).	Plus
ATP13A2	Kufor-Rakeb syndrome; Spastic paraplegia, type 78, autosomal recessive Kufor-Rakeb syndrome; Spastic paraplegia, type 78, autosomal recessive Descrição da doença: Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; 234200) (Bruggemann et al., 2010). Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia, type 78, an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (Estrada-Cuzcano et al., 2017).	NM_022089.3	c.3418C>T;c.3057delC;c.2629G>A;c.2552_2553delTT;c. c.3418C>T;c.3057delC;c.2629G>A;c.2552_2553delTT;c.2455C>T;c.1903C>T;c.1550C>T;c.1459C>T;c.1345C>T;c.1101_1102dupGA;c.364C>T;c.212G>A	Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; 234200) (Bruggemann et al., 2010). Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia, type 78, an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (Estrada-Cuzcano et al., 2017).	Plus
ATP2A1	Brody myopathy Brody myopathy Descrição da doença: Brody myopathy, a disorder of fast-twitch skeletal muscle function, is characterized by exercise-induced impairment of skeletal muscle relaxation, stiffening, and cramps, predominantly in the arms, legs, and eyelids (Odermatt et al., 2000).	NM_173201.3	c.100G>T;c.325-2A>T;c.592C>T;c.1184+1G>A;c.1742_17 c.100G>T;c.325-2A>T;c.592C>T;c.1184+1G>A;c.1742_1743delCT;c.2025C>A;c.2366C>T;c.2464dupC;c.2758C>T;c.2862+1G>A	Brody myopathy, a disorder of fast-twitch skeletal muscle function, is characterized by exercise-induced impairment of skeletal muscle relaxation, stiffening, and cramps, predominantly in the arms, legs, and eyelids (Odermatt et al., 2000).	Plus
ATP6V0A2	Cutis laxa, autosomal recessive, type 2A; Wrinkly skin syndrome Cutis laxa, autosomal recessive, type 2A; Wrinkly skin syndrome Descrição da doença: Autosomal recessive cutis laxa type 2 (ARCL2) represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type 2), and ARCL2B, those without a metabolic disorder (Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. Mutation in the ATP6V0A2 gen can also cause wrinkly skin syndrome (WWS). WSS is characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple skeletal abnormalities (joint laxity and congenital hip dislocation), late closing of the anterior fontanel, microcephaly, pre- and postnatal growth retardation, developmental delay and facial dysmorphism (a broad nasal bridge, downslanting palpebral fissures and hypertelorism). The occurrence of mutations in the same gene in WSS indicates that ARCL2 and some cases of WSS represent variable manifestations of the same genetic defect.	NM_012463.3	c.78dupC;c.187C>T;c.294+1G>A;c.304C>T;c.353_354del c.78dupC;c.187C>T;c.294+1G>A;c.304C>T;c.353_354delTG;c.732-2A>G;c.825+2T>C;c.840delC;c.1324G>T;c.1514+1G>A;c.1929delA;c.2176-3_2176-2delCA;c.2293C>T;c.2356_2362delGGCGTCT	Autosomal recessive cutis laxa type 2 (ARCL2) represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type 2), and ARCL2B, those without a metabolic disorder (Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. Mutation in the ATP6V0A2 gen can also cause wrinkly skin syndrome (WWS). WSS is characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple skeletal abnormalities (joint laxity and congenital hip dislocation), late closing of the anterior fontanel, microcephaly, pre- and postnatal growth retardation, developmental delay and facial dysmorphism (a broad nasal bridge, downslanting palpebral fissures and hypertelorism). The occurrence of mutations in the same gene in WSS indicates that ARCL2 and some cases of WSS represent variable manifestations of the same genetic defect.	Plus
ATP6V0A4	Renal tubular acidosis, distal, autosomal recessive Renal tubular acidosis, distal, autosomal recessive Descrição da doença: Renal tubular acidosis, distal (dRTA), autosomal recessive is a disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.	NM_020632.2	c.2419C>T;c.2257C>T;c.1691+1G>A;c.1506T>A;c.1006_1 c.2419C>T;c.2257C>T;c.1691+1G>A;c.1506T>A;c.1006_1007delAA;c.418-1G>A;c.334C>T;c.105delT	Renal tubular acidosis, distal (dRTA), autosomal recessive is a disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.	Plus
ATP6V1B1	Renal tubular acidosis with deafness Renal tubular acidosis with deafness Descrição da doença: Renal tubular acidosis with deafness is an autosomal recessive disease characterized by the association of renal distal tubular acidosis with sensorineural hearing loss. Distal renal tubular acidosis is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.	NM_001692.3	c.91C>T;c.232G>A;c.242T>C;c.340C>T;c.484G>T;c.497d c.91C>T;c.232G>A;c.242T>C;c.340C>T;c.484G>T;c.497delC;c.785+1G>A;c.943C>T;c.1037C>G;c.1123delA;c.1155dupC;c.1248+1G>C	Renal tubular acidosis with deafness is an autosomal recessive disease characterized by the association of renal distal tubular acidosis with sensorineural hearing loss. Distal renal tubular acidosis is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.	Plus
ATP7A	Menkes disease; Occipital horn syndrome Menkes disease; Occipital horn syndrome Descrição da doença: Menkes disease follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ATP7A gene located on chromosomal region Xq21.1. The age of onset is neonatal/infantile. This disease is characterized by progressive neurodegeneration and marked connective tissue anomalies as well as typical sparse abnormal steely hair. The birth incidence is 1:300,000 in Europe, 1:360,000 in Japan and 1:50,000-1:100,000 in Australia, and the prevalence is 1:100,000 newborns. Mutations in the ATP7A can also cause occipital horn syndrome, which is considered a mild form of Menkes syndrome. Occipital horn syndrome is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).	NM_000052.6	c.408_415delCAATCAGA;c.422_423delAG;c.598C>T;c.601 c.408_415delCAATCAGA;c.422_423delAG;c.598C>T;c.601C>T;c.876delG;c.1006G>T;c.1020_1024dupGGGGC;c.1205delA;c.1225C>T;c.1355delT;c.1460C>A;c.1537G>T;c.1544-1G>A;c.1639C>T;c.1667_1668delTA;c.1707+1G>A;c.1782C>G;c.1831G>T;c.1974_1977dupGTTT;c.2160T>A;c.2172G>T;c.2173-2A>G;c.2179G>A;c.2179G>T;c.2187G>A;c.2248_2251dupATTG;c.2302delG;c.2383C>T;c.2395_2405delCATATAGCAAAinsAGCATC;c.2405_2406+1delAGGinsT;c.2498+2T>A;c.2499-1G>A;c.2555C>T;c.2645dupC;c.2694delG;c.2938C>T;c.2956C>T;c.2981C>T;c.3056G>A;c.3111+1G>A;c.3112-1G>A;c.3124delG;c.3257_3258delAC;c.3285T>G;c.3288C>A;c.3294+1G>T;c.3294+2T>G;c.3340delG;c.3379G>T;c.3466C>T;c.3473C>A;c.3502C>T;c.3537delA;c.3774delTinsATGACTGG;c.3775_3776delAAinsTTAC;c.3801+1G>T;c.3802-1G>T;c.3911A>G;c.3915_3921delCTCCCCA;c.3920delC;c.3920C>G;c.3943G>A;c.4005+1G>T;c.4006-1G>A;c.4123+1G>A;c.4132dupA;c.4156C>T;c.4352delG	Menkes disease follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ATP7A gene located on chromosomal region Xq21.1. The age of onset is neonatal/infantile. This disease is characterized by progressive neurodegeneration and marked connective tissue anomalies as well as typical sparse abnormal steely hair. The birth incidence is 1:300,000 in Europe, 1:360,000 in Japan and 1:50,000-1:100,000 in Australia, and the prevalence is 1:100,000 newborns. Mutations in the ATP7A can also cause occipital horn syndrome, which is considered a mild form of Menkes syndrome. Occipital horn syndrome is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).	Plus
ATP7B	Wilson disease Wilson disease Descrição da doença: Wilson disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATP7B gene located on chromosomal region 13q14.3. The age of onset is infantile. This disease is characterized by the toxic accumulation of copper, mainly in the liver and central nervous system, and symptomatic patients may present with hepatic, neurologic or psychiatric forms. The birth incidence is 1:30,000-1:100,000 in France and The prevalence is 1:10,000-1:30,000.	NM_000053.3	c.4195delC;c.4125-2A>G;c.4114C>T;c.4092_4093delGT; c.4195delC;c.4125-2A>G;c.4114C>T;c.4092_4093delGT;c.4088C>T;c.4058G>A;c.4051C>T;c.4039G>A;c.4022-2A>C;c.4021G>A;c.4006delA;c.3990_3993delTTAT;c.3992A>C;c.3955C>T;c.3948delG;c.3942_3943delCA;c.3904-2A>G;c.3895C>T;c.3818C>A;c.3818C>T;c.3809A>G;c.3800delA;c.3800A>C;c.3796G>A;c.3700-1G>A;c.3694A>C;c.3664delG;c.3662G>A;c.3659C>T;c.3649_3654delGTTCTG;c.3646G>A;c.3598C>T;c.3556+1G>A;c.3556+1G>T;c.3552dupT;c.3529C>T;c.3517G>A;c.3451C>T;c.3449delA;c.3443T>C;c.3436G>A;c.3402delC;c.3359T>A;c.3350_3353delAGCG;c.3317T>A;c.3305T>C;c.3301G>A;c.3295G>A;c.3284A>C;c.3263T>A;c.3244-2A>G;c.3243+1G>A;c.3236G>T;c.3207C>A;c.3191A>C;c.3182G>A;c.3157dupC;c.3147delC;c.3121C>T;c.3107dupT;c.3104G>T;c.3083delA;c.3053C>T;c.3011A>C;c.3008C>T;c.3007G>A;c.2998G>A;c.2975C>T;c.2972C>T;c.2963G>A;c.2962G>C;c.2953T>C;c.2930C>T;c.2906G>A;c.2905C>T;c.2901delC;c.2865+1G>A;c.2826_2832delCGGTTTT;c.2828G>A;c.2817G>T;c.2810delT;c.2807T>A;c.2804C>T;c.2795C>A;c.2755C>G;c.2755C>T;c.2743C>T;c.2731-2A>G;c.2730+1G>A;c.2621C>T;c.2605G>A;c.2576-2A>G;c.2575+1G>A;c.2575+1G>C;c.2570T>C;c.2532delA;c.2519C>T;c.2513delA;c.2447+2T>G;c.2438_2440delTAAinsAT;c.2428G>T;c.2383C>T;c.2356-1G>A;c.2356-1G>C;c.2356-2A>G;c.2336G>A;c.2335T>G;c.2333G>A;c.2333G>T;c.2332C>G;c.2332C>T;c.2304delC;c.2304dupC;c.2305A>G;c.2303C>T;c.2297C>G;c.2294A>G;c.2293G>A;c.2233_2234delCT;c.2217dupT;c.2165dupT;c.2157C>A;c.2149C>T;c.2145C>A;c.2131G>A;c.2128G>A;c.2123T>C;c.2122-1G>A;c.2122-8T>G;c.2097_2100delCTTT;c.2072G>T;c.2071G>A;c.2038C>T;c.2035delC;c.2009_2015delATATGCT;c.2000T>A;c.1934T>G;c.1924G>C;c.1877G>C;c.1847G>A;c.1846C>T;c.1820dupA;c.1782delT;c.1772G>A;c.1745_1746delTA;c.1739delA;c.1716delG;c.1708-1G>A;c.1708-1G>C;c.1708-2A>G;c.1708-5T>G;c.1639C>T;c.1605_1609dupGGTCA;c.1568T>A;c.1544-2A>C;c.1543+1G>T;c.1512dupT;c.1470C>A;c.1392dupG;c.1374_1377delAGTG;c.1372G>T;c.1340_1343delAAAC;c.1337_1338insTT;c.1285+2T>A;c.1145_1151delCCCAACT;c.1063C>T;c.994G>T;c.915T>A;c.865C>T;c.845delT;c.841C>T;c.813C>A;c.778dupC;c.738dupT;c.650T>G;c.562C>T;c.524_525delAA;c.525dupA;c.388_389dupGC;c.383delG;c.331C>T;c.314C>A;c.254G>T;c.174dupC;c.122A>G;c.111dupT;c.103A>T;c.52-1G>T;c.51+4A>T;c.19_20delCA	Wilson disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATP7B gene located on chromosomal region 13q14.3. The age of onset is infantile. This disease is characterized by the toxic accumulation of copper, mainly in the liver and central nervous system, and symptomatic patients may present with hepatic, neurologic or psychiatric forms. The birth incidence is 1:30,000-1:100,000 in France and The prevalence is 1:10,000-1:30,000.	Plus
ATP8B1	Cholestasis, progressive familial intrahepatic, type 1; Cholestasis, benign recurrent intrahepatic, type 1 Cholestasis, progressive familial intrahepatic, type 1; Cholestasis, benign recurrent intrahepatic, type 1 Descrição da doença: Progressive familial intrahepatic, type 1 (PFIC1) is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., 1994; Klomp et al., 2004). Mutations in the ATP8B1 gene can cause benign recurrent intrahepatic cholestasis type 1 (BRIC1). BRIC1 is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months (Summerskill and Walshe, 1959; Schapiro and Isselbacher, 1963; Brenard et al., 1989). Tygstrup et al. (1999) stated that referring to this disorder as 'benign' is a misnomer, because the disease has an impact on the quality of life in some patients. They preferred the term 'recurrent familial intrahepatic cholestasis.' Mutation in the ATP8B1 gene can also cause ).	NM_005603.4	c.3410C>G;c.2854C>T;c.2674G>A;c.2599C>T;c.2286-2A> c.3410C>G;c.2854C>T;c.2674G>A;c.2599C>T;c.2286-2A>G;c.2097+2T>C;c.1993G>T;c.1982T>C;c.1804C>T;c.1660G>A;c.1367C>T;c.923G>T;c.863T>C;c.625C>A	Progressive familial intrahepatic, type 1 (PFIC1) is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., 1994; Klomp et al., 2004). Mutations in the ATP8B1 gene can cause benign recurrent intrahepatic cholestasis type 1 (BRIC1). BRIC1 is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months (Summerskill and Walshe, 1959; Schapiro and Isselbacher, 1963; Brenard et al., 1989). Tygstrup et al. (1999) stated that referring to this disorder as 'benign' is a misnomer, because the disease has an impact on the quality of life in some patients. They preferred the term 'recurrent familial intrahepatic cholestasis.' Mutation in the ATP8B1 gene can also cause ).	Plus
ATR	Seckel syndrome type 1 Seckel syndrome type 1 Descrição da doença: Seckel syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATR gene located on chromosomal region 3q23. The age of onset is neonatal/infantile. This disease is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. The prevalence is <1:1,000,000.	NM_001184.3	c.6488delT;c.6037dupA;c.5645delA;c.5635G>T;c.5196+ c.6488delT;c.6037dupA;c.5645delA;c.5635G>T;c.5196+1G>A;c.4641+1G>T;c.2341+1G>A;c.975_976delCT	Seckel syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATR gene located on chromosomal region 3q23. The age of onset is neonatal/infantile. This disease is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. The prevalence is <1:1,000,000.	Plus
ATRX	Mental retardation-hypotonic facies syndrome, X-linked Mental retardation-hypotonic facies syndrome, X-linked Descrição da doença: X-linked mental retardation-hypotonic facies syndrome comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (Abidi et al., 2005). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.	NM_000489.4	c.7394delG;c.7201-2A>G;c.7192C>T;c.7162G>T;c.7156C c.7394delG;c.7201-2A>G;c.7192C>T;c.7162G>T;c.7156C>T;c.6532C>T;c.6488A>G;c.6392G>A;c.6254G>A;c.6250T>C;c.6104A>T;c.6003G>A;c.5957-1G>A;c.5225G>A;c.4865C>T;c.4840T>C;c.4826A>G;c.1753G>T;c.1738delG;c.736C>T;c.569C>T;c.568C>G;c.536A>G;c.533T>A;c.109C>T;c.20+1G>A	X-linked mental retardation-hypotonic facies syndrome comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (Abidi et al., 2005). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.	Plus
AUH	3-methylglutaconic aciduria, type 1 3-methylglutaconic aciduria, type 1 Descrição da doença: 3-Methylglutaconic aciduria type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AUH gene located on chromosomal region 9q22.31. The age of onset is neonatal/infantile. This disease is characterized by a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. The prevalence is <1:1,000,000.	NM_001698.2	c.991A>T;c.824C>T;c.656-2A>G;c.650G>A;c.589C>T;c.5 c.991A>T;c.824C>T;c.656-2A>G;c.650G>A;c.589C>T;c.559G>A;c.471delT;c.263-2A>G	3-Methylglutaconic aciduria type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AUH gene located on chromosomal region 9q22.31. The age of onset is neonatal/infantile. This disease is characterized by a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. The prevalence is <1:1,000,000.	Plus
AURKC	Male infertility spermatogenic failure, type 5 Male infertility spermatogenic failure, type 5 Descrição da doença: Spermatogenic failure, type 5 is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (Dieterich et al., 2007).	NM_001015878.1	c.145delC;c.436-2A>G c.145delC;c.436-2A>G	Spermatogenic failure, type 5 is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (Dieterich et al., 2007).	Plus
AVPR2	Diabetes insipidus, nephrogenic, type 1; Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) Diabetes insipidus, nephrogenic, type 1; Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) Descrição da doença: Nephrogenic diabetes insipidus (NDI) is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopression (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form (type I), which is caused by a defect in the vasopressin V2 receptor in renal collecting duct cells. The remaining 10% of patients have autosomal NDI (125800) (type II), which is caused by mutations in the gene encoding the aquaporin-2 water channel (AQP2; 107777) on chromosome 12q13 (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (125700) is caused by mutation in the gene encoding arginine vasopression, located on 20p13. Gain-of-function mutations in the AVPR2 gene result in nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. When the cardinal features of SIADH were defined by Bartter and Schwartz (1967), levels of AVP could not be measured. Subsequently, radioimmunoassays revealed that SIADH is usually associated with measurably elevated serum levels of AVP. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterized by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP (Feldman et al., 2005).	NM_000054.4	c.102delG;c.176T>C;c.213G>A;c.253G>A;c.310C>T;c.31 c.102delG;c.176T>C;c.213G>A;c.253G>A;c.310C>T;c.313T>G;c.337C>T;c.383A>C;c.388A>T;c.392T>C;c.395C>A;c.409C>G;c.409C>T;c.410G>A;c.410G>T;c.424delT;c.472delC;c.541C>T;c.554delG;c.602G>A;c.614A>G;c.673C>T;c.752_758delGCCGGAC;c.770delG;c.838dupT;c.839A>G;c.853G>C;c.857C>T;c.878G>A;c.911-2A>G;c.1009C>T	Nephrogenic diabetes insipidus (NDI) is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopression (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form (type I), which is caused by a defect in the vasopressin V2 receptor in renal collecting duct cells. The remaining 10% of patients have autosomal NDI (125800) (type II), which is caused by mutations in the gene encoding the aquaporin-2 water channel (AQP2; 107777) on chromosome 12q13 (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (125700) is caused by mutation in the gene encoding arginine vasopression, located on 20p13. Gain-of-function mutations in the AVPR2 gene result in nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. When the cardinal features of SIADH were defined by Bartter and Schwartz (1967), levels of AVP could not be measured. Subsequently, radioimmunoassays revealed that SIADH is usually associated with measurably elevated serum levels of AVP. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterized by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP (Feldman et al., 2005).	Plus
B2M	Immunodeficiency, type 43 Immunodeficiency, type 43 Descrição da doença: Immunodeficiency, type 43 is a disorder characterized by marked reduction in serum concentrations of immunoglobulins and albumin, and hypoproteinemia due to hypercatabolism. Patients may suffer from recurrent respiratory tract infections and severe skin disease.	NM_004048.2	c.67+1G>T;c.286G>A c.67+1G>T;c.286G>A	Immunodeficiency, type 43 is a disorder characterized by marked reduction in serum concentrations of immunoglobulins and albumin, and hypoproteinemia due to hypercatabolism. Patients may suffer from recurrent respiratory tract infections and severe skin disease.	Plus
B3GAT3	Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects Descrição da doença: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects (JDSCD). is an autosomal recessive disease characterized by dysmorphic facies, bilateral dislocations of the elbows, hips, and knees, clubfeet, and short stature, as well as cardiovascular defects.	NM_012200.3	c.830G>A;c.667G>A;c.593C>T;c.419C>T;c.331G>A c.830G>A;c.667G>A;c.593C>T;c.419C>T;c.331G>A	Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects (JDSCD). is an autosomal recessive disease characterized by dysmorphic facies, bilateral dislocations of the elbows, hips, and knees, clubfeet, and short stature, as well as cardiovascular defects.	Plus
B3GLCT	Peters-plus syndrome Peters-plus syndrome Descrição da doença: Peters-plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, developmental delay, characteristic craniofacial features, cleft lip and/or palate.	NM_194318.3	c.459+1G>A;c.660+1G>A;c.1065-1G>A;c.1098T>A;c.1178 c.459+1G>A;c.660+1G>A;c.1065-1G>A;c.1098T>A;c.1178G>A	Peters-plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, developmental delay, characteristic craniofacial features, cleft lip and/or palate.	Plus
B4GALT1	Congenital disorder of glycosylation, type 2D Congenital disorder of glycosylation, type 2D Descrição da doença: Congenital disorder of glycosylation type 2D follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the B4GALT1 gene located on chromosomal region 9p13. The age of onset is neonatal/infantile. This disease is characterized by macrocephaly, hydrocephaly, hypotonia, myopathy and coagulation anomalies. The prevalence is <1:1,000,000.	NM_001497.3	c.1031dupC c.1031dupC	Congenital disorder of glycosylation type 2D follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the B4GALT1 gene located on chromosomal region 9p13. The age of onset is neonatal/infantile. This disease is characterized by macrocephaly, hydrocephaly, hypotonia, myopathy and coagulation anomalies. The prevalence is <1:1,000,000.	Plus
B4GALT7	Ehlers-Danlos syndrome, spondylodysplastic, type 1 Ehlers-Danlos syndrome, spondylodysplastic, type 1 Descrição da doença: Ehlers-Danlos syndrome spondylodysplastic, type 1 is characterized by short stature, developmental anomalies of the forearm bones and elbow, and bowing of extremities, in addition to the classic stigmata of Ehlers-Danlos syndrome, including joint laxity, skin hyperextensibility, and poor wound healing. Significant developmental delay is not a consistent feature (Guo et al., 2013).	NM_007255.2	c.268delT;c.277dupC;c.641G>A c.268delT;c.277dupC;c.641G>A	Ehlers-Danlos syndrome spondylodysplastic, type 1 is characterized by short stature, developmental anomalies of the forearm bones and elbow, and bowing of extremities, in addition to the classic stigmata of Ehlers-Danlos syndrome, including joint laxity, skin hyperextensibility, and poor wound healing. Significant developmental delay is not a consistent feature (Guo et al., 2013).	Plus
B9D1	Joubert syndrome, type 27 Joubert syndrome, type 27 Descrição da doença: Joubert syndrome, type 27 is a form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly.	NM_001243473.2	c.400+2T>C c.400+2T>C	Joubert syndrome, type 27 is a form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly.	Plus
B9D2	Joubert syndrome type 34; Meckel syndrome type 10 Joubert syndrome type 34; Meckel syndrome type 10 Descrição da doença: Joubert syndrome (JBTS) 34 is an autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. On the other side, Meckel syndrome (MKS) type 10 (MKS10) is a very rare autosomal-recessive disorder resulting in perinatal lethality and characterized by renal cysts, hepatic ductal plate malformation, and central nervous system defects, such as occipital encephalocele. JBST34 and MKS10 are caused by pathogenic variants in the B9D2 gene located on chromosomal region 19q13.2.	NM_030578.3	c.301A>C;c.156_163delGGACATGG c.301A>C;c.156_163delGGACATGG	Joubert syndrome (JBTS) 34 is an autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. On the other side, Meckel syndrome (MKS) type 10 (MKS10) is a very rare autosomal-recessive disorder resulting in perinatal lethality and characterized by renal cysts, hepatic ductal plate malformation, and central nervous system defects, such as occipital encephalocele. JBST34 and MKS10 are caused by pathogenic variants in the B9D2 gene located on chromosomal region 19q13.2.	Plus
BBS1	Bardet-Biedl syndrome, type 1 Bardet-Biedl syndrome, type 1 Descrição da doença: Bardet-Biedl syndrome 1 is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism. Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014).	NM_024649.4	c.17dupC;c.47+2T>C;c.48-3C>G;c.48-2A>C;c.48-1G>T;c c.17dupC;c.47+2T>C;c.48-3C>G;c.48-2A>C;c.48-1G>T;c.124+1G>A;c.124+1G>C;c.182delC;c.223_224delCT;c.416G>A;c.432+1G>A;c.433-2A>G;c.436C>T;c.479+2T>G;c.480-1G>C;c.518+1G>A;c.519-2A>G;c.724-1G>C;c.786delG;c.831-2A>G;c.851delA;c.855C>A;c.871C>T;c.887delT;c.951+1G>A;c.952-1G>A;c.952-1G>C;c.952G>A;c.981delC;c.1012C>T;c.1072delT;c.1131_1135delCTTTG;c.1169T>G;c.1232_1235delGAGG;c.1240G>T;c.1285C>T;c.1318C>T;c.1340-2A>G;c.1340-1G>T;c.1405C>T;c.1423delC;c.1424dupT;c.1514_1515delTG;c.1609-2A>T;c.1642delC;c.1643dupT;c.1645G>T;c.1713delA	Bardet-Biedl syndrome 1 is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism. Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014).	Plus
BBS10	Bardet-Biedl syndrome, type 10 Bardet-Biedl syndrome, type 10 Descrição da doença: Bardet-Biedl syndrome 10 (BBS10) is characterized by progressive retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal dysplasia (Stoetzel et al., 2006). BBS10 represents a major locus for BBS, with mutations in the BBS10 gene accounting for approximately 20% of BBS patients (Stoetzel et al., 2006; Zaghloul and Katsanis, 2009).	NM_024685.3	c.2119_2120delGT;c.1856_1865delAAAAATGCCA;c.1767C> c.2119_2120delGT;c.1856_1865delAAAAATGCCA;c.1767C>A;c.1677delC;c.1677C>A;c.1677C>G;c.1599_1602delAACT;c.1547delC;c.1542delA;c.1510_1511delAT;c.1495G>T;c.1448_1452delCTCAA;c.1244delA;c.1241T>C;c.1202G>A;c.1184dupA;c.11840>A;c.11380>A;c.1091delA;c.1044_1045delTT;c.1024dupA;c.10240>A;c.959_962delGTTA;c.931T>G;c.909_912delTCAG;c.858_859dupTC;c.859del0insTC;c.850C>T;c.728_731delAAGA;c.687delT;c.6460>G;c.590A>G;c.574C>T;c.539G>A;c.531C>A;c.378G>A;c.3650>A;c.361A>T;c.273C>G;c.271dupT;c.2710>T;c.235dupA;c.215del0insGT;c.198-1G>C;c.197+1G>T;c.164T>C;c.145C>T;c.101G>C;c.83_84delGCinsAG;c.39_46delGGCGTTGC;c.32T>G	Bardet-Biedl syndrome 10 (BBS10) is characterized by progressive retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal dysplasia (Stoetzel et al., 2006). BBS10 represents a major locus for BBS, with mutations in the BBS10 gene accounting for approximately 20% of BBS patients (Stoetzel et al., 2006; Zaghloul and Katsanis, 2009).	Plus
BBS12	Bardet-Biedl syndrome, type 12 Bardet-Biedl syndrome, type 12 Descrição da doença: Bardet-Biedl syndrome 12 (BBS12) is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts).	NM_001178007.1	c.104C>A;c.270delT;c.323C>G;c.787dupT;c.1063C>T;c. c.104C>A;c.270delT;c.323C>G;c.787dupT;c.1063C>T;c.1082delG;c.1115_1116delTT;c.1151delG;c.1483_1484delGA;c.1531_1539delCAGATGCAA;c.2020C>T;c.2023C>T	Bardet-Biedl syndrome 12 (BBS12) is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts).	Plus
BBS2	Bardet-Biedl syndrome, type 2 Bardet-Biedl syndrome, type 2 Descrição da doença: Bardet-Biedl syndrome 2 (BBS2) is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009).	NM_031885.3	c.2107C>T;c.2060-1G>T;c.2038C>T;c.1969G>T;c.1946_1 c.2107C>T;c.2060-1G>T;c.2038C>T;c.1969G>T;c.1946_1952delACCTTAA;c.1911-1G>A;c.1909_1910delAT;c.1895G>C;c.1864C>T;c.1814C>G;c.1797+1G>A;c.1780C>T;c.1770delT;c.1705C>T;c.1438C>T;c.1237C>T;c.1099dupC;c.1081-1G>T;c.1015C>T;c.941-1G>T;c.941-2A>C;c.940delA;c.823C>T;c.814C>T;c.806T>G;c.717+2T>G;c.717+1G>A;c.700C>T;c.646C>T;c.627_628delTT;c.565C>T;c.563delT;c.535-2A>G;c.534+1G>T;c.508G>A;c.472delG;c.472-2A>G;c.471+1G>A;c.416G>T;c.311A>C;c.263delG;c.224T>G;c.175C>T;c.98C>A;c.72C>G	Bardet-Biedl syndrome 2 (BBS2) is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009).	Plus
BBS4	Bardet-Biedl syndrome, type 4 Bardet-Biedl syndrome, type 4 Descrição da doença: Bardet-Biedl syndrome 4 (BBS4) is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (Katsanis et al., 2002). Anosmia has been described in patients with BBS4 (Iannaccone et al., 2005), as well as polydactyly confined to the hands (Carmi et al., 1995).	NM_033028.4	c.157-2A>G;c.172C>T;c.220+1G>C;c.341delT;c.406-2A> c.157-2A>G;c.172C>T;c.220+1G>C;c.341delT;c.406-2A>C;c.406-2A>G;c.513T>A;c.638T>A;c.712-1G>A;c.883C>T;c.884G>C;c.1091C>A;c.1106+2T>A;c.1226delG	Bardet-Biedl syndrome 4 (BBS4) is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (Katsanis et al., 2002). Anosmia has been described in patients with BBS4 (Iannaccone et al., 2005), as well as polydactyly confined to the hands (Carmi et al., 1995).	Plus
BBS5	Bardet-Biedl syndrome, type 5 Bardet-Biedl syndrome, type 5 Descrição da doença: Bardet-Biedl syndrome 5 (BBS5) is a ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism, and learning difficulties (Scheidecker et al., 2015). Patients described by Young et al. (1999) and Moore et al. (2005) with mutations in the BBS5 gene did not have polydactyly. The contribution of BBS5 mutations to all cases of BBS has been estimated at 2% (Li et al., 2004) and 0.40% (Zaghloul and Katsanis, 2009).	NM_152384.2	c.265C>T;c.966dupT c.265C>T;c.966dupT	Bardet-Biedl syndrome 5 (BBS5) is a ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism, and learning difficulties (Scheidecker et al., 2015). Patients described by Young et al. (1999) and Moore et al. (2005) with mutations in the BBS5 gene did not have polydactyly. The contribution of BBS5 mutations to all cases of BBS has been estimated at 2% (Li et al., 2004) and 0.40% (Zaghloul and Katsanis, 2009).	Plus
BBS7	Bardet-Biedl syndrome, type 7 Bardet-Biedl syndrome, type 7 Descrição da doença: Bardet-Biedl syndrome 7 (BBS7) is an autosomal recessive disorder characterized by retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity, renal anomalies, and hypogenitalism (Harville et al., 2010). Zaghloul and Katsanis (2009) estimated the contribution of BBS7 gene mutations to the total BBS mutational load to be 1.50%.	NM_176824.2	c.1986_1988delGCAinsT;c.1967_1968delTAinsC;c.1891- c.1986_1988delGCAinsT;c.1967_1968delTAinsC;c.1891-2A>C;c.1786+1G>T;c.1712_1713delCTinsAGA;c.1413T>A;c.1062_1063delTA;c.712_715delAGAG;c.709_712delAAGA;c.649dupG;c.632C>T;c.389_390delAC	Bardet-Biedl syndrome 7 (BBS7) is an autosomal recessive disorder characterized by retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity, renal anomalies, and hypogenitalism (Harville et al., 2010). Zaghloul and Katsanis (2009) estimated the contribution of BBS7 gene mutations to the total BBS mutational load to be 1.50%.	Plus
BBS9	Bardet-Biedl syndrome, type 9 Bardet-Biedl syndrome, type 9 Descrição da doença: Bardet-Biedl syndrome 9 (BBS9) is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (Abu-Safieh et al., 2012).	NM_198428.2	c.104_112+4delATGGACAAGGTAA;c.223C>T;c.263C>A;c.26 c.104_112+4delATGGACAAGGTAA;c.223C>T;c.263C>A;c.263+1G>A;c.421G>A;c.442+1G>C;c.445C>T;c.956delC;c.1063C>T;c.1167delG;c.1370T>A;c.1423G>T;c.1759C>T;c.1789+1G>A;c.1789+1G>T;c.1792C>T;c.1877_1880delAACA;c.2045dupC;c.2115+1G>A	Bardet-Biedl syndrome 9 (BBS9) is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (Abu-Safieh et al., 2012).	Plus
BCAP31	Deafness, dystonia, and cerebral hypomyelination Deafness, dystonia, and cerebral hypomyelination Descrição da doença: Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (Cacciagli et al., 2013).	NM_001139457.2	c.542+2T>G;c.510_511delCT;c.395-2A>G;c.298C>T;c.10 c.542+2T>G;c.510_511delCT;c.395-2A>G;c.298C>T;c.107C>A	Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (Cacciagli et al., 2013).	Plus
BCKDHA	Maple syrup urine disease, type 1A Maple syrup urine disease, type 1A Descrição da doença: Maple syrup urine disease, type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHA gene located on chromosomal region 19q13.1-13.2. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:1,000,000-9:1,000,000.	NM_000709.3	c.14delT;c.117delC;c.117dupC;c.127C>T;c.137C>A;c.1 c.14delT;c.117delC;c.117dupC;c.127C>T;c.137C>A;c.143delT;c.288+1G>A;c.399delCinsAA;c.470A>C;c.476G>A;c.511delC;c.632C>T;c.647-1G>C;c.661_664delTACG;c.659C>T;c.718delG;c.741dupT;c.745G>A;c.797delA;c.844G>C;c.853G>C;c.853+1G>T;c.854-2A>G;c.861_868delAGGCCCCG;c.859C>T;c.868G>A;c.905A>C;c.909_910delGT;c.917delT;c.929C>G;c.940C>T;c.964C>T;c.979G>A;c.1008_1015delCAGCACCA;c.1036C>T;c.1037G>A;c.1119G>A;c.1168-2A>G;c.1198A>T;c.1226T>G;c.1234G>A;c.1310_1311delAC;c.1312T>A	Maple syrup urine disease, type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHA gene located on chromosomal region 19q13.1-13.2. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:1,000,000-9:1,000,000.	Plus
BCKDHB	Maple syrup urine disease, type 1B Maple syrup urine disease, type 1B Descrição da doença: Maple syrup urine disease, type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHB gene located on chromosomal region 6q14.1. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:10,000-5:10,000.	NM_000056.4	c.93_103delGGCGCGGGGCT;c.93_103dupGGCGCGGGGCT;c.19 c.93_103delGGCGCGGGGCT;c.93_103dupGGCGCGGGGCT;c.196+1G>C;c.196+1G>T;c.197-2A>G;c.275-2A>G;c.281_291delTTGGTGAAGAT;c.302G>A;c.344-1G>A;c.348delA;c.356T>G;c.368delC;c.401T>A;c.403G>A;c.410C>T;c.479T>G;c.487G>T;c.488A>T;c.508C>A;c.508C>G;c.508C>T;c.509G>A;c.526A>T;c.547C>T;c.548G>C;c.554C>T;c.564T>A;c.592_593delCA;c.595_596delAG;c.616C>T;c.633+1G>A;c.633+1G>C;c.633+1G>T;c.730delT;c.742+1G>A;c.748G>T;c.752T>C;c.776delC;c.799C>T;c.811_824delGATGTTACTCTAGT;c.832G>A;c.840+1G>A;c.840+1G>T;c.840+2T>G;c.841-1G>C;c.853delC;c.853C>T;c.885delT;c.902T>G;c.952-2A>G;c.952-1G>A;c.964A>G;c.970C>T;c.1006G>A;c.1016C>T;c.1022T>A;c.1046G>A;c.1065delT;c.1114G>T;c.1149T>A	Maple syrup urine disease, type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHB gene located on chromosomal region 6q14.1. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:10,000-5:10,000.	Plus
BCOR	Microphthalmia, syndromic, type 2 Microphthalmia, syndromic, type 2 Descrição da doença: Microphthalmia, syndromic, type 2 (MCOPS2) is a very rare multiple congenital anomaly syndrome characterized by eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma), facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate), cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve) and dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length). Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities.	NM_001123385.1	c.4936dupC;c.4862dupC;c.4390_4393delGAGA;c.4304_43 c.4936dupC;c.4862dupC;c.4390_4393delGAGA;c.4304_4308delCATGC;c.4174-1G>T;c.4111C>T;c.4063G>T;c.3646_3647delGA;c.3468delT;c.3108dupA;c.2926C>T;c.2613delC;c.2488_2489delAG;c.2428C>T;c.1136_1139delTTAG;c.1024C>T;c.776C>A	Microphthalmia, syndromic, type 2 (MCOPS2) is a very rare multiple congenital anomaly syndrome characterized by eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma), facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate), cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve) and dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length). Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities.	Plus
BCS1L	BCS1L-related disorders, including Leigh syndrome BCS1L-related disorders, including Leigh syndrome Descrição da doença: Leigh syndrome caused by mutations in the BCS1L gene -located on chromosomal region 2q35- follows an autosomal recessive pattern of inheritance. Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation; It presents extensive genetic heterogeneity (more than 75 different genes) with mutations identified in both nuclear- and mitochondrial-encoded genes involved in energy metabolism, including mitochondrial respiratory chain complexes I, II, III, IV, and V. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The BCS1L protein is critical for the formation of mitochondrial complex III. This syndrome affects at least 1 in 40,000 newborns.	NM_001079866.1	c.103G>C;c.133C>T;c.148A>G;c.166C>T;c.232A>G;c.245 c.103G>C;c.133C>T;c.148A>G;c.166C>T;c.232A>G;c.245C>A;c.296C>T;c.320+1G>T;c.349C>T;c.385G>A;c.418delC;c.431G>A;c.460+1G>A;c.460+2T>C;c.464G>C;c.534delC;c.547C>T;c.548G>A;c.550C>T;c.556C>T;c.598C>T;c.607dupA;c.625_626delAT;c.655+1G>A;c.696delT;c.772delG;c.821delC;c.830G>A;c.871C>T;c.889+1G>A;c.889+1G>T;c.901T>A;c.973dupC;c.980T>C;c.1007+2_1007+5delTAGG;c.1057G>A	Leigh syndrome caused by mutations in the BCS1L gene -located on chromosomal region 2q35- follows an autosomal recessive pattern of inheritance. Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation; It presents extensive genetic heterogeneity (more than 75 different genes) with mutations identified in both nuclear- and mitochondrial-encoded genes involved in energy metabolism, including mitochondrial respiratory chain complexes I, II, III, IV, and V. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The BCS1L protein is critical for the formation of mitochondrial complex III. This syndrome affects at least 1 in 40,000 newborns.	Plus
BEST1	Bestrophinopathy, AR Bestrophinopathy, AR Descrição da doença: Bestrophinopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BEST1 gene located on chromosomal region 11q13. The age of onset is variable. This disease is characterized by central visual loss in the first 2 decades of life associated with an absent electrooculogram light rise, and a reduced electroretinogram. Genetic heterogeneity: Mutations in this gene may cause dominant phenotypes like Macular dystrophy, vitelliform, 2 ( OMIM 153700) and Vitreoretinochoroidopathy (193220).	NM_004183.3;NM_001139443.1	c.25G>A;c.38G>C;c.44G>A;c.87C>G;c.122T>C;c.172_173 c.25G>A;c.38G>C;c.44G>A;c.87C>G;c.122T>C;c.172_173dupCA;c.92C>T;c.94C>T;c.99G>C;c.242G>A;c.341_342delTG;c.344delG;c.404C>T;c.418C>T;c.422T>C;c.434T>C;c.456+1G>A;c.472C>T;c.473G>A;c.478C>T;c.499T>A;c.500A>G;c.502G>A;c.524T>C;c.527A>G;c.694G>A;c.704_706delTCA;c.708C>A;c.709C>T;c.716G>A;c.723T>G;c.730G>A;c.740C>T;c.754G>A;c.769G>A;c.1129_1130insCCAAAGA;c.1203_1204insGCCTTGATGGA;c.1311_1317dupCAAAGAC	Bestrophinopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BEST1 gene located on chromosomal region 11q13. The age of onset is variable. This disease is characterized by central visual loss in the first 2 decades of life associated with an absent electrooculogram light rise, and a reduced electroretinogram. Genetic heterogeneity: Mutations in this gene may cause dominant phenotypes like Macular dystrophy, vitelliform, 2 ( OMIM 153700) and Vitreoretinochoroidopathy (193220).	Plus
BHLHA9	Syndactyly, mesoaxial synostotic, with phalangeal reduction Syndactyly, mesoaxial synostotic, with phalangeal reduction Descrição da doença: Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) represents a distinctive combination of clinical features that includes mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (Malik et al., 2014).	NM_001164405.1	c.211A>G;c.218G>C;c.224G>T c.211A>G;c.218G>C;c.224G>T	Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) represents a distinctive combination of clinical features that includes mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (Malik et al., 2014).	Plus
BIN1	Centronuclear myopathy, type 2 Centronuclear myopathy, type 2 Descrição da doença: Centronuclear myopathy, type 2 is a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers.	NM_139343.2	c.1723A>T;c.1371+1G>T;c.1132-2A>G;c.1002+2T>C;c.46 c.1723A>T;c.1371+1G>T;c.1132-2A>G;c.1002+2T>C;c.461G>A;c.451G>A	Centronuclear myopathy, type 2 is a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers.	Plus
BLM	Bloom syndrome Bloom syndrome Descrição da doença: Bloom syndrome is an autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability.	NM_000057.3	c.2T>C;c.98+1G>A;c.98+1G>T;c.205G>A;c.205G>T;c.213 c.2T>C;c.98+1G>A;c.98+1G>T;c.205G>A;c.205G>T;c.213_214delTT;c.275delA;c.298_299delCA;c.311C>A;c.320dupT;c.443dupT;c.479_480delTT;c.557_559delCAA;c.581_582delTT;c.582delT;c.608_609delCA;c.662_665delCTGA;c.772_773delCT;c.835G>T;c.959+1_959+9delGTAAACTAG;c.991_995delAAAGA;c.1003_1006dupCTTA;c.1083_1084delTG;c.1087+1G>A;c.1088-2A>G;c.1088-1G>A;c.1129delG;c.1220+1G>A;c.1221-2A>C;c.1284G>A;c.1295dupC;c.1301C>G;c.1358T>G;c.1385delC;c.1429_1432delACAG;c.1462G>T;c.1479_1480delTA;c.1500delT;c.1544delA;c.1544dupA;c.1628T>A;c.1642C>T;c.1722_1725delAGCAinsGGC;c.1740delC;c.1752delT;c.1764_1777delGGAAGGTCGGCCAA;c.1795delA;c.1883-2A>G;c.1933C>T;c.1968dupG;c.1985_1986delAA;c.2074+1G>T;c.2098C>T;c.2193+1_2193+9delGTAAGTTAT;c.2193+2T>G;c.2206dupT;c.2207_2212delATCTGAinsTAGATTC;c.2250_2251insAAAT;c.2258T>A;c.2291_2292delAT;c.2308-2A>G;c.2343_2344dupGA;c.2406+2T>G;c.2407-1G>A;c.2407dupT;c.2488dupA;c.2506_2507delAG;c.2555+1G>T;c.2580_2581delTA;c.2643G>A;c.2662+2T>C;c.2663-2A>G;c.2695C>T;c.2720_2726delCGTTACA;c.2821C>T;c.2824-2A>T;c.2824-1G>C;c.2855G>T;c.2875C>T;c.2887C>T;c.2923delC;c.3014_3015insTATCA;c.3016_3017delAT;c.3022delG;c.3028delG;c.3107G>T;c.3164G>C;c.3191A>T;c.3197G>A;c.3210+2delT;c.3222_3223delAA;c.3223dupA;c.3255_3256insT;c.3261delT;c.3278C>G;c.3305_3306delAT;c.3400G>T;c.3415C>T;c.3439A>T;c.3475_3476delTT;c.3499delG;c.3558+1G>A;c.3558+1G>T;c.3559-1G>A;c.3566_3567delTT;c.3587delG;c.3638delA;c.3667dupA;c.3681delA;c.3692_3693delAA;c.3727dupA;c.3847C>T;c.3855C>A;c.3874+2T>C;c.3901delC;c.3917delG;c.3937G>T;c.3956delT;c.4000_4004delAGGAA	Bloom syndrome is an autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability.	Plus
BLVRA	Hyperbiliverdinemia Hyperbiliverdinemia Descrição da doença: Hyperbiliverdinemia can manifest as green jaundice, which is a green discoloration of the skin, urine, serum, and other bodily fluids, due to increased biliverdin resulting from inefficient conversion to bilirubin. Although rarely reported, affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Green jaundice has also been associated with malnutrition, medication, and congenital biliary atresia (Huffman et al., 2009).	NM_000712.3	c.52C>T;c.131C>A c.52C>T;c.131C>A	Hyperbiliverdinemia can manifest as green jaundice, which is a green discoloration of the skin, urine, serum, and other bodily fluids, due to increased biliverdin resulting from inefficient conversion to bilirubin. Although rarely reported, affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Green jaundice has also been associated with malnutrition, medication, and congenital biliary atresia (Huffman et al., 2009).	Plus
BMP1	Osteogenesis imperfecta, type 13 Osteogenesis imperfecta, type 13 Descrição da doença: Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity. OI type 13, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity (Martinez-Glez et al., 2012).	NM_006129.4	c.747C>G;c.808A>G;c.1297G>T;c.2107G>C c.747C>G;c.808A>G;c.1297G>T;c.2107G>C	Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity. OI type 13, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity (Martinez-Glez et al., 2012).	Plus
BMP15	Ovarian dysgenesis 2 Ovarian dysgenesis 2 Descrição da doença: Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis 2. Ovarian dysgenesis 2 accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). Most cases are associated with major X chromosome abnormalities. Accordingly, genetic studies have identified several loci at Xq and Xp11.2-p.22.1 whose functions are relevant for ovarian development (Zinn et al., 1998; Simpson and Rajkovic, 1999; Marozzi et al., 2000).	NM_005448.2	c.631C>T c.631C>T	Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis 2. Ovarian dysgenesis 2 accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). Most cases are associated with major X chromosome abnormalities. Accordingly, genetic studies have identified several loci at Xq and Xp11.2-p.22.1 whose functions are relevant for ovarian development (Zinn et al., 1998; Simpson and Rajkovic, 1999; Marozzi et al., 2000).	Plus
BMPER	Diaphanospondylodysostosis Diaphanospondylodysostosis Descrição da doença: Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (Funari et al., 2010).	NM_133468.4	c.925C>T;c.1638T>A c.925C>T;c.1638T>A	Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (Funari et al., 2010).	Plus
BMPR1B	Acromesomelic dysplasia, Demirhan type Acromesomelic dysplasia, Demirhan type Descrição da doença: Acromesomelic dysplasia, Demirhan type (AMDD) is a form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers).	NM_001256793.1	c.181C>T;c.247T>C;c.451_458delGGACCTAT;c.537-1G>A; c.181C>T;c.247T>C;c.451_458delGGACCTAT;c.537-1G>A;c.689T>A;c.747G>A;c.1546C>T;c.1547G>A	Acromesomelic dysplasia, Demirhan type (AMDD) is a form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers).	Plus
BOLA3	Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia Descrição da doença: Multiple mitochondrial dysfunctions syndrome, type 2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (Baker et al., 2014).	NM_212552.2	c.136C>T;c.123dupA c.136C>T;c.123dupA	Multiple mitochondrial dysfunctions syndrome, type 2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (Baker et al., 2014).	Plus
BPGM	Erythrocytosis due to bisphosphoglycerate mutase deficiency Erythrocytosis due to bisphosphoglycerate mutase deficiency Descrição da doença: Erythrocytosis due to bisphosphoglycerate mutase deficiency is characterized by hemolytic anemia, splenomegaly, cholelithiasis and cholecystitis.	NM_001293085.1	c.61delC c.61delC	Erythrocytosis due to bisphosphoglycerate mutase deficiency is characterized by hemolytic anemia, splenomegaly, cholelithiasis and cholecystitis.	Plus
BRAT1	Rigidity and multifocal seizure syndrome, lethal neonatal; Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Rigidity and multifocal seizure syndrome, lethal neonatal; Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Descrição da doença: Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (Saitsu et al., 2014). Biallelic mutations in the BRAT1 gene can also cause neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS), a somewhat less severe disorder with overlapping features. NEDCAS is an autosomal recessive disorder characterized by psychomotor developmental delay manifesting in infancy, cerebellar atrophy, decreased myelination, and seizures in most patients. Additional features include intellectual disability, ataxia or dyspraxia, hypertonia, hyperreflexia, poor or absent speech, microcephaly, subtle dysmorphisms, and visual impairment in some patients.	NM_152743.3	c.1925C>A;c.1857G>A;c.1771-1G>A;c.1313_1314delAG;c c.1925C>A;c.1857G>A;c.1771-1G>A;c.1313_1314delAG;c.1203_1204delTG;c.1177delG;c.962_963delTC;c.964C>T;c.803+1G>C;c.803G>A;c.638dupA;c.453_454insGAGAAGAT;c.419T>C;c.176T>C;c.171delG;c.105G>A	Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (Saitsu et al., 2014). Biallelic mutations in the BRAT1 gene can also cause neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS), a somewhat less severe disorder with overlapping features. NEDCAS is an autosomal recessive disorder characterized by psychomotor developmental delay manifesting in infancy, cerebellar atrophy, decreased myelination, and seizures in most patients. Additional features include intellectual disability, ataxia or dyspraxia, hypertonia, hyperreflexia, poor or absent speech, microcephaly, subtle dysmorphisms, and visual impairment in some patients.	Plus
BRIP1	Fanconi anemia, complementation group J Fanconi anemia, complementation group J Descrição da doença: Fanconi anemia, complementation group J is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.	NM_032043.2	c.2992_2995delAAGA;c.2990_2993delCAAA;c.2947delA;c c.2992_2995delAAGA;c.2990_2993delCAAA;c.2947delA;c.2947dupA;c.2905+1G>A;c.2833delG;c.2830C>T;c.2765T>G;c.2732dupT;c.2684_2687delCCAT;c.2605C>T;c.2595delG;c.2589G>A;c.2575+1G>A;c.2517G>A;c.2493-1G>A;c.2493-1G>C;c.2492+2dupT;c.2479C>T;c.2448G>A;c.2447G>A;c.2400C>G;c.2379+1G>A;c.2377C>T;c.2330delG;c.2273dupT;c.2258-1G>A;c.2255_2256delAA;c.2244C>G;c.2237_2240delTCAA;c.2218C>T;c.2205dupT;c.2138T>G;c.2114_2118delAAGAA;c.2111T>A;c.2108delAinsTCC;c.2102T>G;c.2097+1G>C;c.2053C>T;c.2038_2039dupTT;c.2010dupT;c.1970delG;c.1941G>A;c.1941G>C;c.1940G>A;c.1936-1G>A;c.1936-2A>C;c.1936-2A>G;c.1889delC;c.1871C>A;c.1853_1854insG;c.1791delT;c.1776G>A;c.1741C>T;c.1702_1703delAA;c.1629-1G>T;c.1543delG;c.1510delA;c.1510dupA;c.1495C>T;c.1475delG;c.1474-1G>A;c.1473+1G>A;c.1425_1429delAACTT;c.1414G>T;c.1383T>G;c.1372G>T;c.1360G>T;c.1343G>A;c.1340+1G>A;c.1315C>T;c.1312delC;c.1294A>T;c.1240C>T;c.1236delA;c.1234_1235delGA;c.1201_1204dupTGTG;c.1162C>T;c.1156A>T;c.1140+1G>A;c.1126_1127delCA;c.1126C>T;c.1114_1115delCTinsA;c.1098_1102delTTGTC;c.1082delA;c.1066C>T;c.1045G>C;c.1018_1019insCT;c.1005G>A;c.1004G>A;c.958delA;c.939T>G;c.918+1G>A;c.917dupA;c.903delG;c.890_891insT;c.890delA;c.886G>T;c.866delT;c.840delT;c.804T>G;c.777dupT;c.667C>T;c.633delT;c.632delC;c.627+1G>A;c.576delT;c.566C>G;c.548delT;c.535G>T;c.514A>T;c.508-1G>C;c.508-2A>T;c.484C>T;c.477_481delAAGAA;c.463C>T;c.448G>T;c.440dupA;c.438_440delATAinsCT;c.409_410delAA;c.394dupA;c.386delC;c.349G>T;c.314C>G;c.307G>T;c.290_293delACAA;c.270C>A;c.243delA;c.206-1G>T;c.206-2A>G;c.205+2T>G;c.193C>T;c.141delC;c.133G>T;c.128_131delTGTT;c.103G>T;c.93+1G>A;c.93+1G>T;c.78dupT;c.68dupC;c.55dupT;c.46delT;c.40A>T;c.24T>A	Fanconi anemia, complementation group J is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.	Plus
BRWD3	Mental retardation, X-linked, type 93 Mental retardation, X-linked, type 93 Descrição da doença: Mental retardation, X-linked, type 93 (MRX93) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX93 is associated with macrocephaly.	NM_153252.4	c.3718C>T;c.2598_2601dupAAAT;c.946dupA;c.568C>T c.3718C>T;c.2598_2601dupAAAT;c.946dupA;c.568C>T	Mental retardation, X-linked, type 93 (MRX93) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX93 is associated with macrocephaly.	Plus
BSCL2	Congenital generalized lipodystrophy, type 2; Encephalopathy, progressive, with or without lipodystrophy Congenital generalized lipodystrophy, type 2; Encephalopathy, progressive, with or without lipodystrophy Descrição da doença: Congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 2 is a rare condition caused by pathogenic variants in the BSCL2 gene located on chromosomal region 11q12.3. Its characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. In some cases, this form of the condition is also associated with intellectual disability, which is usually mild to moderate. Progressive encephalopathy follows an autosomal recessive pattern of inheritance and is also caused by pathogenic variants in the BSCL2 gene. This is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance.	NM_001122955.3	c.1166_1167insG;c.1015C>T;c.1006-2A>G;c.985C>T;c.9 c.1166_1167insG;c.1015C>T;c.1006-2A>G;c.985C>T;c.974dupG;c.864-2A>C;c.864-2A>G;c.864-3C>G;c.863+5G>A;c.844_854delGCGCACTTCAC;c.828delC;c.826G>C;c.766-2A>G;c.757G>T;c.631-1G>C;c.604C>T;c.538G>T;c.517dupA;c.509_513delATCGT;c.507_508delGT;c.493_494insAA;c.461C>T;c.455A>G;c.384_385delCCinsGGA;c.385delCinsGGA;c.346_347dupTT	Congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 2 is a rare condition caused by pathogenic variants in the BSCL2 gene located on chromosomal region 11q12.3. Its characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. In some cases, this form of the condition is also associated with intellectual disability, which is usually mild to moderate. Progressive encephalopathy follows an autosomal recessive pattern of inheritance and is also caused by pathogenic variants in the BSCL2 gene. This is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance.	Plus
BSND	Bartter syndrome, type 4A Bartter syndrome, type 4A Descrição da doença: Bartter syndrome, type 4A with deafness follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BSND gene located on chromosomal region 1p32.3. The age of onset is neonatal/infantile. This disease is characterized by maternal polyhydramnios, premature delivery, polyuria, sensorineural deafness and is associated with hypokalemic alkalosis, increased levels of plasma renin and aldosterone, low blood pressure, and vascular resistance to angiotensin II.	NM_057176.2	c.1A>T;c.3G>A;c.10G>T;c.22C>T;c.23G>T;c.35T>C;c.13 c.1A>T;c.3G>A;c.10G>T;c.22C>T;c.23G>T;c.35T>C;c.139G>A	Bartter syndrome, type 4A with deafness follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BSND gene located on chromosomal region 1p32.3. The age of onset is neonatal/infantile. This disease is characterized by maternal polyhydramnios, premature delivery, polyuria, sensorineural deafness and is associated with hypokalemic alkalosis, increased levels of plasma renin and aldosterone, low blood pressure, and vascular resistance to angiotensin II.	Plus
BTD	Biotinidase deficiency Biotinidase deficiency Descrição da doença: Biotinidase deficiency an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BTD gene located on chromosomal region 3p25. The age of onset is neonatal/infantile. This disease is characterized by seizures, breathing difficulties, hypotonia, skin rash, alopecia, hearing loss and delayed development.	NM_001281726.1;NM_001281723.2	c.44+1G>A;c.44+1G>C;c.44+1G>T;c.104_110delGCGGCTGi c.44+1G>A;c.44+1G>C;c.44+1G>T;c.104_110delGCGGCTGinsTCC;c.113dupA;c.124_125delCT;c.142G>T;c.166G>T;c.177T>G;c.190G>A;c.190G>T;c.196G>A;c.198G>C;c.208_211dupATCC;c.200A>G;c.241C>T;c.251C>A;c.263T>G;c.268C>T;c.272delA;c.284A>G;c.289C>T;c.304G>A;c.316-1G>T;c.316G>T;c.322C>T;c.329_330dupTA;c.332dupT;c.332T>G;c.340G>A;c.340G>C;c.347G>T;c.378_381dupCATT;c.388T>G;c.399delC;c.412delC;c.426G>A;c.430C>A;c.449G>A;c.451T>C;c.460A>C;c.461C>G;c.465G>A;c.472C>T;c.475C>T;c.476G>A;c.496_497delAG;c.517G>A;c.534G>T;c.550delA;c.563G>A;c.565C>T;c.589A>G;c.590A>G;c.593delC;c.593C>G;c.600delC;c.601G>A;c.632G>A;c.635A>G;c.637delC;c.637C>T;c.643delC;c.649C>T;c.652T>A;c.658G>C;c.660G>C;c.670G>A;c.670G>C;c.689A>G;c.699delC;c.707C>T;c.715G>A;c.740G>A;c.761A>G;c.764C>T;c.789C>G;c.800A>T;c.838C>G;c.842T>A;c.842T>G;c.871G>C;c.893T>G;c.901G>C;c.902C>T;c.904A>C;c.935G>A;c.938G>A;c.939delT;c.939T>G;c.1007T>A;c.1055delC;c.1058delC;c.1102_1103dupTC;c.1132C>T;c.1163G>A;c.1164G>A;c.1197_1198delGA;c.1213T>G;c.1233_1247delGGGAAAGGAAGGCTAinsTTCCAATGGCC;c.1245delC;c.1247_1258delATCTCCACGTCT;c.1270dupC;c.1281T>G;c.1290C>A;c.1320T>A;c.1330delG;c.1336G>C;c.1345C>T;c.1358_1359delGC;c.1358G>A;c.1367A>G;c.1374A>C;c.1378dupT;c.1390delA;c.1400dupG;c.1461C>G;c.1464delG;c.1465delT;c.1495C>T;c.1499dupT;c.1514_1518delGGATG;c.1563T>G;c.1601C>T;c.1618C>T;c.1622dupT	Biotinidase deficiency an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BTD gene located on chromosomal region 3p25. The age of onset is neonatal/infantile. This disease is characterized by seizures, breathing difficulties, hypotonia, skin rash, alopecia, hearing loss and delayed development.	Plus
BTK	Agammaglobulinemia X-linked, type 1 Agammaglobulinemia X-linked, type 1 Descrição da doença: Agammaglobulinemia X-linked (XLA), type 1 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the BTK gene located on chromosomal region Xq21.33-q22. The age of onset is neonatal. Individuals with XLA are more susceptible to infections because their body makes very few antibodies. In children with XLA, infections generally take longer to get better and then they come back again, even with antibiotic medications. The most common bacterial infections that occur in people with XLA are lung infections (pneumonia and bronchitis), ear infections (otitis), pink eye (conjunctivitis), and sinus infections (sinusitis). Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage. The X-linked form accounts for approximately 85 to 90% of cases of agammaglobulinemia. The prevalence is 3:1,000,000-6:1,000,000 men.	NM_001287344.1;NM_000061.2	c.2008G>T;c.1991T>A;c.1990A>C;c.1940G>A;c.1922C>A; c.2008G>T;c.1991T>A;c.1990A>C;c.1940G>A;c.1922C>A;c.1882G>A;c.1875C>A;c.1868A>G;c.1862T>C;c.1859T>C;c.1843T>C;c.1790G>A;c.1790G>T;c.1787G>C;c.1786C>T;c.1775_1782delAATTTCCA;c.1734-2A>G;c.1733+1G>T;c.1727T>C;c.1661G>A;c.1660C>G;c.1660C>T;c.1628T>C;c.1618T>C;c.1613A>T;c.1608C>A;c.1591C>T;c.1557C>A;c.1544G>C;c.1543T>A;c.1390A>G;c.1377C>A;c.1325T>C;c.1287G>A;c.1227T>G;c.1205G>A;c.1184A>G;c.1166T>A;c.1103A>C;c.1021A>G;c.997-2A>G;c.996+1G>A;c.965G>A;c.964C>T;c.942-1G>A;c.879-2A>G;c.865C>T;c.857G>A;c.828dupT;c.820G>T;c.771T>A;c.755delA;c.744_745delTG;c.574_577delACAG;c.571C>T;c.537C>A;c.491delA;c.473G>A;c.472T>C;c.440T>A;c.412-1G>C;c.412-2A>G;c.409C>T;c.380C>A;c.330_333delAAGA;c.317dupA;c.266C>A;c.263delG;c.221A>G;c.199A>C;c.185G>A;c.148C>T;c.145C>T;c.143C>A;c.139C>T;c.2T>C	Agammaglobulinemia X-linked (XLA), type 1 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the BTK gene located on chromosomal region Xq21.33-q22. The age of onset is neonatal. Individuals with XLA are more susceptible to infections because their body makes very few antibodies. In children with XLA, infections generally take longer to get better and then they come back again, even with antibiotic medications. The most common bacterial infections that occur in people with XLA are lung infections (pneumonia and bronchitis), ear infections (otitis), pink eye (conjunctivitis), and sinus infections (sinusitis). Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage. The X-linked form accounts for approximately 85 to 90% of cases of agammaglobulinemia. The prevalence is 3:1,000,000-6:1,000,000 men.	Plus
BUB1B	Mosaic variegated aneuploidy syndrome 1 Mosaic variegated aneuploidy syndrome 1 Descrição da doença: Mosaic variegated aneuploidy is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies but is usually more than 25% and is substantially greater than in normal individuals. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases (Hanks et al., 2004).	NM_001211.5	c.340C>T;c.580C>T;c.1387A>T;c.1402-1G>T;c.1648C>T; c.340C>T;c.580C>T;c.1387A>T;c.1402-1G>T;c.1648C>T;c.1833delT;c.1954C>T;c.2208_2211dupGTTA;c.2210T>G;c.2308C>T	Mosaic variegated aneuploidy is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies but is usually more than 25% and is substantially greater than in normal individuals. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases (Hanks et al., 2004).	Plus
C12orf57	Temtamy syndrome Temtamy syndrome Descrição da doença: Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (Akizu et al., 2013).	NM_001301834.1	c.1A>G;c.184C>T c.1A>G;c.184C>T	Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (Akizu et al., 2013).	Plus
C12orf65	Combined oxidative phosphorylation deficiency 7; Spastic paraplegia, type 55, autosomal recessive Combined oxidative phosphorylation deficiency 7; Spastic paraplegia, type 55, autosomal recessive Descrição da doença: Combined oxidative phosphorylation deficiency 7 (COXPD7) is a mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness. Homozygous mutation in the C12ORF65 gene can also cause a less severe disorder, autosomal recessive spastic paraplegia-55 (SPG55). SPG55 is a form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations.	NM_001143905.2	c.96_99dupATCC;c.210delA;c.248delT;c.282+2T>A;c.34 c.96_99dupATCC;c.210delA;c.248delT;c.282+2T>A;c.346delG;c.394C>T;c.413_417delAACAA;c.415C>T	Combined oxidative phosphorylation deficiency 7 (COXPD7) is a mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness. Homozygous mutation in the C12ORF65 gene can also cause a less severe disorder, autosomal recessive spastic paraplegia-55 (SPG55). SPG55 is a form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations.	Plus
C19orf12	Neurodegeneration with brain iron accumulation, type 4 Neurodegeneration with brain iron accumulation, type 4 Descrição da doença: Neurodegeneration with brain iron accumulation, type 4 (NBIA4) is an autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (Dogu et al., 2013). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (Deschauer et al., 2012)	NM_001031726.3	c.238C>T;c.205G>A;c.194G>T;c.187G>C;c.157G>A;c.32C c.238C>T;c.205G>A;c.194G>T;c.187G>C;c.157G>A;c.32C>T	Neurodegeneration with brain iron accumulation, type 4 (NBIA4) is an autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (Dogu et al., 2013). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (Deschauer et al., 2012)	Plus
C1QA	C1q deficiency C1q deficiency Descrição da doença: C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	NM_015991.2	c.622C>T;c.648G>A c.622C>T;c.648G>A	C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	Plus
C1QB	C1q deficiency C1q deficiency Descrição da doença: C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	NM_000491.3	c.187+1G>T c.187+1G>T	C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	Plus
C1QC	C1q deficiency C1q deficiency Descrição da doença: C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	NM_001114101.1	c.205C>T;c.213delC c.205C>T;c.213delC	C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).	Plus
C1S	C1s deficiency C1s deficiency Descrição da doença: C1s deficiency is a rare defect resulting in impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis.	NM_001734.3	c.880T>C c.880T>C	C1s deficiency is a rare defect resulting in impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis.	Plus
C3	Complement component 3 deficiency Complement component 3 deficiency Descrição da doença: C3 deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the C3 gene located on chromosomal region 19p13.3-p13.2. The age of onset is infantile. It is a rare defect of the complement classical pathway. The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus, and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by Reis et al., 2006). The prevalence is <1:1.000.000.	NM_000064.3	c.4851-1G>A;c.3627_3628insGGGGCCC;c.3116dupT;c.256 c.4851-1G>A;c.3627_3628insGGGGCCC;c.3116dupT;c.2562C>G;c.2354+1G>A;c.1119+1G>T;c.1004-2A>T	C3 deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the C3 gene located on chromosomal region 19p13.3-p13.2. The age of onset is infantile. It is a rare defect of the complement classical pathway. The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus, and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by Reis et al., 2006). The prevalence is <1:1.000.000.	Plus
C5	Complement component 5 deficiency Complement component 5 deficiency Descrição da doença: C5 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.	NM_001317163.1;NM_001735.2	c.4890_4891delCCinsG;c.4444C>T;c.55C>T c.4890_4891delCCinsG;c.4444C>T;c.55C>T	C5 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.	Plus
C7	Complement component 7 deficiency Complement component 7 deficiency Descrição da doença: C7 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.	NM_000587.2	c.281-1G>T;c.1135G>C;c.1458T>A;c.2184T>A c.281-1G>T;c.1135G>C;c.1458T>A;c.2184T>A	C7 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.	Plus
C8B	Complement component 8 deficiency, type 2 Complement component 8 deficiency, type 2 Descrição da doença: Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (Ross and Densen, 1984).Two kinds of inherited C8 deficiency have been reported in man: type 1, in which only C8 alpha and C8 gamma are deficient, and type 2 (613789), in which only C8 beta (C8B; 120960) is deficient (Marcus et al., 1982; Tedesco et al., 1983). The 2 types are clinically indistinguishable (Ross and Densen, 1984).	NM_000066.3	c.1282C>T;c.1041_1047dupGGCTGTG;c.820C>T;c.605delC c.1282C>T;c.1041_1047dupGGCTGTG;c.820C>T;c.605delC;c.361C>T;c.336delC;c.271C>T	Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (Ross and Densen, 1984).Two kinds of inherited C8 deficiency have been reported in man: type 1, in which only C8 alpha and C8 gamma are deficient, and type 2 (613789), in which only C8 beta (C8B; 120960) is deficient (Marcus et al., 1982; Tedesco et al., 1983). The 2 types are clinically indistinguishable (Ross and Densen, 1984).	Plus
C8orf37	Bardet-Biedl syndrome, type 21; Cone-rod dystrophy 16 and Retintis pigmentosa 64 Bardet-Biedl syndrome, type 21; Cone-rod dystrophy 16 and Retintis pigmentosa 64 Descrição da doença: Bardet-Biedl syndrome 21 (BBS21) is an autosomal recessive ciliopathy characterized by obesity, postaxial polydactyly, retinal degeneration, and mild cognitive impairment (Heon et al., 2016; Khan et al., 2016). Mutation in the C8ORF37 gene can also cause cone-rod dystrophy (CORD16) and isolated retinitis pigmentosa (RP64). CORD16 and RP64 are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (Estrada-Cuzcano et al., 2012).	NM_177965.3	c.555G>A;c.497T>A;c.304A>T;c.156-2A>G;c.155+2T>C c.555G>A;c.497T>A;c.304A>T;c.156-2A>G;c.155+2T>C	Bardet-Biedl syndrome 21 (BBS21) is an autosomal recessive ciliopathy characterized by obesity, postaxial polydactyly, retinal degeneration, and mild cognitive impairment (Heon et al., 2016; Khan et al., 2016). Mutation in the C8ORF37 gene can also cause cone-rod dystrophy (CORD16) and isolated retinitis pigmentosa (RP64). CORD16 and RP64 are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (Estrada-Cuzcano et al., 2012).	Plus
CA12	Hyperchlorhidrosis, isolated Hyperchlorhidrosis, isolated Descrição da doença: Isolated hyperchlorhidrosis is an autosomal recessive condition in which excessive salt wasting in sweat can result in severe infantile hyponatremic dehydration and hyperkalemia (Muhammad et al., 2011).	NM_001218.4	c.908-1G>A;c.427G>A;c.363C>A c.908-1G>A;c.427G>A;c.363C>A	Isolated hyperchlorhidrosis is an autosomal recessive condition in which excessive salt wasting in sweat can result in severe infantile hyponatremic dehydration and hyperkalemia (Muhammad et al., 2011).	Plus
CA2	Osteopetrosis with renal tubular acidosis (osteopetrosis, autosomal recessive, type 3) Osteopetrosis with renal tubular acidosis (osteopetrosis, autosomal recessive, type 3) Descrição da doença: Osteopetrosis with renal tubular acidosis, also known as osteopetrosis, autosomal recessive, type 3, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CA2 gene located on chromosomal region 8q22. The age of onset is neonatal/infantile. This disease is characterized by osteopetrosis, renal tubular acidosis, and neurological disorders related to cerebral calcifications. The prevalence is <1:1.000.000.	NM_000067.2	c.120T>G;c.232+1G>A;c.319C>T;c.663+2T>C c.120T>G;c.232+1G>A;c.319C>T;c.663+2T>C	Osteopetrosis with renal tubular acidosis, also known as osteopetrosis, autosomal recessive, type 3, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CA2 gene located on chromosomal region 8q22. The age of onset is neonatal/infantile. This disease is characterized by osteopetrosis, renal tubular acidosis, and neurological disorders related to cerebral calcifications. The prevalence is <1:1.000.000.	Plus
CABP4	Congenital stationary night blindness, type 2B Congenital stationary night blindness, type 2B Descrição da doença: Congenital nonprogressive cone-rod synaptic disorder is characterized by stable low vision, nystagmus, photophobia, a normal or near-normal fundus appearance, and no night blindness. Electroretinography shows an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased to nonrecordable cone responses (Traboulsi, 2013; Khan, 2014).	NM_145200.3	c.81_82insA;c.646C>T;c.673C>T;c.800_801delAG c.81_82insA;c.646C>T;c.673C>T;c.800_801delAG	Congenital nonprogressive cone-rod synaptic disorder is characterized by stable low vision, nystagmus, photophobia, a normal or near-normal fundus appearance, and no night blindness. Electroretinography shows an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased to nonrecordable cone responses (Traboulsi, 2013; Khan, 2014).	Plus
CACNA1D	Sinoatrial node dysfunction and deafness Sinoatrial node dysfunction and deafness Descrição da doença: Patients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (Baig et al., 2011).	NM_000720.3	c.1208_1209insGGG;c.1208G>A;c.2305G>A;c.4422+1G>C c.1208_1209insGGG;c.1208G>A;c.2305G>A;c.4422+1G>C	Patients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (Baig et al., 2011).	Plus
CACNA1F	Cone-rod dystrophy, X-linked, type 3; Night blindness, congenital stationary, type 2A; Aland Island eye disease Cone-rod dystrophy, X-linked, type 3; Night blindness, congenital stationary, type 2A; Aland Island eye disease Descrição da doença: Cone-rod dystrophy is a retinal disorder with predominantly cone involvement. Rod impairment may occur at the same time as the cone impairment or appear later. Patients with CORD usually have reduced visual acuity, photophobia, and color vision defects (Huang et al., 2013). Mutation in the CACNA1F gene can also cause Aland Island eye disease (AIED) and X-linked incomplete congenital stationary night blindness (CSNB2A). AIED is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (303900), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (King et al., 2001). CSNB2A is a nonprogressive retinal disorder characterized by decreased visual acuity and loss of night vision. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa.	NM_005183.3	c.4723G>T;c.3742-2A>C;c.3628C>T;c.3472-1_3475delGC c.4723G>T;c.3742-2A>C;c.3628C>T;c.3472-1_3475delGCGTCinsTGG;c.3433G>T;c.3341_3342delCA;c.3269+1G>A;c.3166dupC;c.3070-2A>G;c.2905C>T;c.2766+1G>A;c.2683C>T;c.2576+1G>A;c.2267T>C;c.1873C>T;c.1538_1542delGAGCC;c.1537C>T;c.1338_1339insT;c.1218delC;c.1106G>A;c.784C>T;c.694A>T;c.276delG;c.244C>T;c.148C>T	Cone-rod dystrophy is a retinal disorder with predominantly cone involvement. Rod impairment may occur at the same time as the cone impairment or appear later. Patients with CORD usually have reduced visual acuity, photophobia, and color vision defects (Huang et al., 2013). Mutation in the CACNA1F gene can also cause Aland Island eye disease (AIED) and X-linked incomplete congenital stationary night blindness (CSNB2A). AIED is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (303900), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (King et al., 2001). CSNB2A is a nonprogressive retinal disorder characterized by decreased visual acuity and loss of night vision. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa.	Plus
CANT1	Desbuquois dysplasia, type 1; Epiphyseal dysplasia, multiple, type 7 Desbuquois dysplasia, type 1; Epiphyseal dysplasia, multiple, type 7 Descrição da doença: Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (Huber et al., 2009).Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Other forms of skeletal dysplasia caused by mutation in the CANT1 gene include epiphyseal dysplasia, type 7 (EDM7). EDM7 is a form of multiple epiphyseal dysplasia, a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. EDM7 inheritance is autosomal recessive.	NM_001159772.1	c.902_906dupGCGCC;c.899G>A;c.898C>T;c.734delC;c.37 c.902_906dupGCGCC;c.899G>A;c.898C>T;c.734delC;c.374G>A;c.277_278delCT;c.278delT;c.228dupC	Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (Huber et al., 2009).Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Other forms of skeletal dysplasia caused by mutation in the CANT1 gene include epiphyseal dysplasia, type 7 (EDM7). EDM7 is a form of multiple epiphyseal dysplasia, a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. EDM7 inheritance is autosomal recessive.	Plus
CAPN3	Limb-girdle muscular dystrophy, type 1 (LGMD R1) Limb-girdle muscular dystrophy, type 1 (LGMD R1) Descrição da doença: Limb-girdle muscular dystrophy type 1 (LGMDR1; formerly LGMD2A) follows an autosomal recessive pattern of inheritance and is caused by biallelic pathogenic variants in the CAPN3 gene located on chromosomal region 15q15.1. The age of onset is variable. This disease is characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.The prevalence is 1:100,000- 9:100,000. Genetic heterogeneity: Heterozygous mutation in the CAPN3 gene can cause autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4; OMIM 618129), which has a later onset and milder features.	NM_000070.2;NM_173088.1	c.59delC;c.133G>A;c.145C>T;c.146G>A;c.223dupT;c.24 c.59delC;c.133G>A;c.145C>T;c.146G>A;c.223dupT;c.245C>T;c.257C>T;c.258dupT;c.310G>T;c.319G>T;c.327_328dupCC;c.328C>T;c.402delC;c.439C>T;c.483delG;c.499-1G>A;c.503G>A;c.509A>G;c.518G>A;c.533T>C;c.550delA;c.580delT;c.598_612delTTCTGGAGTGCTCTG;c.639dupT;c.640G>A;c.649G>A;c.664G>A;c.701G>A;c.717delT;c.741_751delCATGTACAAGA;c.742_743delAT;c.759_761delGAA;c.801+1G>A;c.802-9G>A;c.853dupG;c.855_864dupGTTGATTGCA;c.865C>T;c.883_886delGATAinsCTT;c.946-1G>A;c.956C>T;c.985G>A;c.1027G>T;c.1030-1G>A;c.1043delG;c.1063C>T;c.1069C>T;c.1079G>A;c.1080G>C;c.1115+1G>A;c.1115+2T>A;c.1115+2T>C;c.1118G>A;c.1127G>A;c.-3311A>G;c.1234G>T;c.1250C>T;c.1256A>G;c.1257T>G;c.1276_1277delCT;c.1292dupT;c.1298_1299delTG;c.1303G>A;c.1309C>T;c.1318C>T;c.1322delG;c.1319G>A;c.1333G>A;c.1342C>G;c.1342C>T;c.1343G>A;c.1355-1G>C;c.1373delC;c.1381C>T;c.1435A>G;c.1465C>T;c.1466G>A;c.1468C>T;c.1469G>A;c.1477C>T;c.1517T>C;c.1524+1G>A;c.1524+1G>T;c.1524+2T>C;c.1599_1602delGAGC;c.1611C>A;c.1621C>T;c.1622G>A;c.1642delC;c.1662C>G;c.1699G>T;c.1711delC;c.1714C>T;c.1715G>A;c.1722delC;c.1743_1744delTG;c.1771delG;c.1795dupA;c.1801-1G>A;c.1817C>T;c.1838delA;c.1855C>T;c.1858G>T;c.1863dupA;c.1882delA;c.1914+2T>C;c.1939G>T;c.1944_1945delTG;c.1948G>T;c.1957C>T;c.1981delA;c.1992+1G>T;c.1992+2T>A;c.1993-1G>A;c.1999dupG;c.2007T>A;c.2036_2037delCA;c.2050+1delG;c.2050+1G>A;c.2051-1G>C;c.2051-1G>T;c.2069_2070delAC;c.2092C>T;c.2105C>T;c.2115+1_2115+2dupGT;c.2115+1G>A;c.2115+2T>C;c.2120A>G;c.2134C>T;c.2179delT;c.2184+2T>C;c.2185-2A>G;c.2207_2208delCA;c.2212C>T;c.2242C>T;c.2243G>A;c.2251_2254dupGTCA;c.2263+1G>A;c.2279dupA;c.2288A>G;c.2290delG;c.2305C>T;c.2306G>A;c.2314_2317delGACA;c.2338G>C;c.2361_2362insTC;c.2362_2363delAGinsTCATCT;c.2380+1G>T;c.2381-2A>G;c.2381-1G>A;c.2393C>A;c.2440-2A>G;c.2440-1G>A	Limb-girdle muscular dystrophy type 1 (LGMDR1; formerly LGMD2A) follows an autosomal recessive pattern of inheritance and is caused by biallelic pathogenic variants in the CAPN3 gene located on chromosomal region 15q15.1. The age of onset is variable. This disease is characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.The prevalence is 1:100,000- 9:100,000. Genetic heterogeneity: Heterozygous mutation in the CAPN3 gene can cause autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4; OMIM 618129), which has a later onset and milder features.	Plus
CARD9	Candidiasis, familial, type 2, autosomal recessive Candidiasis, familial, type 2, autosomal recessive Descrição da doença: Candidiasis, familial, type 2, autosomal recessive is a primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans.	NM_052813.4	c.883C>T;c.865C>T c.883C>T;c.865C>T	Candidiasis, familial, type 2, autosomal recessive is a primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans.	Plus
CASK	Mental retardation, X-linked, syndromic, Najm type Mental retardation, X-linked, syndromic, Najm type Descrição da doença: Mental retardation, X-linked, syndromic, Najm type is an X-linked disorder affecting females and characterized by severe intellectual disability, microcephaly, and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (Moog et al., 2011).	NM_003688.3	c.2589+1G>T;c.2512A>T;c.2506-2A>G;c.2470C>T;c.2377 c.2589+1G>T;c.2512A>T;c.2506-2A>G;c.2470C>T;c.2377C>T;c.2368C>T;c.2329G>T;c.2302+1G>A;c.2255dupA;c.2168A>G;c.2155+2T>C;c.2155+1G>C;c.2100G>A;c.2074C>T;c.2065A>T;c.2041C>T;c.2040-1G>A;c.1981delC;c.1976G>A;c.1915C>T;c.1864G>T;c.1644_1645delAG;c.1639C>T;c.1609C>T;c.1480C>T;c.1465C>T;c.1033+1G>A;c.1015+1G>C;c.764G>A;c.708+1G>A;c.626T>C;c.609G>A;c.523dupG;c.430-2A>T;c.429+1G>A;c.316C>T;c.109C>T;c.82C>T;c.79C>T;c.68delT;c.59+2T>C	Mental retardation, X-linked, syndromic, Najm type is an X-linked disorder affecting females and characterized by severe intellectual disability, microcephaly, and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (Moog et al., 2011).	Plus
CASQ2	Ventricular tachycardia, catecholaminergic polymorphic, type 2 Ventricular tachycardia, catecholaminergic polymorphic, type 2 Descrição da doença: Ventricular tachycardia, catecholaminergic polymorphic, type 2 is an arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress.	NM_001232.3	c.940-1G>T;c.939+1G>T;c.923C>T;c.919G>C;c.783G>A;c c.940-1G>T;c.939+1G>T;c.923C>T;c.919G>C;c.783G>A;c.606+1G>C;c.578_580delTCAinsAC;c.546delT;c.500T>A;c.235-2A>G;c.234+2T>C;c.164A>G;c.97C>T;c.62delA	Ventricular tachycardia, catecholaminergic polymorphic, type 2 is an arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress.	Plus
CASR	Hyperparathyroidism, neonatal Hyperparathyroidism, neonatal Descrição da doença: Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (Egbuna and Brown, 2008).	NM_001178065.1	c.73C>T;c.108dupG;c.115C>G;c.141A>C;c.164C>T;c.166 c.73C>T;c.108dupG;c.115C>G;c.141A>C;c.164C>T;c.166delG;c.185G>T;c.186-1G>T;c.196C>T;c.280G>T;c.354C>A;c.374T>C;c.380A>C;c.380A>G;c.382T>C;c.393C>G;c.413C>T;c.428G>A;c.452C>T;c.514A>G;c.539T>G;c.553C>T;c.554delG;c.554G>A;c.577C>T;c.649G>T;c.658C>T;c.662C>A;c.662C>T;c.679C>G;c.679C>T;c.680G>A;c.680G>T;c.733C>T;c.889G>A;c.1183T>C;c.1512_1515delGTTT;c.1525G>A;c.1660C>T;c.1687G>A;c.1706C>A;c.1715G>C;c.1775G>T;c.1840G>A;c.1865T>C;c.1867G>A;c.1876C>G;c.1943G>T;c.1964C>A;c.1972C>T;c.2039G>A;c.2068C>T;c.2131delC;c.2210T>A;c.2273C>A;c.2348T>G;c.2392T>C;c.2393T>G;c.2413C>T;c.2447T>C;c.2461A>G;c.2479G>A;c.2489C>T;c.2558C>A;c.2687G>C	Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (Egbuna and Brown, 2008).	Plus
CAST	Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads Descrição da doença: Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads is an autosomal recessive disease characterized by generalized, continuous shedding of the outer layers of the epidermis, leukonychia, acral punctate keratosis, cheilitis, knuckle pads with multiple hyperkeratotic micropapules involving the interphalangeal joints, and palmoplantar keratoderma.	NM_001042442.2	c.481A>T;c.664dupA;c.1807delG c.481A>T;c.664dupA;c.1807delG	Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads is an autosomal recessive disease characterized by generalized, continuous shedding of the outer layers of the epidermis, leukonychia, acral punctate keratosis, cheilitis, knuckle pads with multiple hyperkeratotic micropapules involving the interphalangeal joints, and palmoplantar keratoderma.	Plus
CATSPER1	Male infertility spermatogenic failure, type 7 Male infertility spermatogenic failure, type 7 Descrição da doença: Spermatogenic failure, type 7 is an infertility disorder characterized by non-motile sperm or sperm motility below the normal threshold, low sperm count, increased abnormally structured spermatozoa, and reduced semen volume.	NM_053054.3	c.944_948dupATGGC;c.539dupT c.944_948dupATGGC;c.539dupT	Spermatogenic failure, type 7 is an infertility disorder characterized by non-motile sperm or sperm motility below the normal threshold, low sperm count, increased abnormally structured spermatozoa, and reduced semen volume.	Plus
CAVIN1	Lipodystrophy, congenital generalized, type 4 Lipodystrophy, congenital generalized, type 4 Descrição da doença: Congenital generalized lipodystrophy type 4 combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009).	NM_012232.5	c.696dupC;c.526delG;c.518_521delAAGA;c.478_481dupG c.696dupC;c.526delG;c.518_521delAAGA;c.478_481dupGTGA;c.471+1G>T;c.362dupT;c.160delG;c.135delG	Congenital generalized lipodystrophy type 4 combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009).	Plus
CBS	Homocystinuria due to cystathionine beta-synthase Homocystinuria due to cystathionine beta-synthase Descrição da doença: Homocystinuria due to cystathionine beta-synthase follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CBS gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by the multiple involvement of the eye, skeleton, central nervous system and vascular system. The prevalence is 1:200,000-1:335,000.	NM_000071.2	c.1566delG;c.1552+1G>A;c.1545delG;c.1468-1G>A;c.13 c.1566delG;c.1552+1G>A;c.1545delG;c.1468-1G>A;c.1359-1G>C;c.1358+2T>C;c.1358+1G>A;c.1330G>A;c.1321A>T;c.1280C>T;c.1224-2A>C;c.1219_1223+8delCCCTGGTAAGACC;c.1223G>A;c.1221delC;c.1218delG;c.1150A>G;c.1136G>A;c.1111G>A;c.1109G>A;c.1087delG;c.1058C>T;c.1039G>A;c.1009_1012delATGC;c.1007G>A;c.1006C>T;c.992C>A;c.969G>A;c.959T>C;c.954+2T>G;c.954+1G>A;c.919G>A;c.904G>A;c.903C>G;c.833T>C;c.829-1G>C;c.828+1G>A;c.816T>A;c.797G>A;c.785C>T;c.770C>T;c.738delG;c.737-1G>C;c.736+2T>G;c.707_708delCCinsGGTG;c.700G>A;c.689delT;c.676G>A;c.667-14_667-7delCTCTTTCT;c.572C>T;c.532-2A>G;c.526G>T;c.502G>A;c.494G>A;c.467delT;c.451+1G>T;c.442G>A;c.434C>T;c.430G>A;c.415G>A;c.402delG;c.393G>C;c.374G>A;c.373C>T;c.362G>A;c.346G>A;c.341C>T;c.325T>C;c.316+1G>A;c.306G>C;c.302T>C;c.253G>A;c.233C>G;c.209+2T>C;c.209+1G>C;c.153_165delGTGCACCTGGCAG;c.162G>A;c.146C>T;c.28delG;c.19dupC	Homocystinuria due to cystathionine beta-synthase follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CBS gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by the multiple involvement of the eye, skeleton, central nervous system and vascular system. The prevalence is 1:200,000-1:335,000.	Plus
CC2D1A	Mental retardation, autosomal recessive, type 3 Mental retardation, autosomal recessive, type 3 Descrição da doença: Mental retardation, autosomal recessive, type 3 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs.	NM_017721.4	c.748+1G>T;c.2176C>T c.748+1G>T;c.2176C>T	Mental retardation, autosomal recessive, type 3 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs.	Plus
CC2D2A	Joubert syndrome type 9 Joubert syndrome type 9 Descrição da doença: Joubert syndrome type 9 defect follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CC2D2A gene located on chromosomal region 4p15.32. The age of onset is neonatal/infantile. This disease is characterized neonatal hypotonia, developmental delay, intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia, primary position nystagmus and congenital hepatic fibrosis.	NM_001080522.2	c.100C>T;c.176delA;c.394C>T;c.517C>T;c.585_586dupT c.100C>T;c.176delA;c.394C>T;c.517C>T;c.585_586dupTA;c.834delG;c.1017dupC;c.1017+1G>A;c.1149+1G>A;c.1267C>T;c.1339delG;c.1370T>A;c.1558C>T;c.1696G>T;c.2486+1G>C;c.2624C>A;c.2683C>T;c.2773C>T;c.2848C>T;c.3055C>T;c.3084delG;c.3134T>C;c.3145C>T;c.3288G>C;c.3289delG;c.3341C>T;c.3364C>T;c.3452T>C;c.3522_3523insTG;c.3544T>C;c.3545G>A;c.3584delT;c.3594+1G>A;c.3652C>T;c.3744_3747dupGGTT;c.3772-1G>T;c.3774dupT;c.3850C>T;c.3892_3893delGT;c.3893T>A;c.3975+4_3975+7delAGTA;c.3988C>T;c.4065+2T>C;c.4179+1delG;c.4179+1G>A;c.4181delG;c.4333C>T;c.4437+1G>A;c.4465_4468delGACA;c.4483G>T;c.4489C>T;c.4496+2T>A;c.4497-2A>G;c.4582C>T;c.4667A>T;c.4844_4847delCTCT	Joubert syndrome type 9 defect follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CC2D2A gene located on chromosomal region 4p15.32. The age of onset is neonatal/infantile. This disease is characterized neonatal hypotonia, developmental delay, intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia, primary position nystagmus and congenital hepatic fibrosis.	Plus
CCBE1	Hennekam lymphangiectasia-lymphedema syndrome, type 1 Hennekam lymphangiectasia-lymphedema syndrome, type 1 Descrição da doença: Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (Alders et al., 2014).	NM_133459.3	c.683_684insT;c.520T>C;c.305G>C c.683_684insT;c.520T>C;c.305G>C	Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (Alders et al., 2014).	Plus
CCDC103	Ciliary dyskinesia, primary, type 17 Ciliary dyskinesia, primary, type 17 Descrição da doença: Ciliary dyskinesia, primary, type 17 (CILD17) is an autosomal recessive disorder characterized by early infantile onset of respiratory distress associated with a defect in the function of ciliary outer dynein arms. Situs inversus is variable (Panizzi et al., 2012).	NM_001258395.1	c.115C>T;c.383dupG;c.461A>C c.115C>T;c.383dupG;c.461A>C	Ciliary dyskinesia, primary, type 17 (CILD17) is an autosomal recessive disorder characterized by early infantile onset of respiratory distress associated with a defect in the function of ciliary outer dynein arms. Situs inversus is variable (Panizzi et al., 2012).	Plus
CCDC39	Ciliary dyskinesia, primary, type 14 Ciliary dyskinesia, primary, type 14 Descrição da doença: Ciliary dyskinesia, primary, type 14 (CILD14) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011).	NM_181426.1	c.2551G>T;c.2497_2498delCA;c.2357_2359delGTAinsT;c c.2551G>T;c.2497_2498delCA;c.2357_2359delGTAinsT;c.2226C>A;c.2190delA;c.1874+1G>A;c.1795C>T;c.1744delG;c.1665+1G>A;c.1644delT;c.1073_1076delCAAA;c.1072delA;c.830_831delCA;c.610-2A>G;c.526_527delCT;c.402T>A;c.357+1G>C;c.286C>T;c.163_164delAT	Ciliary dyskinesia, primary, type 14 (CILD14) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011).	Plus
CCDC40	Ciliary dyskinesia, primary, type 15 Ciliary dyskinesia, primary, type 15 Descrição da doença: Ciliary dyskinesia, primary, type 15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Becker-Heck et al., 2011).	NM_017950.3	c.248delC;c.855+1G>A;c.940-2A>G;c.961C>T;c.1276G>T c.248delC;c.855+1G>A;c.940-2A>G;c.961C>T;c.1276G>T;c.1315C>T;c.1345C>T;c.1416delG;c.1440+1G>C;c.1620delC;c.1951C>T;c.1989+1G>A;c.2235+1G>T;c.2440C>T;c.2450-1G>A;c.2591_2592delCAinsACCG;c.2671G>T;c.2712-1G>A;c.2712-1G>T;c.2824_2825insCTGT;c.2824_2825insTGT;c.2852dupT;c.3097A>T;c.3129delC;c.3181-2A>G	Ciliary dyskinesia, primary, type 15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Becker-Heck et al., 2011).	Plus
CCDC88C	Hydrocephalus, congenital, type 1 Hydrocephalus, congenital, type 1 Descrição da doença: Hydrocephalus, congenital, type 1 is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (Drielsma et al., 2012).Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014).	NM_001080414.3	c.5841_5842delAG;c.5058+1G>A;c.1219C>T;c.934C>T c.5841_5842delAG;c.5058+1G>A;c.1219C>T;c.934C>T	Hydrocephalus, congenital, type 1 is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (Drielsma et al., 2012).Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014).	Plus
CD19	Immunodeficiency, common variable, type 3 Immunodeficiency, common variable, type 3 Descrição da doença: Immunodeficiency, common variable, type 3 is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	NM_001178098.1	c.947-1G>T;c.1303+1G>C;c.1372+1G>A;c.1464delC c.947-1G>T;c.1303+1G>C;c.1372+1G>A;c.1464delC	Immunodeficiency, common variable, type 3 is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	Plus
CD27	Lymphoproliferative syndrome 2 Lymphoproliferative syndrome 2 Descrição da doença: Lymphoproliferative syndrome ,type 2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (Salzer et al., 2013).	NM_001242.4	c.24G>A;c.158G>A;c.541C>T c.24G>A;c.158G>A;c.541C>T	Lymphoproliferative syndrome ,type 2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (Salzer et al., 2013).	Plus
CD3D	Immunodeficiency, type 19 Immunodeficiency, type 19 Descrição da doença: Immunodeficiency, type 19 is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype. The disorder is lethal in early childhood without bone marrow transplantation (Yu et al., 2011).	NM_000732.4	c.279C>A;c.202C>T c.279C>A;c.202C>T	Immunodeficiency, type 19 is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype. The disorder is lethal in early childhood without bone marrow transplantation (Yu et al., 2011).	Plus
CD3E	Immunodeficiency, type 18 Immunodeficiency, type 18 Descrição da doença: Immunodeficiency, type 18 is an autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18 (de Saint Basile et al., 2004).	NM_000733.3	c.128_129delCC;c.176G>A;c.520+2T>C c.128_129delCC;c.176G>A;c.520+2T>C	Immunodeficiency, type 18 is an autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18 (de Saint Basile et al., 2004).	Plus
CD3G	Immunodeficiency, type 17, CD3 gamma deficient Immunodeficiency, type 17, CD3 gamma deficient Descrição da doença: Immunodeficiency, type 17 is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (Timon et al. (1993) and Recio et al. (2007)).	NM_000073.2	c.1A>G;c.205A>T c.1A>G;c.205A>T	Immunodeficiency, type 17 is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (Timon et al. (1993) and Recio et al. (2007)).	Plus
CD40	Immunodeficiency with hyper-IgM, type 3 Immunodeficiency with hyper-IgM, type 3 Descrição da doença: Immunodeficiency with hyper-IgM, type 3 (HIGM3), first described in humans by Ferrari et al. (2001), is characterized by hypogammaglobulinemia with normal or elevated levels of IgM.	NM_001322421.1	c.247T>C;c.256+2T>C c.247T>C;c.256+2T>C	Immunodeficiency with hyper-IgM, type 3 (HIGM3), first described in humans by Ferrari et al. (2001), is characterized by hypogammaglobulinemia with normal or elevated levels of IgM.	Plus
CD40LG	Hyper-IgM syndrome, type 1 (immunodeficiency, X-linked, with hyper-IgM, type 1) Hyper-IgM syndrome, type 1 (immunodeficiency, X-linked, with hyper-IgM, type 1) Descrição da doença: Hyper-IgM syndrome, type 1, also known as X-linked immunodeficiency with hyper-IgM, type 1 (HIGM1) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the CD40LG gene located on chromosomal region Xq26. The age of onset is neonatal/infantile. This disease is characterized by lower-respiratory tract bacterial infections, opportunistic infections, recurrent or protracted diarrhea associated with failure to thrive, neutropenia, thrombocytopenia and anemia. The prevalence is 2:1,000,000 male newborns.	NM_000074.2	c.31C>T;c.107T>G;c.189delT;c.216C>A;c.346+1delG;c. c.31C>T;c.107T>G;c.189delT;c.216C>A;c.346+1delG;c.347-2A>G;c.368C>A;c.418T>G;c.419G>A;c.431G>A;c.440C>A;c.464T>C;c.506A>G;c.559delG;c.658C>T;c.680G>T;c.703G>C;c.719_720delAT;c.761C>T;c.767T>C	Hyper-IgM syndrome, type 1, also known as X-linked immunodeficiency with hyper-IgM, type 1 (HIGM1) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the CD40LG gene located on chromosomal region Xq26. The age of onset is neonatal/infantile. This disease is characterized by lower-respiratory tract bacterial infections, opportunistic infections, recurrent or protracted diarrhea associated with failure to thrive, neutropenia, thrombocytopenia and anemia. The prevalence is 2:1,000,000 male newborns.	Plus
CD55	Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) Descrição da doença: Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).	NM_001300902.1	c.110delG;c.149_150delAAinsCCTT;c.287-1G>A;c.800G> c.110delG;c.149_150delAAinsCCTT;c.287-1G>A;c.800G>C	Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).	Plus
CD59	CD59 Deficiency CD59 Deficiency Descrição da doença: Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (Nevo et al., 2013).	NM_000611.5	c.266G>A;c.146delA c.266G>A;c.146delA	Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (Nevo et al., 2013).	Plus
CD79A	Agammaglobulinemia 3 Agammaglobulinemia 3 Descrição da doença: Agammaglobulinemia 3 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.	NM_001783.3	c.198G>A c.198G>A	Agammaglobulinemia 3 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.	Plus
CD79B	Agammaglobulinemia 6 Agammaglobulinemia 6 Descrição da doença: Agammaglobulinemia 6 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.	NM_001039933.2	c.412G>A;c.241C>T c.412G>A;c.241C>T	Agammaglobulinemia 6 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.	Plus
CD81	Immunodeficiency, common variable, type 6 Immunodeficiency, common variable, type 6 Descrição da doença: Immunodeficiency, common variable, type 6 (CVID6) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	NM_004356.3	c.561+1G>A c.561+1G>A	Immunodeficiency, common variable, type 6 (CVID6) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	Plus
CD8A	CD8 deficiency, familial CD8 deficiency, familial Descrição da doença: CD8 deficiency, familial is a immunologic defect characterized by absence of CD8+ cells, leading to recurrent bacterial infections.	NM_001145873.1	c.331G>A c.331G>A	CD8 deficiency, familial is a immunologic defect characterized by absence of CD8+ cells, leading to recurrent bacterial infections.	Plus
CDAN1	Dyserythropoietic anemia, congenital, type 1A Dyserythropoietic anemia, congenital, type 1A Descrição da doença: Dyserythropoietic anemia, congenital, type 1A is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary et al., 2005). Striking morphologic abnormalities of erythroblasts, reviewed by Wickramasinghe and Wood (2005), include the 'Swiss-cheese' abnormality of erythroblasts on electron microscopy.Four types of CDA, all of which show show ineffective erythropoiesis and multinuclear erythroblasts, have been characterized by clinical and hematopoietic findings. The classification of the first 3 types is based on that described by Wendt and Heimpel (1967). Type 1 is characterized by megaloblastic changes. The more common type 2 (224100) is characterized by normocytic binuclear or multinuclear red cells, which on electron microscopy contain double cytoplasmic membranes. Type 3 (105600), which shows autosomal dominant inheritance, has prominent erythroblastic multinuclearity forming 'gigantoblasts' with up to 12 nuclei. Type 4 (613673) is the designation given to a form of CDA with characteristics different from those of types 1, 2 and 3 (Wickramasinghe et al., 1991; Arnaud et al., 2010).	NM_138477.2	c.3145dupT;c.2867_2868+1dupCCG;c.2602T>A c.3145dupT;c.2867_2868+1dupCCG;c.2602T>A	Dyserythropoietic anemia, congenital, type 1A is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary et al., 2005). Striking morphologic abnormalities of erythroblasts, reviewed by Wickramasinghe and Wood (2005), include the 'Swiss-cheese' abnormality of erythroblasts on electron microscopy.Four types of CDA, all of which show show ineffective erythropoiesis and multinuclear erythroblasts, have been characterized by clinical and hematopoietic findings. The classification of the first 3 types is based on that described by Wendt and Heimpel (1967). Type 1 is characterized by megaloblastic changes. The more common type 2 (224100) is characterized by normocytic binuclear or multinuclear red cells, which on electron microscopy contain double cytoplasmic membranes. Type 3 (105600), which shows autosomal dominant inheritance, has prominent erythroblastic multinuclearity forming 'gigantoblasts' with up to 12 nuclei. Type 4 (613673) is the designation given to a form of CDA with characteristics different from those of types 1, 2 and 3 (Wickramasinghe et al., 1991; Arnaud et al., 2010).	Plus
CDH23	Deafness, autosomal recessive, type 12; Usher syndrome, type 1D Deafness, autosomal recessive, type 12; Usher syndrome, type 1D Descrição da doença: Non-syndromic autosomal recessive deafness, type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH23 gene located on chromosomal region 10p22.1. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. Mutation in the CDH23 gene can also cause the more severe Usher syndrome 1D. Usher syndrome type 1 is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction.	NM_022124.5	c.46delG;c.146-2A>G;c.193delC;c.288+1G>A;c.288+1G> c.46delG;c.146-2A>G;c.193delC;c.288+1G>A;c.288+1G>C;c.380A>G;c.478G>A;c.945+1G>A;c.945+1G>T;c.1036C>T;c.1037C>T;c.1428dupG;c.1675C>T;c.1858+2T>G;c.1949dupC;c.1987-1G>A;c.2012delT;c.2289+1G>A;c.3141C>A;c.3181G>A;c.3221-2A>G;c.3241C>T;c.3481C>T;c.3516_3519delATCC;c.3579+2T>C;c.3628C>T;c.3706C>T;c.3880C>T;c.4021G>A;c.4309C>T;c.4504C>T;c.5237G>A;c.5272C>T;c.5663T>C;c.5712+1G>A;c.5923+1G>A;c.6049+1G>A;c.6050-9G>A;c.6133G>A;c.6253+1G>A;c.6393delC;c.6402_6405delAGAG;c.6412delG;c.6442G>A;c.6604G>A;c.6667delC;c.6712+1G>A;c.6968delC;c.7054+1G>A;c.7225-1G>A;c.7362G>A;c.7483-1G>C;c.7660+1G>T;c.7776G>A;c.7873-2A>T;c.7908C>G;c.7921G>C;c.7979_7986delACTGGGAG;c.8064+1G>T;c.8222C>A;c.8770_8771insTGGCTGTA;c.8781C>A;c.9129delG;c.9556C>T;c.9629_9632delTCAA	Non-syndromic autosomal recessive deafness, type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH23 gene located on chromosomal region 10p22.1. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. Mutation in the CDH23 gene can also cause the more severe Usher syndrome 1D. Usher syndrome type 1 is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction.	Plus
CDH3	Ectodermal dysplasia, ectrodactyly, and macular dystrophy Ectodermal dysplasia, ectrodactyly, and macular dystrophy Descrição da doença: Ectodermal dysplasia, ectrodactyly, and macular dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH3 gene located on chromosomal region 16q22.1. The age of onset is neonatal/infantile. This disease is characterized by the association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. The prevalence is <1:1,000,000.	NM_001793.5	c.461dupC;c.830delG;c.895C>T;c.965A>T;c.981delG;c. c.461dupC;c.830delG;c.895C>T;c.965A>T;c.981delG;c.1085G>A;c.1508G>A	Ectodermal dysplasia, ectrodactyly, and macular dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH3 gene located on chromosomal region 16q22.1. The age of onset is neonatal/infantile. This disease is characterized by the association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. The prevalence is <1:1,000,000.	Plus
CDHR1	Cone-rod dystrophy, type 15 Cone-rod dystrophy, type 15 Descrição da doença: Cone-rod dystrophy, type 15 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDHR1 gene located on chromosomal region 10q23.1. This disease is characterized by decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. The overall prevalence of all types of cone-rod dystrophy is 1-9:100,000.	NM_033100.3	c.270dupC;c.338delG;c.476C>A;c.524dupA;c.640delG;c c.270dupC;c.338delG;c.476C>A;c.524dupA;c.640delG;c.709delG;c.863-1G>A;c.1112delC;c.1463delG;c.1485+2T>C;c.1485+2T>G;c.1527T>G;c.1536T>A	Cone-rod dystrophy, type 15 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDHR1 gene located on chromosomal region 10q23.1. This disease is characterized by decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. The overall prevalence of all types of cone-rod dystrophy is 1-9:100,000.	Plus
CDK5RAP2	Primary microcephaly type 3, autosomal recessive Primary microcephaly type 3, autosomal recessive Descrição da doença: Primary autosomal recessive microcephaly type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDK5RAP2 gene located on chromosomal region 9q33.2. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	NM_018249.5	c.5227C>T;c.5127_5128dupGT;c.4672C>T;c.4658_4661du c.5227C>T;c.5127_5128dupGT;c.4672C>T;c.4658_4661dupTATT;c.4604+1G>C;c.4546G>T;c.4441C>T;c.4207C>T;c.4005-1G>A;c.3097delG;c.1066C>T;c.1018delG;c.700G>T;c.524_528delAGGCA;c.246T>A;c.140delT;c.127+1G>C	Primary autosomal recessive microcephaly type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDK5RAP2 gene located on chromosomal region 9q33.2. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	Plus
CDKL5	Epileptic encephalopathy, early infantile, type 2 Epileptic encephalopathy, early infantile, type 2 Descrição da doença: Epileptic encephalopathy, early infantile, type 2 (EIEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in mental retardation and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but EIEE2 is considered to be a distinct entity (Fehr et al., 2013).	NM_001037343.1;NM_001323289.1	c.39delT;c.58G>C;c.59G>A;c.64+2delT;c.65dupG;c.65- c.39delT;c.58G>C;c.59G>A;c.64+2delT;c.65dupG;c.65-1G>A;c.73G>A;c.99+1G>T;c.100-2A>G;c.119C>T;c.145+2T>C;c.146-1G>A;c.163_166delGAAA;c.173T>A;c.175C>T;c.183delT;c.191T>C;c.200_201delTC;c.199C>T;c.207_213delGGAAAAC;c.212delA;c.211A>G;c.214_216delATT;c.215T>A;c.215T>C;c.220G>T;c.229_232delGAAG;c.248delG;c.250A>T;c.258C>G;c.275_276insAA;c.282+1G>T;c.282+2T>G;c.351T>A;c.352C>T;c.356T>G;c.400C>T;c.403+1G>A;c.425T>A;c.455G>A;c.455G>T;c.458A>G;c.464-2A>G;c.464-1G>A;c.473G>C;c.506_507delCA;c.508G>T;c.510_511dupGT;c.513C>A;c.526T>A;c.526T>C;c.526T>G;c.532C>T;c.533G>A;c.533G>C;c.539C>T;c.542A>C;c.549_552delACTT;c.549dupA;c.554+1G>A;c.555-2A>G;c.577G>A;c.578A>G;c.587C>T;c.602T>C;c.607G>T;c.622C>T;c.660_664dupTTTTA;c.693delA;c.700C>T;c.766C>T;c.768dupG;c.801_802delTA;c.808dupC;c.826-2A>G;c.826-1G>C;c.838_847delTTGGACCCAG;c.854G>A;c.855A>C;c.858C>A;c.867dupA;c.868C>T;c.871T>C;c.884delC;c.902_903dupGA;c.942delA;c.964dupA;c.978-2A>G;c.1007_1014delAGTCTCAC;c.1006C>T;c.1039C>T;c.1071delC;c.1079delT;c.1082dupC;c.1090G>T;c.1108_1109dupAA;c.1111delC;c.1152C>G;c.1165C>T;c.1211_1212dupAC;c.1238C>A;c.1238C>G;c.1247_1248delAG;c.1246G>T;c.1311dupC;c.1324C>T;c.1341delC;c.1345_1346delGA;c.1345G>T;c.1365_1366insA;c.1375C>T;c.1417dupA;c.1432_1433insT;c.1449_1452dupGACC;c.1471_1472dupGC;c.1519C>T;c.1550delT;c.1553delC;c.1648C>T;c.1670C>G;c.1671dupA;c.1675C>T;c.1708G>T;c.1776_1777delTT;c.1777delT;c.1784dupG;c.1795dupA;c.1797dupC;c.1854delC;c.1885_1886dupTT;c.1892_1893dupTA;c.1897C>T;c.1909delG;c.1944+2T>G;c.1954C>T;c.2016delC;c.2016dupC;c.2022delC;c.2046+1G>A;c.2047-1G>A;c.2066delC;c.2095G>T;c.2105_2106delAC;c.2148_2149delCA;c.2152+1G>A;c.2205_2206delAG;c.2254dupA;c.2413C>T;c.2469delC;c.2494C>T;c.2500C>T;c.2504delC;c.2522dupA;c.2529delA;c.2531dupA;c.2549delA;c.2572delC;c.2593C>T;c.2596C>T;c.2608dupT;c.2635_2636delCT;c.2641C>T;c.2671C>T;c.2704C>T;c.2716C>T;c.2828_2829delGA	Epileptic encephalopathy, early infantile, type 2 (EIEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in mental retardation and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but EIEE2 is considered to be a distinct entity (Fehr et al., 2013).	Plus
CDT1	Meier-Gorlin syndrome, type 4 Meier-Gorlin syndrome, type 4 Descrição da doença: Meier-Gorlin syndrome 4 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.	NM_030928.3	c.832+1G>A;c.1385G>A;c.1402G>A c.832+1G>A;c.1385G>A;c.1402G>A	Meier-Gorlin syndrome 4 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.	Plus
CENPJ	Primary microcephaly type 6, autosomal recessive Primary microcephaly type 6, autosomal recessive Descrição da doença: Primary autosomal recessive microcephaly type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CENPJ gene located on chromosomal region 13q12.12. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	NM_018451.4	c.3842_3843dupTA;c.3704A>T;c.3699_3702dupAATA;c.35 c.3842_3843dupTA;c.3704A>T;c.3699_3702dupAATA;c.3568_3571dupGTCA;c.3448C>T;c.3415G>T;c.3367-1G>A;c.3309dupA;c.3302-1G>C;c.3243_3246delTCAG;c.3007dupA;c.2968_2972delAAAAA;c.2872C>T;c.2704C>T;c.2614delT;c.2460_2463delGACG;c.2167_2168delAG;c.1969C>T;c.1949_1952dupAGTG;c.1882delG;c.1850_1851delCT;c.1696C>T;c.1681_1684delTTAG;c.1642G>T;c.1404_1407delTTCT;c.1339A>T;c.1132C>T;c.1029delA;c.898_899delGA;c.757_760delGTCT;c.469C>T;c.289dupA;c.232_236delCAGAA;c.133C>T;c.129_130delGA;c.59G>A;c.40C>T;c.18delC	Primary autosomal recessive microcephaly type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CENPJ gene located on chromosomal region 13q12.12. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	Plus
CEP135	Microcephaly 8, primary, autosomal recessive Microcephaly 8, primary, autosomal recessive Descrição da doença: Microcephaly 8, primary, autosomal recessive is a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals present mental retardation. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder.	NM_025009.4	c.874C>T;c.970delC;c.1473+1G>A;c.2594G>A c.874C>T;c.970delC;c.1473+1G>A;c.2594G>A	Microcephaly 8, primary, autosomal recessive is a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals present mental retardation. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder.	Plus
CEP152	Primary microcephaly type 9, autosomal recessive Primary microcephaly type 9, autosomal recessive Descrição da doença: Primary autosomal recessive microcephaly type 9 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP152 gene located on chromosomal region 15q21.1. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	NM_001194998.1	c.3016delA;c.3014_3015delAAinsT;c.2959C>T;c.2694+1 c.3016delA;c.3014_3015delAAinsT;c.2959C>T;c.2694+1G>T;c.2679delC;c.2038C>T;c.2034T>G;c.1155delC;c.794A>C;c.749_750delGA;c.695_696delCT;c.314G>A;c.261+1G>C	Primary autosomal recessive microcephaly type 9 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP152 gene located on chromosomal region 15q21.1. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.	Plus
CEP290	Meckel syndrome, type 4; Joubert syndrome, type 5; Leber congenital amaurosis, type 10 Meckel syndrome, type 4; Joubert syndrome, type 5; Leber congenital amaurosis, type 10 Descrição da doença: Meckel syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP290 gene located on chromosomal region 12q21.32. The age of onset is neonatal. This disease is characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly. The prevalence is <1/1,000,000. Other ciliopathies are associated with mutation in CEP290 gene as Joubert syndrome, type 5 and Leber congenital amaurosis, type 10. Joubert syndrome (JBTS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities (Valente et al., 2006). Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (den Hollander et al., 2006).	NM_025114.3	c.7341delA;c.7341dupA;c.7324G>T;c.6939C>A;c.6869du c.7341delA;c.7341dupA;c.7324G>T;c.6939C>A;c.6869dupA;c.6798G>A;c.6645+1G>A;c.6624delG;c.6604delA;c.6516delA;c.6448_6455delCAGTTGAA;c.6364A>T;c.6358-1G>A;c.6277delG;c.6135+2T>A;c.6072C>A;c.5932C>T;c.5803G>T;c.5707A>T;c.5704G>T;c.5668G>T;c.5649dupA;c.5611_5614delCAAA;c.5493delA;c.5434_5435delGA;c.5344C>T;c.5212G>T;c.5182G>T;c.5012+2T>C;c.4966_4967delGA;c.4966G>T;c.4962_4963delAA;c.4960C>T;c.4916C>A;c.4882C>T;c.4813-2A>G;c.4811G>A;c.4801C>T;c.4723A>T;c.4705-1G>T;c.4621delA;c.4522C>T;c.4452_4455delAGAA;c.4438-3delC;c.4437+1G>A;c.4393C>T;c.4384delG;c.4276_4277delAA;c.4243G>T;c.3943G>T;c.3904C>T;c.3784_3785insTT;c.3777_3778delAG;c.3461+1G>A;c.3446_3447delAA;c.3190delA;c.3185delT;c.3181_3182delAT;c.3176delT;c.3175delA;c.3175dupA;c.3104-2A>G;c.3097A>T;c.3012delA;c.2941C>T;c.2911G>T;c.2722C>T;c.2668C>T;c.2251C>T;c.2248_2249delTT;c.2249T>G;c.2112delA;c.1984C>T;c.1936C>T;c.1860_1863delAAGA;c.1860_1861delAA;c.1781T>A;c.1711+1G>A;c.1709C>G;c.1681C>T;c.1665_1666delAA;c.1666delA;c.1623+1G>A;c.1523-1G>T;c.1219_1220delAT;c.1190-2A>G;c.673_674delTT;c.654T>G;c.613C>T;c.508A>T;c.451C>T;c.437delA;c.384_387delTAGA;c.381_382delAGinsT;c.289G>T;c.268A>T;c.181-2A>G;c.180+2T>A;c.180+1G>A;c.164_167delCTCA;c.103-1G>T;c.21G>T	Meckel syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP290 gene located on chromosomal region 12q21.32. The age of onset is neonatal. This disease is characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly. The prevalence is <1/1,000,000. Other ciliopathies are associated with mutation in CEP290 gene as Joubert syndrome, type 5 and Leber congenital amaurosis, type 10. Joubert syndrome (JBTS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities (Valente et al., 2006). Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (den Hollander et al., 2006).	Plus
CEP41	Joubert syndrome, type 15 Joubert syndrome, type 15 Descrição da doença: Joubert syndrome, type 15 is an autosomal recessive developmental disorder characterized by ataxia, hypotonia, delayed psychomotor development, and variable mental retardation. Other features, such as polydactyly, breathing abnormalities, and oculomotor apraxia, are variable (Lee et al., 2012).	NM_018718.2	c.536G>A;c.418C>T c.536G>A;c.418C>T	Joubert syndrome, type 15 is an autosomal recessive developmental disorder characterized by ataxia, hypotonia, delayed psychomotor development, and variable mental retardation. Other features, such as polydactyly, breathing abnormalities, and oculomotor apraxia, are variable (Lee et al., 2012).	Plus
CEP57	Mosaic variegated aneuploidy syndrome 2 Mosaic variegated aneuploidy syndrome 2 Descrição da doença: Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (Snape et al., 2011).	NM_014679.4	c.241C>T;c.520_521delGA;c.915_925dupCAATGTTCAGC c.241C>T;c.520_521delGA;c.915_925dupCAATGTTCAGC	Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (Snape et al., 2011).	Plus
CERKL	Retinitis pigmentosa, type 26 Retinitis pigmentosa, type 26 Descrição da doença: Retinitis pigmentosa, type 26 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CERKL gene located on chromosomal region 2q31.3. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.	NM_001030311.2	c.1425T>A;c.1381C>T;c.1090C>T;c.1045_1046delAT;c.8 c.1425T>A;c.1381C>T;c.1090C>T;c.1045_1046delAT;c.858delT;c.847C>T;c.598A>T;c.481+2T>G;c.420delT;c.312delA;c.239-1G>A;c.239-2A>G	Retinitis pigmentosa, type 26 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CERKL gene located on chromosomal region 2q31.3. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.	Plus
CFD	Complement factor D deficiency Complement factor D deficiency Descrição da doença: Complement factor D deficiency is an autosomal recessive immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway (Biesma et al., 2001).	NM_001317335.1	c.146C>A c.146C>A	Complement factor D deficiency is an autosomal recessive immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway (Biesma et al., 2001).	Plus
CFH	Complement factor H deficiency Complement factor H deficiency Descrição da doença: Complement factor H deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFH gene located on chromosomal region 1q32. This disease is characterized by increased susceptibility to recurrent, usually severe, infections (particularly by Neisseria meningitidis, Escherichia coli, and Haemophilus influenzae), renal impairment and/or autoimmune diseases.	NM_000186.3	c.565G>T;c.1222C>T;c.1291T>A;c.1606T>C;c.2397delA; c.565G>T;c.1222C>T;c.1291T>A;c.1606T>C;c.2397delA;c.2876G>A	Complement factor H deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFH gene located on chromosomal region 1q32. This disease is characterized by increased susceptibility to recurrent, usually severe, infections (particularly by Neisseria meningitidis, Escherichia coli, and Haemophilus influenzae), renal impairment and/or autoimmune diseases.	Plus
CFI	Complement factor I deficiency Complement factor I deficiency Descrição da doença: Hereditary deficiency of complement factor I is associated with a propensity to pyogenic infection and follows an autosomal recessive pattern of inheritance (Vyse et al., 1996).	NM_001318057.1	c.1277A>T;c.80_81delAT c.1277A>T;c.80_81delAT	Hereditary deficiency of complement factor I is associated with a propensity to pyogenic infection and follows an autosomal recessive pattern of inheritance (Vyse et al., 1996).	Plus
CFL2	Nemaline myopathy, type 7, autosomal recessive Nemaline myopathy, type 7, autosomal recessive Descrição da doença: Nemaline myopathy, type 7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (Ockeloen et al., 2012).	NM_021914.7	c.103G>A c.103G>A	Nemaline myopathy, type 7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (Ockeloen et al., 2012).	Plus
CFP	Properdin deficiency, X-linked Properdin deficiency, X-linked Descrição da doença: Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001).	NM_001145252.1	c.617C>G;c.481C>T c.617C>G;c.481C>T	Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001).	Plus
CFTR	Cystic fibrosis Cystic fibrosis Descrição da doença: Cystic fibrosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFTR gene located on chromosomal region 7q31.2. The age of onset of severe form is neonatal or infantile but there are also variants associated with moderate clinical or late onset. This disease is characterized by the production of sweat with a high salt content, mucus secretions with an abnormal viscosity, chronic bronchitis, pancreatic insufficiency, adolescent diabetes and, more rarely, stercoral obstruction and cirrhosis. Male sterility is a constant feature. Late-onset forms, which are usually only mild or monosymptomatic. The prevalence is 1:10,000-9:10,000.	NM_000492.3	c.1A>G;c.4C>T;c.11C>A;c.50delT;c.44T>C;c.53+1G>T;c c.1A>G;c.4C>T;c.11C>A;c.50delT;c.44T>C;c.53+1G>T;c.57G>A;c.79G>T;c.88C>T;c.115C>T;c.137C>A;c.164+1G>A;c.164+1G>T;c.164+2T>C;c.164+4dupT;c.165-3C>T;c.165-1G>A;c.166G>A;c.169T>G;c.170G>A;c.171G>A;c.174_177delTAGA;c.175dupA;c.178G>A;c.178G>T;c.200C>T;c.223C>T;c.233dupT;c.254G>A;c.262_263delTT;c.263T>A;c.263T>G;c.271G>A;c.273+1G>A;c.273+3A>C;c.274-2A>G;c.274-1G>A;c.274G>A;c.274G>T;c.292C>T;c.305T>G;c.310delA;c.313delA;c.325_327delTATinsG;c.328G>C;c.328G>T;c.349C>T;c.350G>A;c.350G>T;c.366T>A;c.409delC;c.413_415dupTAC;c.416A>G;c.442delA;c.445G>A;c.445G>T;c.489+1G>T;c.531delT;c.532G>A;c.543_546delTAGT;c.577G>T;c.579+1G>T;c.579+3A>G;c.579+5G>A;c.580-1G>T;c.595C>T;c.613C>T;c.617T>G;c.647G>A;c.658C>T;c.680T>G;c.695T>A;c.708delT;c.717delG;c.803delA;c.825C>G;c.828C>A;c.850dupA;c.861_865delCTTAA;c.935_937delTCT;c.933C>G;c.948delT;c.987delA;c.988G>T;c.1000C>T;c.1001G>T;c.1006_1007insG;c.1007T>A;c.1013C>T;c.1021_1022dupTC;c.1021T>C;c.1029delC;c.1037T>C;c.1040G>A;c.1040G>C;c.1055G>A;c.1075C>A;c.1079C>A;c.1081delT;c.1116+1G>A;c.1117-1G>A;c.1130dupA;c.1155_1156dupTA;c.1202G>A;c.1203G>A;c.1209+1G>A;c.1211delG;c.1240C>T;c.1301_1307delCACTTCT;c.1327_1330dupGATA;c.1340delA;c.1364C>A;c.1365_1366delGG;c.1393-2A>G;c.1393-1G>A;c.1397C>A;c.1397C>G;c.1400T>C;c.1418delG;c.1420G>A;c.1438G>T;c.1466C>A;c.1475C>T;c.1477_1478delCA;c.1477C>T;c.1487G>A;c.1505T>C;c.1519_1521delATC;c.1521_1523delCTT;c.1538A>G;c.1545_1546delTA;c.1558G>T;c.1572C>A;c.1573C>T;c.1584+1G>A;c.1585-8G>A;c.1585-1G>A;c.1624G>T;c.1645A>C;c.1646G>A;c.1647T>G;c.1648G>T;c.1650delA;c.1651G>A;c.1652G>A;c.1654C>T;c.1657C>T;c.1670delC;c.1673T>C;c.1675G>A;c.1679G>A;c.1679G>C;c.1679+1G>A;c.1679+1G>C;c.1826A>G;c.1882G>C;c.1923_1931delCTCAAAACTinsA;c.1973_1985delGAAATTCAATCCTinsAGAAA;c.1986_1989delAACT;c.2012delT;c.2017G>T;c.2052delA;c.2052dupA;c.2051_2052delAAinsG;c.2053dupC;c.2053C>T;c.2125C>T;c.2128A>T;c.2143C>T;c.2158C>T;c.2175dupA;c.2195T>G;c.2215delG;c.2241_2248delGATACTGC;c.2290C>T;c.2491G>T;c.2537G>A;c.2538G>A;c.2547C>A;c.2551C>T;c.2583delT;c.2589_2599delAATTTGGTGCT;c.2601dupA;c.2645G>A;c.2657+5G>A;c.2658-1G>C;c.2668C>T;c.2735C>A;c.2737_2738insG;c.2739T>A;c.2763_2764dupAG;c.2780T>C;c.2810dupT;c.2825delT;c.2834C>T;c.2869_2870insG;c.2875delG;c.2896delA;c.2908G>C;c.2930C>T;c.2936A>T;c.2988G>A;c.2988+1G>A;c.2989-2A>G;c.2989-1G>A;c.3002_3003delTG;c.3011_3019delCTATAGCAG;c.3017C>A;c.3039delC;c.3039dupC;c.3067_3072delATAGTG;c.3107C>A;c.3124C>T;c.3139_3139+1delGG;c.3140-26A>G;c.3160C>G;c.3181G>C;c.3194T>C;c.3196C>T;c.3197G>A;c.3230T>C;c.3266G>A;c.3276C>A;c.3276C>G;c.3292T>C;c.3293G>A;c.3294G>A;c.3294G>C;c.3294G>T;c.3302T>A;c.3302T>G;c.3304A>T;c.3310G>T;c.3353C>T;c.3368-2A>G;c.3435G>A;c.3468G>A;c.3468+5G>A;c.3472C>T;c.3484C>T;c.3528delC;c.3532_3535dupTCAA;c.3536_3539delCCAA;c.3587C>G;c.3605delA;c.3611G>A;c.3612G>A;c.3659delC;c.3691delT;c.3700A>G;c.3717+4A>G;c.3717+5G>A;c.3717+40A>G;c.3718-3T>G;c.3718-1G>A;c.3719T>G;c.3731G>A;c.3744delA;c.3747delG;c.3752G>A;c.3761T>G;c.3763T>C;c.3764C>A;c.3773dupT;c.3846G>A;c.3848G>T;c.3873+1G>A;c.3873+2T>C;c.3909C>G;c.3937C>T;c.3971T>C;c.4036_4042delCTAAGCC;c.4046G>A;c.4077_4080delTGTTinsAA;c.4086dupT;c.4111G>T;c.4127_4131delTGGAT;c.4144C>T;c.4147dupA;c.4197_4198delCT;c.4231C>T;c.4234C>T;c.4242+1G>A;c.4242+1G>T;c.4251delA;c.4300_4301dupAG;c.4426C>T	Cystic fibrosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFTR gene located on chromosomal region 7q31.2. The age of onset of severe form is neonatal or infantile but there are also variants associated with moderate clinical or late onset. This disease is characterized by the production of sweat with a high salt content, mucus secretions with an abnormal viscosity, chronic bronchitis, pancreatic insufficiency, adolescent diabetes and, more rarely, stercoral obstruction and cirrhosis. Male sterility is a constant feature. Late-onset forms, which are usually only mild or monosymptomatic. The prevalence is 1:10,000-9:10,000.	Plus
CHAT	Myasthenic syndrome, congenital, type 6, presynaptic Myasthenic syndrome, congenital, type 6, presynaptic Descrição da doença: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 6, presynaptic (CMS6) is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (Engel et al., 2015).	NM_020549.4	c.406G>A;c.418C>T;c.620G>A;c.1642C>T c.406G>A;c.418C>T;c.620G>A;c.1642C>T	Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 6, presynaptic (CMS6) is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (Engel et al., 2015).	Plus
CHKB	Muscular dystrophy, congenital, megaconial type Muscular dystrophy, congenital, megaconial type Descrição da doença: Muscular dystrophy, congenital, megaconial type is a form of autosomal recessive congenital muscular dystrophy characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (Mitsuhashi et al., 2011).	NM_005198.4	c.1032-2A>G;c.922C>T;c.810T>A;c.736+2T>C;c.677+1G> c.1032-2A>G;c.922C>T;c.810T>A;c.736+2T>C;c.677+1G>A;c.458dupT;c.400C>T;c.116C>A	Muscular dystrophy, congenital, megaconial type is a form of autosomal recessive congenital muscular dystrophy characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (Mitsuhashi et al., 2011).	Plus
CHM	Choroideremia Choroideremia Descrição da doença: Choroideremia is an X-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye (Cremers et al., 1990). The characteristic lesion of choroideremia is chorioretinal scalloped atrophy in the midperipheral fundus, with preservation of the macula (Li et al., 2014).	NM_000390.3	c.1771-1G>A;c.1497C>A;c.1484C>A;c.1471G>T;c.1437du c.1771-1G>A;c.1497C>A;c.1484C>A;c.1471G>T;c.1437dupA;c.1218C>A;c.1213C>T;c.1144G>T;c.1138C>T;c.1019C>A;c.969T>A;c.808C>T;c.799C>T;c.757C>T;c.715C>T;c.649_652delTACT;c.525_526delAG;c.280delA;c.133G>T;c.130G>T;c.116+1G>A;c.116+1G>T;c.49+1G>T	Choroideremia is an X-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye (Cremers et al., 1990). The characteristic lesion of choroideremia is chorioretinal scalloped atrophy in the midperipheral fundus, with preservation of the macula (Li et al., 2014).	Plus
CHRDL1	Megalocornea 1, X-linked Megalocornea 1, X-linked Descrição da doença: Megalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (Skuta et al., 1983).Megalocornea sometimes occurs as part of the Marfan syndrome (154700).	NM_001143981.1	c.872delG;c.807_808delTC;c.782G>T;c.652C>T;c.520du c.872delG;c.807_808delTC;c.782G>T;c.652C>T;c.520dupT;c.301+2T>G;c.102_103delGA	Megalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (Skuta et al., 1983).Megalocornea sometimes occurs as part of the Marfan syndrome (154700).	Plus
CHRND	Myasthenic syndrome, congenital, type 3B, fast-channel; Multiple pterygium syndrome, lethal type Myasthenic syndrome, congenital, type 3B, fast-channel; Multiple pterygium syndrome, lethal type Descrição da doença: Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutations in CHRND gene can also caused multiple pterygium syndrome, lethal type (LMPS). LMPS is a multiple pterygia are found infrequently in children with arthrogryposis and in fetuses with fetal akinesia syndrome. In lethal multiple pterygium syndrome there is intrauterine growth retardation, multiple pterygia, and flexion contractures causing severe arthrogryposis and fetal akinesia. Subcutaneous edema can be severe, causing fetal hydrops with cystic hygroma and lung hypoplasia. Oligohydramnios and facial anomalies are frequent.	NM_000751.2	c.127C>T;c.188T>C;c.234G>A;c.236T>A;c.283T>C;c.812 c.127C>T;c.188T>C;c.234G>A;c.236T>A;c.283T>C;c.812C>A;c.820_820+1delAG;c.822delT;c.866C>T;c.933-2A>G;c.1204G>A;c.1390C>T	Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutations in CHRND gene can also caused multiple pterygium syndrome, lethal type (LMPS). LMPS is a multiple pterygia are found infrequently in children with arthrogryposis and in fetuses with fetal akinesia syndrome. In lethal multiple pterygium syndrome there is intrauterine growth retardation, multiple pterygia, and flexion contractures causing severe arthrogryposis and fetal akinesia. Subcutaneous edema can be severe, causing fetal hydrops with cystic hygroma and lung hypoplasia. Oligohydramnios and facial anomalies are frequent.	Plus
CHRNE	Myasthenic syndrome, congenital, type 4B, fast-channel; Myasthenic syndrome, congenital, type 4C, associated with acetylcholine receptor deficiency Myasthenic syndrome, congenital, type 4B, fast-channel; Myasthenic syndrome, congenital, type 4C, associated with acetylcholine receptor deficiency Descrição da doença: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) ( Engel et al., 2003; Engel et al., 2015). Mutations in the CHRNE gene cause fast-channel congenital myasthenic syndrome (FCCMS), a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutation in the CHRNE gene can also cause congenital myasthenic syndrome, type 4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency. CMS4C associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (Engel et al., 2015).	NM_000080.3	c.1327delG;c.1326+1G>A;c.1291G>C;c.1181_1187dupTGT c.1327delG;c.1326+1G>A;c.1291G>C;c.1181_1187dupTGTTTGA;c.1161_1162insT;c.1093delG;c.1090dupC;c.1033-1G>C;c.1033-2A>T;c.1030delC;c.991C>T;c.971delT;c.918-1G>A;c.905C>G;c.865C>T;c.850A>C;c.794delC;c.794C>T;c.764C>T;c.721C>T;c.614_620delGGGCCAT;c.500G>T;c.422C>T;c.421C>A;c.344+1G>A;c.250C>T;c.223T>C;c.183_187dupCTCAC;c.130dupG	Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) ( Engel et al., 2003; Engel et al., 2015). Mutations in the CHRNE gene cause fast-channel congenital myasthenic syndrome (FCCMS), a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutation in the CHRNE gene can also cause congenital myasthenic syndrome, type 4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency. CMS4C associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (Engel et al., 2015).	Plus
CHRNG	Multiple pterygium syndrome (MPS), Escobar type; MPS, lethal type Multiple pterygium syndrome (MPS), Escobar type; MPS, lethal type Descrição da doença: Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. In people with MPS, Escobar type, the webbing typically affects the skin of the neck, fingers, forearms, inner thighs, and backs of the knee. People with this type may also have arthrogryposis. A side-to-side curvature of the spine (scoliosis) is sometimes seen. Affected individuals may also have respiratory distress at birth due to underdeveloped lungs (lung hypoplasia). People with Escobar type usually have distinctive facial features including droopy eyelids (ptosis), outside corners of the eyes that point downward (downslanting palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), a small jaw, and low-set ears. Males with this condition can have undescended testes (cryptorchidism). This condition does not worsen after birth, and affected individuals typically do not have muscle weakness later in life. Lethal MPS has many of the same signs and symptoms as the Escobar type. In addition, affected fetuses may develop a buildup of excess fluid in the body (hydrops fetalis) or a fluid-filled sac typically found on the back of the neck (cystic hygroma). Individuals with this type have severe arthrogryposis. Lethal type is associated with abnormalities such as underdevelopment (hypoplasia) of the heart, lung, or brain; twisting of the intestines (intestinal malrotation); kidney abnormalities; an opening in the roof of the mouth (a cleft palate); and an unusually small head size (microcephaly). Affected individuals may also develop a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), a condition called a congenital diaphragmatic hernia. Lethal multiple pterygium syndrome is typically fatal in the second or third trimester of pregnancy.	NM_005199.4	c.13C>T;c.55+1G>A;c.117dupC;c.136C>T;c.202C>T;c.25 c.13C>T;c.55+1G>A;c.117dupC;c.136C>T;c.202C>T;c.256C>T;c.320T>G;c.397delT;c.401_402delCT;c.428C>G;c.459dupA;c.715C>T;c.753_754delCT;c.1210C>T;c.1408C>T	Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. In people with MPS, Escobar type, the webbing typically affects the skin of the neck, fingers, forearms, inner thighs, and backs of the knee. People with this type may also have arthrogryposis. A side-to-side curvature of the spine (scoliosis) is sometimes seen. Affected individuals may also have respiratory distress at birth due to underdeveloped lungs (lung hypoplasia). People with Escobar type usually have distinctive facial features including droopy eyelids (ptosis), outside corners of the eyes that point downward (downslanting palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), a small jaw, and low-set ears. Males with this condition can have undescended testes (cryptorchidism). This condition does not worsen after birth, and affected individuals typically do not have muscle weakness later in life. Lethal MPS has many of the same signs and symptoms as the Escobar type. In addition, affected fetuses may develop a buildup of excess fluid in the body (hydrops fetalis) or a fluid-filled sac typically found on the back of the neck (cystic hygroma). Individuals with this type have severe arthrogryposis. Lethal type is associated with abnormalities such as underdevelopment (hypoplasia) of the heart, lung, or brain; twisting of the intestines (intestinal malrotation); kidney abnormalities; an opening in the roof of the mouth (a cleft palate); and an unusually small head size (microcephaly). Affected individuals may also develop a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), a condition called a congenital diaphragmatic hernia. Lethal multiple pterygium syndrome is typically fatal in the second or third trimester of pregnancy.	Plus
CHST14	Ehlers-Danlos syndrome, musculocontractural, type 1 Ehlers-Danlos syndrome, musculocontractural, type 1 Descrição da doença: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998).The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal.	NM_130468.3	c.145delG;c.205A>T;c.453dupC c.145delG;c.205A>T;c.453dupC	The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998).The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal.	Plus
CHST3	Spondyloepiphyseal dysplasia with congenital joint dislocations Spondyloepiphyseal dysplasia with congenital joint dislocations Descrição da doença: Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (245600) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (Unger et al., 2010).	NM_004273.4	c.422C>T;c.491C>T;c.603C>A;c.664C>T;c.776T>C;c.857 c.422C>T;c.491C>T;c.603C>A;c.664C>T;c.776T>C;c.857T>C;c.904G>C;c.911G>A;c.920T>C;c.988C>T;c.1063G>A;c.1114G>A	Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (245600) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (Unger et al., 2010).	Plus
CHST6	Macular corneal dystrophy Macular corneal dystrophy Descrição da doença: Macular corneal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CHST6 gene located on chromosomal region 16q22. The age of onset is variable. This disease is characterized by bilateral ill-defined cloudy regions within a hazy stroma, and eventually severe visual impairment. The prevalence is 1:100,000-9:100,000.	NM_021615.4	c.892C>T;c.853delC;c.827T>C;c.820G>T;c.609C>A;c.59 c.892C>T;c.853delC;c.827T>C;c.820G>T;c.609C>A;c.599T>G;c.521A>G;c.392C>A;c.327_328delCT;c.329A>G;c.304T>G;c.277C>A	Macular corneal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CHST6 gene located on chromosomal region 16q22. The age of onset is variable. This disease is characterized by bilateral ill-defined cloudy regions within a hazy stroma, and eventually severe visual impairment. The prevalence is 1:100,000-9:100,000.	Plus
CHSY1	Temtamy preaxial brachydactyly syndrome Temtamy preaxial brachydactyly syndrome Descrição da doença: Temtamy preaxial brachydactyly syndrome (TPBS)is a syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, and bilateral symmetric digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism.	NM_014918.4	c.1616C>G;c.205C>T c.1616C>G;c.205C>T	Temtamy preaxial brachydactyly syndrome (TPBS)is a syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, and bilateral symmetric digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism.	Plus
CHUK	Cocoon syndrome Cocoon syndrome Descrição da doença: Cocoon syndrome (COCOS) is a lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.	NM_001278.4	c.1264C>T c.1264C>T	Cocoon syndrome (COCOS) is a lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.	Plus
CIB2	Deafness, autosomal recessive, type 48; Usher syndrome, type 1J Deafness, autosomal recessive, type 48; Usher syndrome, type 1J Descrição da doença: Deafness, autosomal recessive, type 48 (DFNB48) is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies. Riazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness. Mutations in CIB2 gene are also associated with Usher syndrome, type 1J (USH1J), a form of USH. This disease is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness.	NM_001301224.1;NM_001271888.1	c.383T>C;c.315_324delGTCGGCTCCC;c.287T>C;c.63G>C c.383T>C;c.315_324delGTCGGCTCCC;c.287T>C;c.63G>C	Deafness, autosomal recessive, type 48 (DFNB48) is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies. Riazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness. Mutations in CIB2 gene are also associated with Usher syndrome, type 1J (USH1J), a form of USH. This disease is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness.	Plus
CIITA	Bare lymphocyte syndrome, type 2, complementation group A Bare lymphocyte syndrome, type 2, complementation group A Descrição da doença: Bare lymphocyte syndrome type 2 (BLS II) is an inherited disorder of the immune system categorized as a form of combined immunodeficiency (CID). People with BLS II lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system. BLS 2 is typically diagnosed in the first year of life. Most affected infants have persistent infections in the respiratory, gastrointestinal, and urinary tracts. Because of the infections, affected infants have difficulty absorbing nutrients (malabsorption), and they grow more slowly than their peers. Eventually, the persistent infections lead to organ failure. Without treatment, individuals with BLS 2 usually do not survive past early childhood.	NM_001286402.1	c.1144G>T;c.2066G>A;c.2293delC;c.2891+1G>A;c.3320+ c.1144G>T;c.2066G>A;c.2293delC;c.2891+1G>A;c.3320+1G>A	Bare lymphocyte syndrome type 2 (BLS II) is an inherited disorder of the immune system categorized as a form of combined immunodeficiency (CID). People with BLS II lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system. BLS 2 is typically diagnosed in the first year of life. Most affected infants have persistent infections in the respiratory, gastrointestinal, and urinary tracts. Because of the infections, affected infants have difficulty absorbing nutrients (malabsorption), and they grow more slowly than their peers. Eventually, the persistent infections lead to organ failure. Without treatment, individuals with BLS 2 usually do not survive past early childhood.	Plus
CISD2	Wolfram syndrome 2 Wolfram syndrome 2 Descrição da doença: Wolfram syndrome-2 is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding (Mozzillo et al., 2014).	NM_001008388.4	c.109G>C c.109G>C	Wolfram syndrome-2 is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding (Mozzillo et al., 2014).	Plus
CLCF1	Cold-induced sweating syndrome 2 Cold-induced sweating syndrome 2 Descrição da doença: Cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis (Hahn et al., 2010).	NM_013246.2	c.676T>C;c.321C>A c.676T>C;c.321C>A	Cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis (Hahn et al., 2010).	Plus
CLCN1	Myotonia congenita, recessive Myotonia congenita, recessive Descrição da doença: Myotonia congenita follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN1 gene located on chromosomal region 7q35. The age of onset is neonatal/infantile. This is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. The prevalence is 1:100,000.	NM_000083.2	c.180+3A>T;c.220C>T;c.225dupC;c.302-1G>A;c.378dupG c.180+3A>T;c.220C>T;c.225dupC;c.302-1G>A;c.378dupG;c.382A>G;c.394A>T;c.409T>G;c.566C>T;c.568_569delGGinsTC;c.577G>A;c.689G>A;c.707T>C;c.774+1G>A;c.803C>T;c.847C>T;c.854G>A;c.857T>C;c.870C>G;c.871G>A;c.895G>C;c.898_899delCGinsTA;c.908G>A;c.920T>C;c.929C>T;c.937G>A;c.949C>T;c.950G>A;c.979G>A;c.1012C>T;c.1013G>A;c.1063G>A;c.1129C>T;c.1167-10T>C;c.1238T>G;c.1261dupC;c.1401+1G>T;c.1412C>T;c.1437_1450delACCCTGCGGAGGCT;c.1438C>A;c.1439C>T;c.1444G>A;c.1453A>G;c.1471+1G>A;c.1488G>T;c.1495G>A;c.1592C>T;c.1649C>T;c.1655A>G;c.1667T>A;c.1876C>T;c.1930+1G>A;c.2023delC;c.2023C>T;c.2172+1G>T;c.2285-1G>C;c.2330delG;c.2364+2T>A;c.2401G>T;c.2419C>T;c.2512_2513insCTCA;c.2518_2519delCT;c.2596-1G>A;c.2635C>T;c.2680C>T	Myotonia congenita follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN1 gene located on chromosomal region 7q35. The age of onset is neonatal/infantile. This is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. The prevalence is 1:100,000.	Plus
CLCN2	Leukoencephalopathy with ataxia Leukoencephalopathy with ataxia Descrição da doença: Leukoencephalopathy with ataxia is an autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggest myelin microvacuolation restricted to certain brain regions. Clinical features include ataxia and unstable gait; more variable abnormalities may include visual field defects, headaches, and learning disabilities (Depienne et al., 2013).	NM_004366.5	c.2386C>T;c.1957A>T;c.1709G>A;c.1507G>A;c.1499C>T; c.2386C>T;c.1957A>T;c.1709G>A;c.1507G>A;c.1499C>T;c.1422_1423delTG;c.1397G>A;c.1304delT;c.1143delT;c.1113delCinsACTGCTCAT;c.1084A>T;c.925C>T;c.828dupG;c.292G>C;c.71G>A	Leukoencephalopathy with ataxia is an autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggest myelin microvacuolation restricted to certain brain regions. Clinical features include ataxia and unstable gait; more variable abnormalities may include visual field defects, headaches, and learning disabilities (Depienne et al., 2013).	Plus
CLCN5	Dent disease; Hypophosphatemic rickets Dent disease; Hypophosphatemic rickets Descrição da doença: Dent disease is a chronic kidney disorder that occurs almost exclusively in males. In affected individuals, kidney problems result from damage to structures called proximal tubules. Signs and symptoms of this condition appear in early childhood and worsen over time. The most frequent sign of Dent disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). Other common signs of the disorder include excess calcium in the urine (hypercalciuria), calcium deposits in the kidneys (nephrocalcinosis), and kidney stones (nephrolithiasis). Researchers have described two forms of Dent disease, which are distinguished by their genetic cause and pattern of signs and symptoms.	NM_001127898.3	c.292C>T;c.310C>T;c.344G>A;c.380G>T;c.415+1G>A;c.5 c.292C>T;c.310C>T;c.344G>A;c.380G>T;c.415+1G>A;c.575G>A;c.809T>G;c.884T>C;c.941C>T;c.989G>T;c.1025A>G;c.1046G>A;c.1047G>A;c.1049G>C;c.1238G>A;c.1249C>T;c.1609C>T;c.1676G>A;c.1727G>A;c.1747G>A;c.1756C>T;c.1768T>C;c.1849T>G;c.2119C>T;c.2152C>T;c.2320C>T;c.2362C>T	Dent disease is a chronic kidney disorder that occurs almost exclusively in males. In affected individuals, kidney problems result from damage to structures called proximal tubules. Signs and symptoms of this condition appear in early childhood and worsen over time. The most frequent sign of Dent disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). Other common signs of the disorder include excess calcium in the urine (hypercalciuria), calcium deposits in the kidneys (nephrocalcinosis), and kidney stones (nephrolithiasis). Researchers have described two forms of Dent disease, which are distinguished by their genetic cause and pattern of signs and symptoms.	Plus
CLCN7	Osteopetrosis, autosomal recessive type 4 Osteopetrosis, autosomal recessive type 4 Descrição da doença: Osteopetrosis type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN7 gene located on chromosomal region 16p13. The age of onset is neonatal/infantile. This disease is characterized bone marrow failure, fractures and visual impairment. The incidence is 1:200,000 live births and the prevalence is 1:100,000.	NM_001287.5	c.622C>T c.622C>T	Osteopetrosis type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN7 gene located on chromosomal region 16p13. The age of onset is neonatal/infantile. This disease is characterized bone marrow failure, fractures and visual impairment. The incidence is 1:200,000 live births and the prevalence is 1:100,000.	Plus
CLCNKA	Bartter syndrome, type 4B, digenic Bartter syndrome, type 4B, digenic Descrição da doença: Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).	NM_004070.3	c.240G>C;c.778C>T c.240G>C;c.778C>T	Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).	Plus
CLCNKB	Bartter syndrome, type 3 Bartter syndrome, type 3 Descrição da doença: Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).	NM_000085.4	c.18dupG;c.359G>T;c.371C>T;c.610G>A;c.1046C>A;c.11 c.18dupG;c.359G>T;c.371C>T;c.610G>A;c.1046C>A;c.1166G>A;c.1312C>T;c.1381dupA;c.1693delG;c.1783C>T;c.1830G>A;c.1897delC	Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).	Plus
CLDN1	Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis Descrição da doença: Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis is a rare autosomal recessive complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, mild diffuse ichthyosis, sclerosing cholangitis and leukocyte vacuolization.	NM_021101.4	c.358delG;c.200_201delTT c.358delG;c.200_201delTT	Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis is a rare autosomal recessive complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, mild diffuse ichthyosis, sclerosing cholangitis and leukocyte vacuolization.	Plus
CLDN14	Deafness type 29, autosomal recessive Deafness type 29, autosomal recessive Descrição da doença: Deafness type 29, autosomal recessive follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN14 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.	NM_001146077.1	c.398delT;c.301G>A;c.254T>A;c.167G>A c.398delT;c.301G>A;c.254T>A;c.167G>A	Deafness type 29, autosomal recessive follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN14 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.	Plus
CLDN16	Hypomagnesemia, type 3, renal Hypomagnesemia, type 3, renal Descrição da doença: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (Muller et al., 2006).A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement.	NM_006580.3	c.350G>A;c.445C>T;c.545_548dupTTAA;c.823A>T;c.831T c.350G>A;c.445C>T;c.545_548dupTTAA;c.823A>T;c.831T>G	Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (Muller et al., 2006).A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement.	Plus
CLDN19	Rena hypomagnesemia type 5, with ocular involvement Rena hypomagnesemia type 5, with ocular involvement Descrição da doença: Renal hypomagnesemia type 5, with ocular involvement follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN19 gene located on chromosomal region 1p34.2. The age of onset is infantile. This disease is characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities. The prevalence is <1:1,000,000.	NM_148960.2	c.425_437delCCCTGGTGACCCA;c.269T>C;c.169C>G;c.169C c.425_437delCCCTGGTGACCCA;c.269T>C;c.169C>G;c.169C>T;c.59G>A	Renal hypomagnesemia type 5, with ocular involvement follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN19 gene located on chromosomal region 1p34.2. The age of onset is infantile. This disease is characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities. The prevalence is <1:1,000,000.	Plus
CLMP	Congenital short bowel syndrome Congenital short bowel syndrome Descrição da doença: Infants with congenital short bowel syndrome are born with a shortened small intestine, with a mean length of 50 cm compared to the normal length of 190 to 280 cm, and intestinal malrotation. Severe malnutrition develops as a result of the hugely reduced absorptive surface of the small intestine, and infants require parenteral nutrition for survival; however, parenteral nutrition itself causes life-threatening complications such as sepsis and liver failure which are associated with a high rate of mortality early in life (van der Werf et al., 2012).	NM_024769.3	c.664C>T;c.508C>T;c.371T>A;c.230delA c.664C>T;c.508C>T;c.371T>A;c.230delA	Infants with congenital short bowel syndrome are born with a shortened small intestine, with a mean length of 50 cm compared to the normal length of 190 to 280 cm, and intestinal malrotation. Severe malnutrition develops as a result of the hugely reduced absorptive surface of the small intestine, and infants require parenteral nutrition for survival; however, parenteral nutrition itself causes life-threatening complications such as sepsis and liver failure which are associated with a high rate of mortality early in life (van der Werf et al., 2012).	Plus
CLN3	Ceroid lipofuscinosis, neuronal, type 3 Ceroid lipofuscinosis, neuronal, type 3 Descrição da doença: Neuronal ceroid lipofuscinosis, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN3 gene located on chromosomal region 16p12.1. The age of onset is infantile. This disease is characterized by onset at early school age with vision loss due to retinopathy, seizures and the decline of mental and motor capacities. The annual birth incidence is 1:217,000-1:450,000 in Sweden and 1:143,000 in Germany, and the prevalence is 1.5:1,000,000-9:1,000,000.	NM_000086.2	c.1272delG;c.1247A>G;c.1198-1G>T;c.1195G>T;c.1116C c.1272delG;c.1247A>G;c.1198-1G>T;c.1195G>T;c.1116C>G;c.1059C>A;c.1056G>C;c.1054C>T;c.1048delC;c.1001G>A;c.1000C>T;c.988G>A;c.988G>T;c.979C>T;c.963-1G>A;c.963-1G>T;c.963-2A>C;c.962+1G>A;c.949C>T;c.944dupA;c.906+2T>A;c.883G>A;c.883G>T;c.816_817delGG;c.791-1G>A;c.784A>T;c.750delG;c.683dupT;c.677+1G>T;c.631C>T;c.622dupT;c.597C>A;c.586dupG;c.569delG;c.565G>C;c.558_559delAG;c.560G>C;c.533+1G>A;c.533+1G>C;c.509T>C;c.494G>A;c.485C>G;c.482C>G;c.472G>C;c.461-1G>A;c.461-1G>C;c.424delG;c.400T>C;c.378_379dupCC;c.379delC;c.374G>A;c.371_372insT;c.370dupT;c.302T>C;c.295-2A>C;c.240delG;c.233dupG;c.223-1G>A;c.222+2T>G;c.214C>T;c.195dupC;c.141delC;c.126-1G>A;c.105G>A;c.49G>T;c.47-1G>A;c.46+1G>A;c.46+1G>C;c.17delG;c.1A>C	Neuronal ceroid lipofuscinosis, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN3 gene located on chromosomal region 16p12.1. The age of onset is infantile. This disease is characterized by onset at early school age with vision loss due to retinopathy, seizures and the decline of mental and motor capacities. The annual birth incidence is 1:217,000-1:450,000 in Sweden and 1:143,000 in Germany, and the prevalence is 1.5:1,000,000-9:1,000,000.	Plus
CLN5	Ceroid lipofuscinosis, neuronal, type 5 Ceroid lipofuscinosis, neuronal, type 5 Descrição da doença: Neuronal ceroid lipofuscinosis, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN5 gene located on chromosomal region 3q21.1-q32. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	NM_006493.2	c.225G>A;c.291dupC;c.335G>C;c.377G>A;c.433C>T;c.51 c.225G>A;c.291dupC;c.335G>C;c.377G>A;c.433C>T;c.518delG;c.524T>G;c.526dupA;c.527_528insA;c.565C>T;c.575A>G;c.593T>C;c.595C>T;c.613C>T;c.620G>C;c.669dupC;c.672delG;c.671G>A;c.694C>T;c.712+1G>A;c.822G>A;c.835G>A;c.919delA;c.924_925delAT;c.1026C>A;c.1054G>T;c.1071_1072delCT;c.1072_1073delTT;c.1083delT;c.1103_1106delAACA;c.1121A>G;c.1175_1176delAT	Neuronal ceroid lipofuscinosis, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN5 gene located on chromosomal region 3q21.1-q32. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	Plus
CLN6	Ceroid lipofuscinosis, neuronal, type 6 Ceroid lipofuscinosis, neuronal, type 6 Descrição da doença: Neuronal ceroid lipofuscinosis, type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN6 gene located on chromosomal region 15q23. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	NM_017882.2	c.890delC;c.665+1G>A;c.665G>A;c.663C>G;c.552dupC;c c.890delC;c.665+1G>A;c.665G>A;c.663C>G;c.552dupC;c.543G>A;c.542+1G>T;c.498dupT;c.486+2T>C;c.486+1G>A;c.395_396delCT;c.316dupC;c.297+1G>A;c.268_271dupAACG;c.214G>T;c.200T>C;c.198+1G>A;c.167G>A;c.150C>G;c.84-1G>A;c.7delG	Neuronal ceroid lipofuscinosis, type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN6 gene located on chromosomal region 15q23. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	Plus
CLN8	Ceroid lipofuscinosis, neuronal, type 8 Ceroid lipofuscinosis, neuronal, type 8 Descrição da doença: Neuronal ceroid lipofuscinosis, type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN8 gene located on chromosomal region 8p23.3. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy, and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	NM_018941.3	c.47delT;c.66delG;c.88delG;c.88G>C;c.204delC;c.226 c.47delT;c.66delG;c.88delG;c.88G>C;c.204delC;c.226C>T;c.227A>G;c.263delA;c.283A>T;c.306G>A;c.312G>A;c.415C>T;c.470A>G;c.473A>G;c.499G>T;c.509C>T;c.543+1G>T;c.581A>G;c.610C>T;c.709G>A;c.763C>T;c.766C>G;c.789G>C	Neuronal ceroid lipofuscinosis, type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN8 gene located on chromosomal region 8p23.3. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy, and vision loss through retinal degeneration. The prevalence is <1:1,000,000.	Plus
CLRN1	Usher syndrome, type 3A Usher syndrome, type 3A Descrição da doença: Usher syndrome type 3A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLRN1 gene located on chromosomal region 3q25.1. The age of onset is neonatal/infantile. This disease is characterized by the association of sensorineural deafness with retinitis pigmentosa and progressive vision loss. The prevalence is 1:1.000.000- 9/1.000.000.	NM_001195794.1;NM_001256819.1	c.669_670insT;c.658C>T;c.630dupT;c.567T>G;c.541dup c.669_670insT;c.658C>T;c.630dupT;c.567T>G;c.541dupA;c.372delT;c.540C>A;c.301_305delGTCAT;c.189C>A;c.149_152delCAGGinsTGTCCAAT;c.144T>G;c.118T>G;c.92C>T	Usher syndrome type 3A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLRN1 gene located on chromosomal region 3q25.1. The age of onset is neonatal/infantile. This disease is characterized by the association of sensorineural deafness with retinitis pigmentosa and progressive vision loss. The prevalence is 1:1.000.000- 9/1.000.000.	Plus
CNGA1	Retinitis pigmentosa type 49 Retinitis pigmentosa type 49 Descrição da doença: Retinitis pigmentosa 49 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGA1 gene located on chromosomal region 4p12. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.	NM_001142564.1	c.2179delA;c.2134C>T;c.1885C>T;c.1840G>A;c.1747C>T c.2179delA;c.2134C>T;c.1885C>T;c.1840G>A;c.1747C>T;c.1196A>G;c.1166C>T;c.1046G>A;c.1037G>A;c.1001G>A;c.656+2T>C;c.634A>T;c.472delC;c.445G>T;c.398delG;c.304dupA;c.301C>T	Retinitis pigmentosa 49 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGA1 gene located on chromosomal region 4p12. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.	Plus
CNGA3	Achromatopsia 2 Achromatopsia 2 Descrição da doença: Achromatopsia 2, also referred to as rod monochromacy or total colorblindness, is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Electroretinographic recordings show that in achromatopsia the rod photoreceptor function is normal, whereas cone photoreceptor responses are absent (Kohl et al., 1998).	NM_001298.2	c.-37-1G>C;c.67C>T;c.101+1G>A;c.107_110delACTC;c.2 c.-37-1G>C;c.67C>T;c.101+1G>A;c.107_110delACTC;c.248G>A;c.513G>A;c.548G>A;c.667C>T;c.829C>T;c.847C>T;c.848G>A;c.872C>G;c.955T>C;c.1279C>T;c.1306C>T;c.1320G>A;c.1457G>A;c.1573G>A;c.1585G>A;c.1641C>A;c.1688G>A;c.1810C>T	Achromatopsia 2, also referred to as rod monochromacy or total colorblindness, is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Electroretinographic recordings show that in achromatopsia the rod photoreceptor function is normal, whereas cone photoreceptor responses are absent (Kohl et al., 1998).	Plus
CNGB1	Retinitis pigmentosa type 45 Retinitis pigmentosa type 45 Descrição da doença: Retinitis pigmentosa 45 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB1 gene located on chromosomal region 16q13. The age of onset is variable. This disease is characterized by night blindness, peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000 to 5:10,000.	NM_001297.4	c.3462+1G>A;c.3425delT;c.3150delG;c.3139_3142dupGT c.3462+1G>A;c.3425delT;c.3150delG;c.3139_3142dupGTGG;c.2980G>T;c.2794+1G>A;c.2762_2765delACGA;c.2676C>A;c.2653delG;c.2556dupC;c.2544dupG;c.2524dupA;c.2508C>A;c.2492+2T>G;c.2185C>T;c.2128C>T;c.1958-1G>A;c.1122-2A>T;c.1120_1121+2delGAGT;c.952C>T;c.761+2T>A;c.664C>T;c.413-1G>A;c.262C>T;c.218-2A>G	Retinitis pigmentosa 45 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB1 gene located on chromosomal region 16q13. The age of onset is variable. This disease is characterized by night blindness, peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000 to 5:10,000.	Plus
CNGB3	Achromatopsia, type 3 Achromatopsia, type 3 Descrição da doença: Achromatopsia type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB3 gene located on chromosomal region 8q21.3. The age of onset is neonatal/Infantile. This disease is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, and reduced or complete loss of color discrimination. Most individuals have complete form, with total lack of function in all three types of cones. Rarely, individuals have incomplete form, with similar, but generally less severe symptoms. The prevalence is 1/30,000-1/50,000.	NM_019098.4	c.2359delA;c.2221delG;c.2103+1G>A;c.2086C>T;c.2048 c.2359delA;c.2221delG;c.2103+1G>A;c.2086C>T;c.2048_2049delCA;c.2011G>T;c.1937delT;c.1929-2A>G;c.1928+2T>C;c.1908delG;c.1815delT;c.1810C>T;c.1782-2A>C;c.1781+1delG;c.1781+1G>A;c.1781+1G>C;c.1635T>A;c.1578+1G>A;c.1578+1G>T;c.1566_1569dupCGAC;c.1534delAinsGT;c.1516delG;c.1493delT;c.1481-2A>C;c.1480+1G>A;c.1460G>A;c.1447T>G;c.1432C>T;c.1430_1431delAGinsC;c.1426C>T;c.1366delC;c.1304C>T;c.1299_1300delGT;c.1285delT;c.1285dupT;c.1260delT;c.1255G>T;c.1243C>T;c.1194T>G;c.1179-2A>T;c.1148delC;c.1119G>A;c.1098_1101dupTAAT;c.1063C>T;c.1056-2A>G;c.1005dupT;c.1006G>T;c.904-2A>T;c.893_897delCAAAA;c.887_896delCTTCTACAAA;c.886_896delACTTCTACAAAinsT;c.886_890delACTTC;c.882C>G;c.873delGinsCAAAC;c.852+1G>C;c.819_826delCAGACTCC;c.791_794delACCT;c.756C>G;c.702_706delTTTTAinsGTTTTT;c.706delAinsTT;c.702T>A;c.682dupG;c.646C>T;c.644-1G>C;c.643+2T>C;c.607C>T;c.589_590delTT;c.567delG;c.556_559delAGGC;c.494-2A>T;c.446_447insT;c.412delA;c.393_394delGCinsTCCTGGTGA;c.391C>T;c.301C>T;c.281_284delCAAC;c.265C>T;c.257delC;c.220_221delTC;c.208C>T;c.190delG;c.163dupA;c.130-1G>T;c.129+2T>C;c.112C>T;c.95dupA;c.31dupG;c.29dupA;c.3G>A;c.2T>C	Achromatopsia type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB3 gene located on chromosomal region 8q21.3. The age of onset is neonatal/Infantile. This disease is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, and reduced or complete loss of color discrimination. Most individuals have complete form, with total lack of function in all three types of cones. Rarely, individuals have incomplete form, with similar, but generally less severe symptoms. The prevalence is 1/30,000-1/50,000.	Plus
CNKSR2	Mental retardation, X-linked, syndromic, Houge type Mental retardation, X-linked, syndromic, Houge type Descrição da doença: The Houge type of X-linked syndromic mental retardation is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (Damiano et al., 2017).	NM_014927.3	c.114delG;c.453dupA;c.1282C>T;c.1303+1G>C;c.2134C> c.114delG;c.453dupA;c.1282C>T;c.1303+1G>C;c.2134C>T;c.2145+1G>A;c.2340_2344delCTTAC	The Houge type of X-linked syndromic mental retardation is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (Damiano et al., 2017).	Plus
CNNM2	Hypomagnesemia, seizures, and mental retardation Hypomagnesemia, seizures, and mental retardation Descrição da doença: Hypomagnesemia, seizures, and mental retardation (HOMGSMR1) is a disorder characterized by onset of seizures associated with low serum magnesium in the first year of life. Affected individuals show variable degrees of delayed psychomotor development (Arjona et al., 2014).	NM_017649.4	c.806C>G;c.1069G>A;c.1703C>T c.806C>G;c.1069G>A;c.1703C>T	Hypomagnesemia, seizures, and mental retardation (HOMGSMR1) is a disorder characterized by onset of seizures associated with low serum magnesium in the first year of life. Affected individuals show variable degrees of delayed psychomotor development (Arjona et al., 2014).	Plus
CNNM4	Jalili syndrome Jalili syndrome Descrição da doença: Jalili syndrome is characterized by the association of cone-rod dystrophy and amelogenesis imperfecta. Cone-rod dystrophy is a rare retinal disorder that leads to an initial loss of central vision, color vision and photophobia before the age of 10 years with subsequent night blindness and visual field restriction. Amelogenesis imperfecta is a generic term for an inherited group of dental diseases in which the common clinical feature is an abnormality of tooth enamel. The enamel may be thin but normal, and/or hypomineralized.	NM_020184.3	c.599C>A;c.707G>A;c.734C>T;c.971T>C;c.1555C>T;c.16 c.599C>A;c.707G>A;c.734C>T;c.971T>C;c.1555C>T;c.1682-1G>C;c.1690C>T;c.1743C>G;c.2149C>T	Jalili syndrome is characterized by the association of cone-rod dystrophy and amelogenesis imperfecta. Cone-rod dystrophy is a rare retinal disorder that leads to an initial loss of central vision, color vision and photophobia before the age of 10 years with subsequent night blindness and visual field restriction. Amelogenesis imperfecta is a generic term for an inherited group of dental diseases in which the common clinical feature is an abnormality of tooth enamel. The enamel may be thin but normal, and/or hypomineralized.	Plus
CNPY3	Epileptic encephalopathy, early infantile, type 60 Epileptic encephalopathy, early infantile, type 60 Descrição da doença: Epileptic encephalopathy, early infantile, type 60 (EIEE60) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE60 is an autosomal recessive condition characterized by onset of seizures in the first months of life.	NM_001318842.1	c.594+1G>A c.594+1G>A	Epileptic encephalopathy, early infantile, type 60 (EIEE60) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE60 is an autosomal recessive condition characterized by onset of seizures in the first months of life.	Plus
CNTNAP2	Pitt-Hopkins like syndrome 1 Pitt-Hopkins like syndrome 1 Descrição da doença: Pitt-Hopkins like syndrome 1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (Smogavec et al., 2016).	NM_014141.5	c.851delA;c.1076C>G;c.1346C>G;c.1447C>T;c.1480G>T; c.851delA;c.1076C>G;c.1346C>G;c.1447C>T;c.1480G>T;c.1651_1652delAT;c.1671-1G>T;c.1819C>T;c.2046C>A;c.2050C>T;c.2153G>A;c.2964delC;c.3046C>T;c.3382-2A>C;c.3408C>A;c.3709delG	Pitt-Hopkins like syndrome 1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (Smogavec et al., 2016).	Plus
COG4	Congenital disorder of glycosylation, type 2J Congenital disorder of glycosylation, type 2J Descrição da doença: Congenital disorder of glycosylation, type 2J (CDG2J) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.	NM_015386.2	c.1809delA;c.844+2T>A;c.697G>T;c.529C>T c.1809delA;c.844+2T>A;c.697G>T;c.529C>T	Congenital disorder of glycosylation, type 2J (CDG2J) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.	Plus
COG5	Congenital disorder of glycosylation, type 2I Congenital disorder of glycosylation, type 2I Descrição da doença: Congenital disorder of glycosylation type 2I (CDG2I) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals. Patients typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking.	NM_006348.3	c.1508dupC;c.189delG c.1508dupC;c.189delG	Congenital disorder of glycosylation type 2I (CDG2I) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals. Patients typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking.	Plus
COG6	Congenital disorder of glycosylation, type 2L; Shaheen syndrome Congenital disorder of glycosylation, type 2L; Shaheen syndrome Descrição da doença: Congenital disorder of glycosylation, type 2L (CDG2L) is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (Rymen et al., 2015). Biallelic mutation in the COG6 gene can also cause Shaheen syndrome, an autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly (Shaheen et al., 2013).	NM_020751.2	c.388C>T;c.511C>T;c.1535T>G c.388C>T;c.511C>T;c.1535T>G	Congenital disorder of glycosylation, type 2L (CDG2L) is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (Rymen et al., 2015). Biallelic mutation in the COG6 gene can also cause Shaheen syndrome, an autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly (Shaheen et al., 2013).	Plus
COG7	Congenital disorder of glycosylation, type 2E Congenital disorder of glycosylation, type 2E Descrição da doença: Congenital disorder of glycosylation, type 2E (CDG2E) is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways.	NM_153603.3	c.1476-1G>T;c.1166_1167insT;c.323dupT c.1476-1G>T;c.1166_1167insT;c.323dupT	Congenital disorder of glycosylation, type 2E (CDG2E) is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways.	Plus
COG8	Congenital disorder of glycosylation, type 2H Congenital disorder of glycosylation, type 2H Descrição da doença: Congenital disorder of glycosylation, type 2H (CDG2H) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions	NM_032382.4	c.1611C>G;c.1580T>G;c.973C>T c.1611C>G;c.1580T>G;c.973C>T	Congenital disorder of glycosylation, type 2H (CDG2H) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions	Plus
COL11A1	Fibrochondrogenesis type 1 Fibrochondrogenesis type 1 Descrição da doença: Fibrochondrogenesis type 1 (FBCG1) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL11A1 gene located on chromosomal region 1p21. The age of onset is neonatal. Fibrochondrogenesis is a severe short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (Tompson et al., 2010). Genetic heterogeneity: Fibrochondrogenesis type 2 (FBCG2; OMIM 614524) is caused by mutations in the COL11A2 gene on chromosome 6p21.3.	NM_080629.2	c.2386G>C;c.1786dupG c.2386G>C;c.1786dupG	Fibrochondrogenesis type 1 (FBCG1) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL11A1 gene located on chromosomal region 1p21. The age of onset is neonatal. Fibrochondrogenesis is a severe short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (Tompson et al., 2010). Genetic heterogeneity: Fibrochondrogenesis type 2 (FBCG2; OMIM 614524) is caused by mutations in the COL11A2 gene on chromosome 6p21.3.	Plus
COL17A1	Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa, junctional, non-Herlitz type Descrição da doença: Epidermolysis bullosa, junctional, non-Herlitz type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL17A1 gene located on chromosomal region 10q24.3. The age of onset is neonatal/infantile. This disease is characterized by a generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.	NM_000494.3	c.4319dupC;c.4050delA;c.4003_4004delGG;c.4000delA; c.4319dupC;c.4050delA;c.4003_4004delGG;c.4000delA;c.3922delA;c.3908G>A;c.3897_3900delATCT;c.3827dupC;c.3795delC;c.3676C>T;c.3277+1G>A;c.3067C>T;c.3046C>T;c.3043C>T;c.2965delA;c.2944_2947+1delGAAGG;c.2564T>G;c.2551+1G>T;c.2430_2431insCCGA;c.2407G>T;c.2383C>T;c.2336-1G>T;c.2336-2A>G;c.2228-3_2235delCAGGTCCTGCTinsTTG;c.1898G>A;c.1706delC;c.1424G>A;c.994delG;c.662G>A;c.520_521delAG;c.433C>T;c.332-1G>A;c.214C>T;c.25C>T	Epidermolysis bullosa, junctional, non-Herlitz type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL17A1 gene located on chromosomal region 10q24.3. The age of onset is neonatal/infantile. This disease is characterized by a generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.	Plus
COL18A1	Knobloch syndrome, type 1 Knobloch syndrome, type 1 Descrição da doença: Knobloch syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL18A1 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by vitreoretinal and macular degeneration, and occipital encephalocele. The prevalence is <1:1,000,000.	NM_130444.2	c.1700_1701insGACGTGAAAGAGGGG;c.2240_2241insGACGTG c.1700_1701insGACGTGAAAGAGGGG;c.2240_2241insGACGTGAAAGAGGGG;c.3294_3295delAG;c.3301delC;c.3363dupC;c.3502C>T;c.3583C>T;c.3918dupC;c.3988C>T;c.4068dupC;c.4072_4084delCCCCCAGGCCCAC;c.4214_4223delCAGGGCCCCC;c.4215_4216delAGinsC;c.4222_4223delCC;c.4323_4323+1delGG;c.4684C>T;c.4759_4760delCT;c.5168dupG	Knobloch syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL18A1 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by vitreoretinal and macular degeneration, and occipital encephalocele. The prevalence is <1:1,000,000.	Plus
COL25A1	Fibrosis of extraocular muscles, congenital, type 5 Fibrosis of extraocular muscles, congenital, type 5 Descrição da doença: Fibrosis of extraocular muscles, congenital, type 5 is an ocular motility disorder characterized by congenital dysinnervation of various cranial nerves to ocular muscles. Clinical features are ophthalmoplegia, anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head.	NM_198721.3	c.1489G>T c.1489G>T	Fibrosis of extraocular muscles, congenital, type 5 is an ocular motility disorder characterized by congenital dysinnervation of various cranial nerves to ocular muscles. Clinical features are ophthalmoplegia, anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head.	Plus
COL4A3	Alport syndrome, autosomal recessive, type 2 Alport syndrome, autosomal recessive, type 2 Descrição da doença: Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.	NM_000091.4	c.2T>C;c.279+1G>A;c.325-1G>A;c.345delG;c.388-1G>T; c.2T>C;c.279+1G>A;c.325-1G>A;c.345delG;c.388-1G>T;c.391G>T;c.547-1G>T;c.645+2T>C;c.663_664delAG;c.713dupC;c.765+2T>C;c.829-2A>C;c.898G>A;c.949_950delAG;c.1201G>A;c.1216C>T;c.1354G>A;c.1504+1G>A;c.1758+1G>A;c.1918G>A;c.1927+2T>C;c.1928-1G>A;c.2031_2038dupATCCCTGG;c.2083G>A;c.2111delC;c.2215G>A;c.2223+1G>A;c.2371C>T;c.2417dupC;c.2452G>A;c.2535delC;c.2621_2622delGAinsT;c.2747-1G>C;c.2768_2778delTAAAGGGCCAG;c.2838_2839delGA;c.2881+1G>T;c.2954G>T;c.3068_3069delCA;c.3070+2T>C;c.3109C>T;c.3148C>T;c.3210+1G>A;c.3211-1G>C;c.3244_3247delAAAG;c.3250G>T;c.3499G>A;c.3751+1G>A;c.3829G>A;c.3883-2A>G;c.4347_4353delCCGACAC;c.4420_4424delCTTTT;c.4441C>T;c.4486C>T;c.4546C>T;c.4571C>G;c.4640+1G>A;c.4756-1G>A;c.4803delT;c.4819G>T;c.4825C>T;c.4872C>G	Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.	Plus
COL4A4	Alport syndrome, autosomal recessive, type 2 Alport syndrome, autosomal recessive, type 2 Descrição da doença: Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.	NM_000092.4	c.4923C>A;c.4715C>T;c.4679_4683delGCCCC;c.4623C>G; c.4923C>A;c.4715C>T;c.4679_4683delGCCCC;c.4623C>G;c.4599T>G;c.4429G>T;c.4333+2T>C;c.4129C>T;c.4002_4005dupACCA;c.3967C>T;c.3734G>T;c.3713C>A;c.3601G>A;c.3222dupA;c.3151-2A>G;c.2969-1G>C;c.2967_2968delAG;c.2906C>G;c.2878G>A;c.2690G>A;c.2638delG;c.2546-1G>C;c.2545+2T>G;c.2420delG;c.2320G>C;c.2312delG;c.2279dupG;c.1889delC;c.1697-1G>A;c.1696+1G>A;c.1696+1G>T;c.1623+1G>A;c.1405G>T;c.1369+1G>A;c.1118G>A;c.1100-2A>C;c.1045C>T;c.1030-1G>C;c.1030-2A>C;c.1029+2T>C;c.975+1G>A;c.975+1G>C;c.871-1G>C;c.673_680delCCAGGGCG;c.657+1G>T;c.594+1G>A;c.489+1G>A;c.372+2T>G;c.328-1G>A;c.114+1G>C;c.71+1G>A;c.71G>A	Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.	Plus
COL4A5	Alport syndrome, X-linked Alport syndrome, X-linked Descrição da doença: Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (rKashtan, 1999). Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type 4 collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance (104200) is rare (Kashtan, 1999).	NM_033380.2	c.1A>G;c.2T>A;c.13G>T;c.38_41dupTCTT;c.81+1G>C;c.8 c.1A>G;c.2T>A;c.13G>T;c.38_41dupTCTT;c.81+1G>C;c.87C>A;c.90T>G;c.107C>G;c.119delG;c.142-1G>A;c.231+1G>A;c.232-1G>A;c.232-1G>T;c.252delG;c.277-1G>T;c.293delC;c.321+1_321+2dupGT;c.322-1G>A;c.359_363delGTATTinsATAC;c.368delG;c.367G>A;c.368G>A;c.384+1G>A;c.385-1G>C;c.385G>A;c.386G>A;c.386G>T;c.388G>T;c.430G>A;c.430G>C;c.431G>A;c.438+2T>C;c.440delG;c.446delC;c.446dupC;c.466-2A>G;c.476delG;c.520G>C;c.529G>C;c.529G>T;c.533delC;c.544_546+4delCAAGTAA;c.544C>T;c.546+1G>A;c.547-2A>G;c.547-1G>A;c.548G>T;c.550dupC;c.560_561dupCC;c.573_574dupAG;c.574G>A;c.584G>A;c.590delC;c.609+1G>A;c.610-2A>G;c.610-2A>T;c.611_612delGC;c.611G>A;c.611G>T;c.635delC;c.645+2T>C;c.647_648dupGG;c.648dupG;c.646G>A;c.655G>A;c.679G>A;c.680G>A;c.682G>T;c.687+1G>A;c.687+2T>C;c.689delG;c.688G>C;c.689G>A;c.698G>T;c.715G>A;c.716G>A;c.761_762delAG;c.780+2T>G;c.781-1_786delGGGACTT;c.788delC;c.790G>C;c.791G>A;c.796C>T;c.801dupG;c.812delC;c.834+1G>A;c.834+2T>G;c.835-2A>G;c.859G>T;c.863delA;c.866delG;c.866G>T;c.871C>T;c.873delA;c.875delG;c.874G>C;c.875G>T;c.891+1G>A;c.892-2A>G;c.892-1G>C;c.892G>A;c.893G>A;c.913G>T;c.929G>A;c.936+1G>A;c.937-1G>A;c.945dupT;c.947G>A;c.955G>C;c.956G>A;c.960C>A;c.965G>A;c.965G>T;c.973G>A;c.973G>T;c.974G>A;c.990+1G>T;c.991-1G>A;c.1032+1G>C;c.1060dupA;c.1062dupT;c.1074delA;c.1073_1074insC;c.1111G>T;c.1112G>A;c.1117C>T;c.1135C>T;c.1165+1G>A;c.1165+2T>G;c.1166-1G>A;c.1181delG;c.1208G>T;c.1213dupA;c.1214_1217dupGGGG;c.1214_1215insA;c.1216G>A;c.1217G>T;c.1219C>T;c.1222A>T;c.1226G>A;c.1243G>A;c.1254delT;c.1259G>A;c.1259G>T;c.1265delC;c.1268G>A;c.1276G>A;c.1280dupA;c.1288dupG;c.1339+1G>A;c.1340-2A>G;c.1340-1G>A;c.1350_1351delAT;c.1376delC;c.1376dupC;c.1414G>A;c.1423+1G>A;c.1424-1G>A;c.1516+1G>A;c.1517-1G>T;c.1542_1543delAG;c.1561G>T;c.1562G>A;c.1567delA;c.1571G>A;c.1587+1delG;c.1587+1G>A;c.1653delC;c.1738C>T;c.1757_1770delTTCCTGGCCCGAAA;c.1779+1G>A;c.1779+1G>T;c.1780-1G>A;c.1780-1G>T;c.1780G>A;c.1781G>A;c.1825G>C;c.1826G>A;c.1826G>T;c.1846_1854delAATATAGGG;c.1843G>C;c.1844G>A;c.1856C>T;c.1861G>T;c.1862G>T;c.1869delT;c.1871G>A;c.1894G>C;c.1895G>A;c.1897G>A;c.1904G>A;c.1912G>A;c.1913G>A;c.1913G>C;c.1913G>T;c.1948+1G>A;c.1949-2A>G;c.1949-2A>T;c.1960delG;c.1957G>A;c.2018delG;c.2041+1G>T;c.2048delC;c.2050G>T;c.2057delC;c.2095G>T;c.2098G>T;c.2245-1G>A;c.2264T>G;c.2287G>A;c.2288G>A;c.2288G>T;c.2297G>A;c.2297G>T;c.2305G>A;c.2306G>T;c.2315G>A;c.2315G>C;c.2322dupA;c.2332G>A;c.2348delC;c.2386G>A;c.2387G>T;c.2395+1G>A;c.2395+1G>C;c.2395+2delT;c.2396-1G>A;c.2396-1G>T;c.2404G>A;c.2414G>A;c.2423delG;c.2431G>A;c.2432G>T;c.2452_2454delATAinsT;c.2473G>T;c.2477delC;c.2482G>A;c.2483G>A;c.2509+1G>A;c.2510-2A>G;c.2510delG;c.2554G>A;c.2555G>A;c.2578G>C;c.2597G>A;c.2605G>A;c.2614G>C;c.2624G>A;c.2625delA;c.2632G>T;c.2633G>T;c.2643delG;c.2659G>C;c.2660G>T;c.2677G>C;c.2687delG;c.2696_2705delGTATGATGGG;c.2696G>T;c.2705G>A;c.2705G>T;c.2708dupC;c.2714G>A;c.2722G>A;c.2722G>T;c.2731G>A;c.2732G>A;c.2766delA;c.2782C>T;c.2788C>T;c.2802dupT;c.2815G>T;c.2821G>T;c.2822G>A;c.2831delG;c.2846delC;c.2917+1G>C;c.2917+1G>T;c.2918-1G>A;c.2918-1G>C;c.2918-1G>T;c.2943delA;c.2947delT;c.2965delG;c.2976_2982delACCTGGA;c.3016+1G>T;c.3017-1G>A;c.3017G>T;c.3044G>T;c.3046delC;c.3046C>T;c.3057delT;c.3088G>A;c.3107-2A>G;c.3115G>A;c.3154C>T;c.3167delC;c.3169G>T;c.3178G>T;c.3181C>T;c.3188G>T;c.3196G>A;c.3196G>C;c.3197G>C;c.3206G>A;c.3206G>T;c.3212C>G;c.3227delC;c.3246+1G>A;c.3247-1G>A;c.3256G>C;c.3257G>A;c.3289A>T;c.3311G>T;c.3314T>A;c.3319G>A;c.3326_3327insT;c.3331delA;c.3334_3337dupCCTG;c.3373+1G>A;c.3410G>A;c.3413delC;c.3427G>A;c.3428G>A;c.3454+1G>T;c.3474delG;c.3472G>A;c.3481G>A;c.3487_3488delCCinsG;c.3499G>A;c.3509delG;c.3508G>A;c.3527delG;c.3526G>A;c.3535G>A;c.3538C>T;c.3543_3549delGGGTGAA;c.3544G>C;c.3545G>T;c.3586G>A;c.3587G>A;c.3605-2A>G;c.3605-1G>A;c.3613G>A;c.3613G>T;c.3631G>C;c.3632G>A;c.3641G>A;c.3647delC;c.3650G>A;c.3659G>A;c.3668G>A;c.3668G>T;c.3685G>A;c.3685G>T;c.3686G>A;c.3692delC;c.3692dupC;c.3694G>A;c.3700C>T;c.3709_3710dupCC;c.3721G>C;c.3721G>T;c.3722G>T;c.3746delG;c.3754_3757dupGGCA;c.3754G>A;c.3769C>T;c.3791delG;c.3793-1A>T;c.3811G>A;c.3818delC;c.3869_3872dupAACC;c.3902delG;c.3923delT;c.3927+1G>C;c.3928-2A>G;c.3928-1G>A;c.3963delA;c.3961A>T;c.3995delT;c.4001-2A>G;c.4001-2A>T;c.4001-1G>A;c.4009G>T;c.4048delG;c.4072+1G>A;c.4074delT;c.4105_4106delAG;c.4150C>T;c.4164_4165insTCCT;c.4174G>T;c.4180delC;c.4180C>T;c.4187delC;c.4199dupC;c.4201_4201+1delGG;c.4202-1G>A;c.4217dupC;c.4238delG;c.4282G>T;c.4283G>C;c.4283G>T;c.4300+1G>A;c.4300+1G>C;c.4301-1G>C;c.4301G>T;c.4327G>C;c.4328G>A;c.4328G>C;c.4345G>A;c.4345G>C;c.4347dupT;c.4352delC;c.4354G>A;c.4355G>A;c.4404_4405dupCA;c.4439_4440delGA;c.4441delA;c.4442C>G;c.4460G>A;c.4460G>C;c.4460G>T;c.4466C>T;c.4494_4495delAG;c.4496C>A;c.4504C>T;c.4513+1G>A;c.4513+1G>C;c.4513+1G>T;c.4566C>A;c.4616G>C;c.4617G>A;c.4690C>T;c.4691+1G>A;c.4692-1G>C;c.4693T>C;c.4694G>C;c.4698delA;c.4702T>C;c.4703G>C;c.4705G>A;c.4748delA;c.4753_4759delCCCCATT;c.4752dupT;c.4754C>T;c.4759T>C;c.4760G>T;c.4769G>T;c.4771T>G;c.4783_4784delTG;c.4785G>A;c.4790G>A;c.4790G>T;c.4793A>G;c.4794T>A;c.4796C>T;c.4806G>A;c.4806+1G>A;c.4807-2A>C;c.4835delG;c.4885_4888delCCCT;c.4897T>G;c.4898G>A;c.4899T>G;c.4916G>A;c.4916G>C;c.4945dupT;c.4949T>G;c.4971delC;c.4979+2T>C;c.4980-2A>G;c.4997_5004delCGCTGAAA;c.5023C>T;c.5032C>T;c.5033G>A;c.5033G>C;c.5033G>T;c.5035T>C;c.5037delT;c.5037T>G;c.5039A>C;c.5044T>G;c.5045G>T	Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (rKashtan, 1999). Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type 4 collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance (104200) is rare (Kashtan, 1999).	Plus
COL6A1	Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1 Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1 Descrição da doença: Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A1 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.	NM_001848.2	c.128A>C;c.362A>G;c.428+1G>A;c.741C>A;c.782_789del c.128A>C;c.362A>G;c.428+1G>A;c.741C>A;c.782_789delTCCGGGGC;c.805-2A>G;c.859-1G>C;c.868G>A;c.868G>C;c.877G>A;c.903+1G>T;c.904-2A>G;c.904G>A;c.928_930delAAG;c.930+1G>A;c.931-1G>A;c.931-1G>C;c.932G>A;c.957_957+7delGGTGAGCG;c.957+1G>A;c.957+2T>C;c.958-2A>G;c.1002+1G>A;c.1002+1G>T;c.1002+2T>G;c.1003-2delA;c.1003-2A>G;c.1003-1G>A;c.1022G>A;c.1022G>T;c.1039_1052delGGCTCGCCCGGGTT;c.1056+1delG;c.1056+1G>A;c.1056+2T>C;c.1398+2T>G;c.1465delG;c.1576-1G>A;c.1611+1G>A;c.1693C>T;c.1823-1G>T;c.1977C>G;c.2122C>T;c.2435-2A>G	Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A1 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.	Plus
COL6A2	Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1 Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1 Descrição da doença: Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A2 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.	NM_001849.3	c.94G>T;c.115+2T>C;c.186dupC;c.244C>T;c.265C>T;c.7 c.94G>T;c.115+2T>C;c.186dupC;c.244C>T;c.265C>T;c.736-2A>G;c.801+1G>A;c.801+1G>T;c.802-2A>G;c.803G>A;c.811G>A;c.812G>A;c.848G>A;c.855+1G>A;c.855+1G>C;c.855+2T>G;c.856-2A>C;c.857G>A;c.865G>T;c.866G>A;c.875G>T;c.892G>A;c.900+1G>A;c.900+1G>C;c.901G>A;c.902G>A;c.955-2A>G;c.955-1G>A;c.1000-2A>C;c.1000-2A>G;c.1000-1G>T;c.1053+1G>A;c.1053+1G>C;c.1054-2A>G;c.1055delG;c.1096C>T;c.1180-1G>C;c.1294A>T;c.1396-1G>A;c.1402C>T;c.1458+1G>A;c.1459-2A>G;c.1461delA;c.1522-1G>A;c.1561C>T;c.1572+1G>A;c.1615C>T;c.1751delC;c.1770+1delG;c.1771-1G>T;c.1861G>A;c.1970-9G>A;c.2002G>T;c.2038_2039delCGinsA;c.2040dupT;c.2133C>G;c.2284_2285delAT;c.2312dupA;c.2329T>C;c.2422+1G>A;c.2455C>T;c.2489G>A;c.2572C>T;c.2611G>A;c.2626C>A;c.2627G>A	Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A2 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.	Plus
COL6A3	Dystonia, type 27 Dystonia, type 27 Descrição da doença: Dystonia, type 27 is an autosomal recessive neurologic disorder characterized by onset of segmental isolated dystonia mainly affecting the craniocervical region and upper limbs in the first 2 decades of life (Zech et al., 2015).	NM_004369.3	c.9193C>T;c.8966-1G>C;c.8965+1G>A;c.7796_7797delTT c.9193C>T;c.8966-1G>C;c.8965+1G>A;c.7796_7797delTT;c.7669-2delA;c.7542delC;c.7264C>T;c.7024C>T;c.6890G>C;c.6604C>T;c.6355-1G>A;c.6354+1G>A;c.6354+1G>T;c.6310-2A>G;c.6309+1G>A;c.6309+1G>T;c.6293G>T;c.6283-2A>C;c.6282+1G>A;c.6239G>A;c.6230G>A;c.6220G>A;c.6212G>A;c.6210+1G>A;c.6193G>A;c.6193G>C;c.6181C>T;c.6175G>T;c.6167G>A;c.6158G>T;c.6157G>T;c.6157-2A>C;c.6156+1G>A;c.6064-2A>G;c.5838+1G>T;c.5480delG;c.5177T>G;c.5010T>A;c.4835C>A;c.4624C>T;c.4390C>T;c.4366C>T;c.4124delA;c.2620C>T;c.2506C>T;c.1897+1G>T;c.1699C>T;c.1393C>T;c.761delG;c.749C>A;c.175C>T;c.76C>T	Dystonia, type 27 is an autosomal recessive neurologic disorder characterized by onset of segmental isolated dystonia mainly affecting the craniocervical region and upper limbs in the first 2 decades of life (Zech et al., 2015).	Plus
COL7A1	Dystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type and non-HS type; DEB pruriginosa; DEB pretibial Dystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type and non-HS type; DEB pruriginosa; DEB pretibial Descrição da doença: Dystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL7A1 gene located on chromosomal region 3p21.1. The age of onset is neonatal/infantile. This disease is characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement. Some mutations may also cause a milder recessive form (non-HS type). Also, distint subclinical types of DEB include like Pruriginosa form (OMIM 604129), Pretibial form (OMIM 131850) and other are caused by mutations in this gene with variable modes of inheritace, including subclinical types caused by dominant mutations. In addition, less commonly, mutations in the COL7A1 gene may cause strictly dominant DEB. The overall prevalence of DEB is <1:1,000,000.	NM_000094.3	c.8524_8527+10delGAAGGTGAGGACAG;c.8479C>T;c.8440C> c.8524_8527+10delGAAGGTGAGGACAG;c.8479C>T;c.8440C>T;c.8393T>A;c.8329C>T;c.8245G>A;c.7957G>A;c.7930-1G>C;c.7912G>T;c.7865G>A;c.7864C>T;c.7828C>T;c.7723G>A;c.7557+1G>T;c.7462C>T;c.7411C>T;c.7345-1G>A;c.7012C>T;c.6946G>A;c.6900+1G>A;c.6859G>A;c.6781C>T;c.6770G>C;c.6752G>A;c.6724G>A;c.6724G>C;c.6670G>T;c.6656dupT;c.6573+1G>T;c.6527dupC;c.6218G>T;c.6205C>T;c.6190G>A;c.6187C>T;c.6127G>A;c.6127G>T;c.6118G>A;c.6110G>A;c.6109G>A;c.6101G>C;c.6100G>A;c.6091G>A;c.6081delC;c.6082G>A;c.6074delG;c.6022C>T;c.6017G>A;c.6007G>A;c.5932C>T;c.5924_5927delAACG;c.5821-1G>A;c.5797C>T;c.5701-1G>T;c.5532+1G>A;c.5443G>A;c.5425-1G>C;c.5344G>A;c.5287C>T;c.5261dupC;c.5096C>T;c.5052+1G>A;c.5048_5051dupGAAA;c.5047C>T;c.5015delA;c.4980+1G>C;c.4919delG;c.4888C>T;c.4871delC;c.4783G>C;c.4767delA;c.4568delC;c.4466delG;c.4373C>T;c.4233delT;c.4119+1G>T;c.4039G>C;c.4027C>T;c.4011+1G>A;c.3971delT;c.3942dupG;c.3840delC;c.3831+1G>T;c.3751_3752insACCA;c.3631C>T;c.3504delC;c.3265C>T;c.3140-1G>A;c.2993-2A>G;c.2710+2T>C;c.2607_2608delCC;c.2471dupG;c.2318_2321dupCTGA;c.2223_2226dupTGGA;c.2005C>T;c.1781-1G>C;c.1732C>T;c.1637-1G>A;c.1573C>T;c.933C>A;c.887delG;c.751C>T;c.706C>T;c.682+1G>A;c.553C>T;c.497dupA;c.425A>G;c.409C>T;c.336C>G;c.58C>T;c.1A>G	Dystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL7A1 gene located on chromosomal region 3p21.1. The age of onset is neonatal/infantile. This disease is characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement. Some mutations may also cause a milder recessive form (non-HS type). Also, distint subclinical types of DEB include like Pruriginosa form (OMIM 604129), Pretibial form (OMIM 131850) and other are caused by mutations in this gene with variable modes of inheritace, including subclinical types caused by dominant mutations. In addition, less commonly, mutations in the COL7A1 gene may cause strictly dominant DEB. The overall prevalence of DEB is <1:1,000,000.	Plus
COL9A1	Stickler syndrome, type 4 Stickler syndrome, type 4 Descrição da doença: Stickler syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL9A1 gene located on chromosomal region 6q13. The age of onset is infantile. This disease is characterized by opthalmological (myopia, retinal detachment and cataracts), orofacial (micrognathia, midface hypoplasia and cleft palate) auditory (sensorineural hearing loss) and articular (epiphyseal dysplasia) symptoms. The prevalence is <1:1,000,000.	NM_001851.4	c.1519C>T;c.1411C>T;c.1120G>T;c.883C>T;c.706C>T;c. c.1519C>T;c.1411C>T;c.1120G>T;c.883C>T;c.706C>T;c.188delT	Stickler syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL9A1 gene located on chromosomal region 6q13. The age of onset is infantile. This disease is characterized by opthalmological (myopia, retinal detachment and cataracts), orofacial (micrognathia, midface hypoplasia and cleft palate) auditory (sensorineural hearing loss) and articular (epiphyseal dysplasia) symptoms. The prevalence is <1:1,000,000.	Plus
COLEC11	3MC syndrome, type 2 3MC syndrome, type 2 Descrição da doença: The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (Rooryck et al., 2011).	NM_001255985.1	c.547T>C;c.652G>A c.547T>C;c.652G>A	The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (Rooryck et al., 2011).	Plus
COLQ	Myasthenic syndrome, congenital, type 5 Myasthenic syndrome, congenital, type 5 Descrição da doença: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (Engel et al., 2015).	NM_005677.3	c.1321A>G;c.1228C>T;c.1082delC;c.943C>T;c.844A>T;c c.1321A>G;c.1228C>T;c.1082delC;c.943C>T;c.844A>T;c.788dupC;c.718G>T;c.679C>T;c.640G>T;c.529-2A>G;c.506C>G;c.393+1G>A;c.157dupC	Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (Engel et al., 2015).	Plus
COQ2	Primary coenzyme Q10 deficiency, type 1 Primary coenzyme Q10 deficiency, type 1 Descrição da doença: Primary coenzyme Q10 deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ2 gene located on chromosomal region 4q21.23. The age of onset is neonatal/infantile. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.	NM_015697.7	c.1197delT;c.1159C>T;c.890A>G;c.735C>G;c.723delT;c c.1197delT;c.1159C>T;c.890A>G;c.735C>G;c.723delT;c.683A>G;c.590G>A;c.545T>G;c.437G>A	Primary coenzyme Q10 deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ2 gene located on chromosomal region 4q21.23. The age of onset is neonatal/infantile. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.	Plus
COQ4	Coenzyme Q10 deficiency, primary, type 7 Coenzyme Q10 deficiency, primary, type 7 Descrição da doença: Coenzyme Q10 deficiency, primary, type 7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (Brea-Calvo et al., 2015).	NM_016035.4	c.202G>C;c.300-2A>G;c.402+1G>C;c.421C>T;c.718C>T c.202G>C;c.300-2A>G;c.402+1G>C;c.421C>T;c.718C>T	Coenzyme Q10 deficiency, primary, type 7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (Brea-Calvo et al., 2015).	Plus
COQ6	Coenzyme Q10 deficiency, primary, type 6 Coenzyme Q10 deficiency, primary, type 6 Descrição da doença: Coenzyme Q10 deficiency, primary, type 6 (COQ10D6) is an autosomal recessive disorder characterized by onset in infancy of severe progressive nephrotic syndrome resulting in end-stage renal failure and sensorineural deafness. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS). Some patients may show a favorable response to oral coenzyme Q supplementation (Heeringa et al., 2011).	NM_182476.2	c.484C>T;c.564G>A;c.763G>A;c.1058C>A;c.1153_1154de c.484C>T;c.564G>A;c.763G>A;c.1058C>A;c.1153_1154delGA;c.1235A>G;c.1341G>A;c.1383delG	Coenzyme Q10 deficiency, primary, type 6 (COQ10D6) is an autosomal recessive disorder characterized by onset in infancy of severe progressive nephrotic syndrome resulting in end-stage renal failure and sensorineural deafness. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS). Some patients may show a favorable response to oral coenzyme Q supplementation (Heeringa et al., 2011).	Plus
COQ8A	Primary coenzyme Q10 deficiency, type 4 Primary coenzyme Q10 deficiency, type 4 Descrição da doença: Primary coenzyme Q10 deficiency type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ8A gene located on chromosomal region 1q42.13. The age of onset is infantile. This disease is characterized by progressive ataxia, cerebellar atrophy, and often exercise intolerance with elevated lactate levels and mild intellectual deficit.	NM_020247.4	c.589-3C>G;c.637C>T;c.811C>T;c.815G>A;c.815G>T;c.9 c.589-3C>G;c.637C>T;c.811C>T;c.815G>A;c.815G>T;c.911C>T;c.1015G>A;c.1042C>T;c.1081-1_1082dupGTA;c.1136T>A;c.1228C>T;c.1334_1335delCA;c.1398+2T>C;c.1523T>C;c.1541A>G;c.1645G>A;c.1651G>A;c.1665G>A;c.1744dupA;c.1750_1752delACC;c.1813dupG;c.1844dupG	Primary coenzyme Q10 deficiency type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ8A gene located on chromosomal region 1q42.13. The age of onset is infantile. This disease is characterized by progressive ataxia, cerebellar atrophy, and often exercise intolerance with elevated lactate levels and mild intellectual deficit.	Plus
COQ9	Coenzyme Q10 deficiency, primary, type 5 Coenzyme Q10 deficiency, primary, type 5 Descrição da doença: Coenzyme Q10 deficiency, primary, type 5 (COQ10D5) is a form of coenzyme Q10 deficiency, an autosomal recessive disorder with variable manifestations consistent with 5 major phenotypes. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.	NM_020312.3	c.730C>T c.730C>T	Coenzyme Q10 deficiency, primary, type 5 (COQ10D5) is a form of coenzyme Q10 deficiency, an autosomal recessive disorder with variable manifestations consistent with 5 major phenotypes. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.	Plus
CORO1A	Immunodeficiency, type 8 Immunodeficiency, type 8 Descrição da doença: Immunodeficiency, type 8 is a disease of the immune system leading to recurrent infections, and characterized by CD4+ T-cells lymphopenia. Patients can develop B-cell lymphoproliferation associated with Epstein-Barr virus infection.	NM_001193333.2	c.248_249delCT;c.400G>A;c.1078delC c.248_249delCT;c.400G>A;c.1078delC	Immunodeficiency, type 8 is a disease of the immune system leading to recurrent infections, and characterized by CD4+ T-cells lymphopenia. Patients can develop B-cell lymphoproliferation associated with Epstein-Barr virus infection.	Plus
COX10	Mitochondrial complex IV deficiency; Leigh syndrome due to mitochondrial COX4 deficiency Mitochondrial complex IV deficiency; Leigh syndrome due to mitochondrial COX4 deficiency Descrição da doença: The COX10 gene encodes a cytochrome c oxidase (COX) assembly protein involved in the mitochondrial heme biosynthetic pathway. Mutations in COX10 gene cause differentes phenotypes such as mitochondrial complex IV deficiency and Leigh syndrome. Complex IV (cytochrome c oxidase) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare. Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation (Dahl, 1998).Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).	NM_001303.3	c.2T>C;c.445C>T;c.674C>T c.2T>C;c.445C>T;c.674C>T	The COX10 gene encodes a cytochrome c oxidase (COX) assembly protein involved in the mitochondrial heme biosynthetic pathway. Mutations in COX10 gene cause differentes phenotypes such as mitochondrial complex IV deficiency and Leigh syndrome. Complex IV (cytochrome c oxidase) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare. Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation (Dahl, 1998).Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).	Plus
COX15	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, type 2; Leigh syndrome due to cytochrome c oxidase deficiency Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, type 2; Leigh syndrome due to cytochrome c oxidase deficiency Descrição da doença: Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, is a multiheteromeric enzyme embedded in the mitochondrial inner membrane. Mutations in COX gene cause different phenotypes susch as cardioencephalomyopathy and Leigh syndrome. Cardioencephalomyopathy due to cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder characterized by onset of cardiomyopathy either in utero or in the first days of life. Most patients also show neurologic abnormalities, such as abnormal breathing pattern, nystagmus, and gyral abnormalities, consistent with encephalopathy. The disorder is usually fatal in early infancy (Papadopoulou et al., 1999). Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).	NM_078470.5	c.281_282delAG c.281_282delAG	Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, is a multiheteromeric enzyme embedded in the mitochondrial inner membrane. Mutations in COX gene cause different phenotypes susch as cardioencephalomyopathy and Leigh syndrome. Cardioencephalomyopathy due to cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder characterized by onset of cardiomyopathy either in utero or in the first days of life. Most patients also show neurologic abnormalities, such as abnormal breathing pattern, nystagmus, and gyral abnormalities, consistent with encephalopathy. The disorder is usually fatal in early infancy (Papadopoulou et al., 1999). Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).	Plus
CP	Aceruloplasminemia Aceruloplasminemia Descrição da doença: Aceruloplasminemia is a disorder in which iron gradually accumulates in the brain and other organs. Iron accumulation in the brain results in neurological problems that generally appear in adulthood and worsen over time. People with aceruloplasminemia develop a variety of movement problems. They may experience involuntary muscle contractions (dystonia) of the head and neck, resulting in repetitive movements and contortions. Other involuntary movements may also occur, such as rhythmic shaking (tremors), jerking movements (chorea), eyelid twitching (blepharospasm), and grimacing. Affected individuals may also have difficulty with coordination (ataxia). Some develop psychiatric problems and a decline of intellectual function (dementia) in their forties or fifties.	NM_000096.3	c.3019-1G>A;c.2962G>A;c.2917dupA;c.2879-1G>A;c.287 c.3019-1G>A;c.2962G>A;c.2917dupA;c.2879-1G>A;c.2879-1G>T;c.2701C>T;c.2689_2690delCT;c.2630G>A;c.2603delG;c.2554+1G>T;c.2511dupT;c.2482delG;c.2389delG;c.2253G>A;c.2185delC;c.2131C>A;c.2068delG;c.2066delC;c.1948G>A;c.1918delG;c.1874G>A;c.1865-1G>A;c.1282_1286dupTACAC;c.1257_1258delTT;c.1209_1210dupTG;c.1209-2A>G;c.1208+1G>A;c.1123T>C;c.1049C>A;c.848G>C;c.650T>C;c.643C>T;c.607+1G>A;c.606dupA;c.587C>G;c.493C>G;c.395-1G>A;c.229G>C;c.147-2A>G;c.146+1G>A;c.82A>T	Aceruloplasminemia is a disorder in which iron gradually accumulates in the brain and other organs. Iron accumulation in the brain results in neurological problems that generally appear in adulthood and worsen over time. People with aceruloplasminemia develop a variety of movement problems. They may experience involuntary muscle contractions (dystonia) of the head and neck, resulting in repetitive movements and contortions. Other involuntary movements may also occur, such as rhythmic shaking (tremors), jerking movements (chorea), eyelid twitching (blepharospasm), and grimacing. Affected individuals may also have difficulty with coordination (ataxia). Some develop psychiatric problems and a decline of intellectual function (dementia) in their forties or fifties.	Plus
CPA6	Febrile seizures, familial, type 11 Febrile seizures, familial, type 11 Descrição da doença: Familial febrile seizures, type 11 is an autosomal recessive seizure disorder characterized by early childhood onset of simple or complex seizures associated with fever. These seizures usually remit later in childhood with no neurologic sequelae (Salzmann et al., 2012).	NM_020361.4	c.587A>G;c.544C>T c.587A>G;c.544C>T	Familial febrile seizures, type 11 is an autosomal recessive seizure disorder characterized by early childhood onset of simple or complex seizures associated with fever. These seizures usually remit later in childhood with no neurologic sequelae (Salzmann et al., 2012).	Plus
CPS1	Carbamoylphosphate synthetase 1 deficiency Carbamoylphosphate synthetase 1 deficiency Descrição da doença: Carbamoylphosphate synthetase deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPS1 gene located on chromosomal region 2q35. The age of onset is infantile. This disease is characterized by congenital hyperammonemia and defective citrulline synthesis. The prevalence is 1:800,000 newborn in Japan.	NM_001122633.2	c.144+1G>A;c.148C>T;c.254+1G>T;c.319delA;c.612_613 c.144+1G>A;c.148C>T;c.254+1G>T;c.319delA;c.612_613delGA;c.729+1G>C;c.730C>T;c.781G>T;c.816delG;c.1028A>G;c.1104+1G>A;c.1105-1G>T;c.1205C>A;c.1431dupC;c.1547delG;c.1649C>T;c.1778G>A;c.1930C>T;c.1931G>C;c.1944delC;c.2179C>T;c.2211-1G>T;c.2245delC;c.2357G>A;c.2377C>T;c.2409+1G>A;c.2410-1G>T;c.2425C>A;c.2447A>G;c.2827_2828delAT;c.2963G>A;c.3159+1G>A;c.3203delA;c.3393delC;c.3574delA;c.3577-2A>G;c.3802C>T;c.4020+2T>A;c.4021-2A>T;c.4021-1G>C;c.4074delC;c.4119+2T>C;c.4292+2T>C	Carbamoylphosphate synthetase deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPS1 gene located on chromosomal region 2q35. The age of onset is infantile. This disease is characterized by congenital hyperammonemia and defective citrulline synthesis. The prevalence is 1:800,000 newborn in Japan.	Plus
CPT1A	Carnitine palmitoyltransferase type 1A deficiency, hepatic Carnitine palmitoyltransferase type 1A deficiency, hepatic Descrição da doença: Carnitine palmitoyl transferase 1A deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT1A gene located on chromosomal region 11q13.2. The age of onset is neonatal/infantile. This disease is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure. The prevalence is 1.3:1,000 newborn.	NM_001876.3	c.2129G>A;c.2071C>T;c.2028+2T>G;c.1997_1998insAAAA c.2129G>A;c.2071C>T;c.2028+2T>G;c.1997_1998insAAAA;c.1876-1G>A;c.1876-1G>C;c.1737C>A;c.1711C>T;c.1600delC;c.1576-2A>G;c.1575+1G>A;c.1494T>A;c.1494T>G;c.1459-1G>A;c.1458+1G>A;c.1436C>T;c.1425G>A;c.1393G>T;c.1386delC;c.1361A>G;c.1348_1352+4delGACAGGTAC;c.1339C>T;c.1298delA;c.1241C>T;c.1216C>T;c.1163+2T>C;c.1163+1G>A;c.1079A>G;c.967+2T>C;c.967+1G>A;c.948delG;c.919C>T;c.772-1G>A;c.772-2A>G;c.771+1G>C;c.727C>T;c.694-2A>G;c.693+1G>C;c.693+1G>T;c.548_549delTG;c.478C>T;c.335_336delCC;c.298C>T;c.282-1G>A;c.281+1G>A;c.222C>A;c.186G>A;c.96T>G	Carnitine palmitoyl transferase 1A deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT1A gene located on chromosomal region 11q13.2. The age of onset is neonatal/infantile. This disease is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure. The prevalence is 1.3:1,000 newborn.	Plus
CPT2	Carnitine palmitoyltransferase type 2 deficiency, lethal neonatal; Carnitine palmitoyltransferase type 2 deficiency, infantile Carnitine palmitoyltransferase type 2 deficiency, lethal neonatal; Carnitine palmitoyltransferase type 2 deficiency, infantile Descrição da doença: Carnitine palmitoyltransferase deficiency, type 2, lethal neonatal form follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT2 gene located on chromosomal region 1p32. The age of onset is neonatal/infantile. This disease is characterized by a severe fasting intolerance leading to metabolic derangements of hypoketotic hypoglycemia, resulting in coma and seizures, and hepatic encephalopathy leading to liver failure. The prevalence is <1:1,000,000.	NM_000098.2	c.38delG;c.98delA;c.110_111dupGC;c.149C>A;c.338C>T c.38delG;c.98delA;c.110_111dupGC;c.149C>A;c.338C>T;c.359A>G;c.370C>T;c.401_404delTTAT;c.452G>A;c.464dupT;c.520G>A;c.520G>T;c.606T>A;c.638A>G;c.670delA;c.680C>T;c.725_726delAC;c.748_749delAA;c.852delC;c.879_880delTG;c.886C>T;c.1046dupA;c.1046_1047delAC;c.1053G>A;c.1148T>A;c.1237C>T;c.1239_1240delGA;c.1324dupA;c.1345C>T;c.1345delCinsTA;c.1348A>T;c.1359_1362delAGAA;c.1360G>T;c.1369A>T;c.1375C>T;c.1414C>T;c.1432C>T;c.1437C>G;c.1446_1447delAG;c.1545_1548delCTTT;c.1737delC;c.1784delC;c.1883A>C;c.1891C>T;c.1925_1937delAGGCCTTAGAAGA	Carnitine palmitoyltransferase deficiency, type 2, lethal neonatal form follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT2 gene located on chromosomal region 1p32. The age of onset is neonatal/infantile. This disease is characterized by a severe fasting intolerance leading to metabolic derangements of hypoketotic hypoglycemia, resulting in coma and seizures, and hepatic encephalopathy leading to liver failure. The prevalence is <1:1,000,000.	Plus
CR2	Immunodeficiency, common variable, type 7 Immunodeficiency, common variable, type 7 Descrição da doença: Immunodeficiency, common variable, type 7 (CVID7) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	NM_001006658.2	c.1225+1G>C;c.2297G>A c.1225+1G>C;c.2297G>A	Immunodeficiency, common variable, type 7 (CVID7) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.	Plus
CRADD	Mental retardation, autosomal recessive, type 34, with variant lissencephaly Mental retardation, autosomal recessive, type 34, with variant lissencephaly Descrição da doença: Mental retardation, autosomal recessive, type 34, with variant lissencephaly (MRT34) is an autosomal recessive neurologic disorder characterized by mild to moderate intellectual disability and megalencephaly or enlarged head circumference. Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures (Di Donato et al., 2016).	NM_001320099.1	c.382G>C;c.491T>G;c.508C>T c.382G>C;c.491T>G;c.508C>T	Mental retardation, autosomal recessive, type 34, with variant lissencephaly (MRT34) is an autosomal recessive neurologic disorder characterized by mild to moderate intellectual disability and megalencephaly or enlarged head circumference. Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures (Di Donato et al., 2016).	Plus
CRB1	Retinitis pigmentosa, type 12; Leber congenital amaurosis, type 8 Retinitis pigmentosa, type 12; Leber congenital amaurosis, type 8 Descrição da doença: Retinitis pigmentosa type 12 and Leber congenital amaurosis type 8 follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the CRB1 gene located on chromosomal region 1q31-q32.1. Retinitis pigmentosa type 12 is characterized by night blindness, peripheral visual field impairment and over time loss of central visionm, and its prevalence is 1-5:10,000. Leber congenital amaurosis, with a neonatal/infantile age of onset, comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Other clinical findings of this disease may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus.	NM_201253.2	c.257_258dupTG;c.498_506delAATTGATGG;c.584G>T;c.61 c.257_258dupTG;c.498_506delAATTGATGG;c.584G>T;c.613_619delATAGGAA;c.799_800delGCinsA;c.807dupA;c.998G>A;c.1180T>C;c.1182C>A;c.1183G>T;c.1459dupT;c.1576C>T;c.1612_1613insCTTA;c.2220dupC;c.2222T>C;c.2234C>T;c.2290C>T;c.2330_2336delCAAACTC;c.2401A>T;c.2416G>T;c.2501G>A;c.2548G>A;c.2688T>A;c.2783G>A;c.2983G>T;c.3055_3059dupTATAT;c.3122T>C;c.3172G>T;c.3299T>C;c.3299T>G;c.3307G>A;c.3383delT;c.3419T>A;c.3541T>C;c.3542dupG;c.3988delG;c.3997G>T;c.4121_4130delCAACTCAGGG	Retinitis pigmentosa type 12 and Leber congenital amaurosis type 8 follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the CRB1 gene located on chromosomal region 1q31-q32.1. Retinitis pigmentosa type 12 is characterized by night blindness, peripheral visual field impairment and over time loss of central visionm, and its prevalence is 1-5:10,000. Leber congenital amaurosis, with a neonatal/infantile age of onset, comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Other clinical findings of this disease may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus.	Plus
CRBN	Mental retardation, autosomal recessive, type 2 Mental retardation, autosomal recessive, type 2 Descrição da doença: Mental retardation, autosomal recessive, type 2A (MRT2A) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. MRT2A patients display mild mental retardation with a standard IQ ranged from 50 to 70. IQ scores are lower in males than females. Developmental milestones are mildly delayed. There are no dysmorphic or autistic features.	NM_016302.3	c.1255C>T;c.1171T>C c.1255C>T;c.1171T>C	Mental retardation, autosomal recessive, type 2A (MRT2A) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. MRT2A patients display mild mental retardation with a standard IQ ranged from 50 to 70. IQ scores are lower in males than females. Developmental milestones are mildly delayed. There are no dysmorphic or autistic features.	Plus
CRLF1	Cold-induced sweating syndrome type 1 Cold-induced sweating syndrome type 1 Descrição da doença: Cold-induced sweating syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRLF1 gene located on chromosomal region 19p12. The age of onset is infantile. This disease is characterized by profuse sweating (involving the chest, face, arms and trunk) induced by cold ambient temperature kyphoscoliosis, a high-arched palate, depressed nasal bridge and impaired peripheral sensitivity to pain and temperature. The prevalence is <1:1,000,000.	NM_004750.4	c.1137C>G;c.1125delG;c.1102A>T;c.983dupG;c.935G>A; c.1137C>G;c.1125delG;c.1102A>T;c.983dupG;c.935G>A;c.857_864delTGGTGGAC;c.856-1G>A;c.852G>T;c.845_846delTG;c.829C>T;c.713dupC;c.708_709delCCinsT;c.676dupA;c.538C>T;c.527+5G>A;c.413C>T;c.397+1G>A;c.322C>T;c.303delC;c.226T>G	Cold-induced sweating syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRLF1 gene located on chromosomal region 19p12. The age of onset is infantile. This disease is characterized by profuse sweating (involving the chest, face, arms and trunk) induced by cold ambient temperature kyphoscoliosis, a high-arched palate, depressed nasal bridge and impaired peripheral sensitivity to pain and temperature. The prevalence is <1:1,000,000.	Plus
CRTAP	Osteogenesis imperfecta, type 7 Osteogenesis imperfecta, type 7 Descrição da doença: Osteogenesis imperfecta, type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRTAP gene located on chromosomal region 3p22.3. The age of onset is variable. This disease is characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity. The prevalence is 6:100,000-7:100,000.	NM_006371.4	c.118_133delGAGCTGATGCCGCTCGinsTACCC;c.118G>T;c.18 c.118_133delGAGCTGATGCCGCTCGinsTACCC;c.118G>T;c.180G>A;c.471+2C>A;c.561T>G;c.634C>T;c.826C>T	Osteogenesis imperfecta, type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRTAP gene located on chromosomal region 3p22.3. The age of onset is variable. This disease is characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity. The prevalence is 6:100,000-7:100,000.	Plus
CRYAA	Cataract 9, multiple types Cataract 9, multiple types Descrição da doença: Mutations in the CRYAA gene have been found to cause multiple types of cataract, which have been described as nuclear, zonular central nuclear, laminar, lamellar, anterior polar, posterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the CRYAA gene. Both autosomal dominant and autosomal recessive modes of inheritance have been reported. The symbol CATC1 was formerly used for the autosomal recessive form of cataract caused by mutation in the CRYAA gene.	NM_000394.3	c.27G>A;c.34C>T;c.61C>T;c.62G>A;c.142T>G;c.145C>T; c.27G>A;c.34C>T;c.61C>T;c.62G>A;c.142T>G;c.145C>T;c.160C>T;c.292G>A;c.346C>T;c.347G>A;c.440delA	Mutations in the CRYAA gene have been found to cause multiple types of cataract, which have been described as nuclear, zonular central nuclear, laminar, lamellar, anterior polar, posterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the CRYAA gene. Both autosomal dominant and autosomal recessive modes of inheritance have been reported. The symbol CATC1 was formerly used for the autosomal recessive form of cataract caused by mutation in the CRYAA gene.	Plus
CRYAB	Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related; Cataract 16, multiple types Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related; Cataract 16, multiple types Descrição da doença: Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related is a severe autosomal recessive muscular dystrophy with onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years (Del Bigio et al., 2011). Mutations in the CRYAB gene have been found to cause multiple types of cataract, which have been described as congenital posterior polar, congenital lamellar, and juvenile. Autosomal dominant and autosomal recessive forms have been described.	NM_001289807.1	c.470G>A;c.451C>T;c.418G>A;c.358A>G;c.343delT;c.32 c.470G>A;c.451C>T;c.418G>A;c.358A>G;c.343delT;c.326A>G;c.325G>C;c.320G>T;c.166C>T;c.60delC;c.58C>T	Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related is a severe autosomal recessive muscular dystrophy with onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years (Del Bigio et al., 2011). Mutations in the CRYAB gene have been found to cause multiple types of cataract, which have been described as congenital posterior polar, congenital lamellar, and juvenile. Autosomal dominant and autosomal recessive forms have been described.	Plus
CRYBB1	Cataract 17, multiple types Cataract 17, multiple types Descrição da doença: Mutations in the CRYBB1 gene have been found to cause multiple types of cataract, which have been described as congenital nuclear, congenital nuclear with anterior and posterior Y-suture and polar opacities, and pulverulent.	NM_001887.3	c.757T>C;c.658G>T;c.387C>A;c.368G>A;c.171delG c.757T>C;c.658G>T;c.387C>A;c.368G>A;c.171delG	Mutations in the CRYBB1 gene have been found to cause multiple types of cataract, which have been described as congenital nuclear, congenital nuclear with anterior and posterior Y-suture and polar opacities, and pulverulent.	Plus
CRYBB3	Cataract 22 Cataract 22 Descrição da doença: Mutations in the CRYBB3 gene have been identified in families with cataract, described as congenital nuclear cataract with cortical riders, nuclear, posterior polar, anterior polar, and cortical.The preferred title/symbol of this entry was formerly 'Cataract, Congenital Nuclear, Autosomal Recessive 2; CATCN2.'	NM_004076.4	c.493G>C;c.581T>A;c.634T>C c.493G>C;c.581T>A;c.634T>C	Mutations in the CRYBB3 gene have been identified in families with cataract, described as congenital nuclear cataract with cortical riders, nuclear, posterior polar, anterior polar, and cortical.The preferred title/symbol of this entry was formerly 'Cataract, Congenital Nuclear, Autosomal Recessive 2; CATCN2.'	Plus
CSF2RB	Surfactant metabolism dysfunction, pulmonary, type 5 Surfactant metabolism dysfunction, pulmonary, type 5 Descrição da doença: Pulmonary surfactant metabolism dysfunction, type 5 (SMDP5) is an autosomal recessive lung disorder manifest clinically and pathologically as pulmonary alveolar proteinosis (PAP). PAP is a rare lung disease characterized by the ineffective clearance of surfactant by alveolar macrophages. This results in the accumulation of surfactant-derived lipoproteinaceous material in the alveoli and terminal bronchioles, causing respiratory failure (Greenhill and Kotton, 2009).	NM_000395.2	c.812C>T c.812C>T	Pulmonary surfactant metabolism dysfunction, type 5 (SMDP5) is an autosomal recessive lung disorder manifest clinically and pathologically as pulmonary alveolar proteinosis (PAP). PAP is a rare lung disease characterized by the ineffective clearance of surfactant by alveolar macrophages. This results in the accumulation of surfactant-derived lipoproteinaceous material in the alveoli and terminal bronchioles, causing respiratory failure (Greenhill and Kotton, 2009).	Plus
CSF3R	Neutropenia, severe congenital, type 7, autosomal recessive Neutropenia, severe congenital, type 7, autosomal recessive Descrição da doença: Neutropenia, severe congenital, type 7 is an autosomal recessive immunodeficiency characterized by onset of recurrent infections in infancy or early childhood. Patients have peripheral neutropenia, although bone marrow biopsy shows normal granulocyte maturation. The neutropenia is not responsive to treatment with G-CSF, but may be responsive to GM-CSF (Triot et al., 2014; Klimiankou et al., 2015).	NM_156039.3	c.1640G>A;c.1245delG;c.998-2A>T c.1640G>A;c.1245delG;c.998-2A>T	Neutropenia, severe congenital, type 7 is an autosomal recessive immunodeficiency characterized by onset of recurrent infections in infancy or early childhood. Patients have peripheral neutropenia, although bone marrow biopsy shows normal granulocyte maturation. The neutropenia is not responsive to treatment with G-CSF, but may be responsive to GM-CSF (Triot et al., 2014; Klimiankou et al., 2015).	Plus
CSTA	Peeling skin syndrome, type 4 Peeling skin syndrome, type 4 Descrição da doença: Peeling skin syndrome 4 (PSS4) is a genodermatosis characterized by congenital exfoliative ichthyosis, sharing some features with ichthyosis bullosa of Siemens and annular epidermolytic ichthyosis. PSS4 presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of non- erythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma.	NM_005213.3	c.67-2A>T c.67-2A>T	Peeling skin syndrome 4 (PSS4) is a genodermatosis characterized by congenital exfoliative ichthyosis, sharing some features with ichthyosis bullosa of Siemens and annular epidermolytic ichthyosis. PSS4 presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of non- erythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma.	Plus
CSTB	Epilepsy, progressive myoclonic type 1A (Unverricht and Lundborg) Epilepsy, progressive myoclonic type 1A (Unverricht and Lundborg) Descrição da doença: Progressive myoclonic epilepsy type 1A (Unverricht and Lundborg) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CSTB gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop. The prevalence is 1:20,000 newborn.	NM_000100.3	c.218_219delTC;c.212A>C;c.202C>T;c.169-2A>G;c.149G c.218_219delTC;c.212A>C;c.202C>T;c.169-2A>G;c.149G>A;c.136C>T;c.125C>A;c.67-1G>C	Progressive myoclonic epilepsy type 1A (Unverricht and Lundborg) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CSTB gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop. The prevalence is 1:20,000 newborn.	Plus
CTC1	Cerebroretinal microangiopathy with calcifications and cysts Cerebroretinal microangiopathy with calcifications and cysts Descrição da doença: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia (Anderson et al., 2012; Polvi et al., 2012). Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome (614561), has similar central nervous system features as CRMCC in the absence of extraneurologic or systemic manifestations. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).	NM_025099.5	c.3583C>T;c.2954_2956delGTT;c.2831delC;c.2758+1G>T c.3583C>T;c.2954_2956delGTT;c.2831delC;c.2758+1G>T;c.1213delG;c.1186C>T;c.1058delC;c.859C>T;c.724_727delAAAG;c.277C>T	Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia (Anderson et al., 2012; Polvi et al., 2012). Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome (614561), has similar central nervous system features as CRMCC in the absence of extraneurologic or systemic manifestations. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).	Plus
CTH	Cystathioninuria Cystathioninuria Descrição da doença: Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).	NM_001902.5	c.718C>G;c.793C>T c.718C>G;c.793C>T	Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).	Plus
CTNS	Nephropathic cystinosis Nephropathic cystinosis Descrição da doença: Nephropathic cystinosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTNS gene located on chromosomal region 17p13. The age of onset is neonatal/infantile. This disease is characterized by hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, and muscle, cerebral and ocular involvement, caused by cystine deposits in various organs. The prevalence is 1:100,000-1:200,000.	NM_001031681.2	c.62-2A>G;c.91dupG;c.120delC;c.206_210delTCCTT;c.2 c.62-2A>G;c.91dupG;c.120delC;c.206_210delTCCTT;c.225+1G>A;c.251delA;c.257_258delCT;c.283G>T;c.292dupA;c.320_323delATCA;c.323delA;c.329G>T;c.329+2T>C;c.357_360delCAGC;c.382C>T;c.397_398delAT;c.414G>A;c.416C>T;c.506G>A;c.516dupC;c.519_520delCA;c.544T>C;c.561+1delG;c.589G>A;c.646dupA;c.681+2T>C;c.682-1G>A;c.696_697dupCG;c.696dupC;c.734G>A;c.751_754delACCAinsCG;c.829dupA;c.853-3C>G;c.853-2A>G;c.853-1G>A;c.870C>G;c.890G>A;c.926dupG;c.922G>A;c.969C>G;c.971-12G>A;c.1015G>A	Nephropathic cystinosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTNS gene located on chromosomal region 17p13. The age of onset is neonatal/infantile. This disease is characterized by hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, and muscle, cerebral and ocular involvement, caused by cystine deposits in various organs. The prevalence is 1:100,000-1:200,000.	Plus
CTSA	Galactosialidosis Galactosialidosis Descrição da doença: Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (d'Azzo et al., 2001).	NM_000308.3	c.200A>G;c.247T>C;c.284delC;c.448G>A;c.571_572delT c.200A>G;c.247T>C;c.284delC;c.448G>A;c.571_572delTT;c.649delC;c.761T>C;c.887_888delAT;c.1238A>G;c.1369G>A;c.1372T>G;c.1411A>G	Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (d'Azzo et al., 2001).	Plus
CTSC	Haim-Munk syndrome; Papillon-Lefevre syndrome Haim-Munk syndrome; Papillon-Lefevre syndrome Descrição da doença: Haim-Munk syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, severe periodonitis, arachnodactyly, acroosteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers (Hart et al., 2000). Mutations in the CTSC gene also cause Papillon-Lefevre syndrome (PLS). PLS is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (Lefevre et al., 2001).	NM_001814.5	c.1287G>C;c.1235A>G;c.1141delC;c.1056delT;c.1047de c.1287G>C;c.1235A>G;c.1141delC;c.1056delT;c.1047delA;c.1040A>G;c.901G>A;c.890-1G>A;c.857A>G;c.856C>T;c.815G>A;c.815G>C;c.755A>T;c.628C>T;c.380A>C;c.116G>C;c.96T>G	Haim-Munk syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, severe periodonitis, arachnodactyly, acroosteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers (Hart et al., 2000). Mutations in the CTSC gene also cause Papillon-Lefevre syndrome (PLS). PLS is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (Lefevre et al., 2001).	Plus
CTSD	Ceroid lipofuscinosis, neuronal, type 10 Ceroid lipofuscinosis, neuronal, type 10 Descrição da doença: Neuronal ceroid lipofuscinosis, type 10 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSD gene located on chromosomal region 11p15.5. The age of onset is adult. This disease is characterized by dementia, seizures and loss of motor capacities, and sometimes associated with visual loss caused by retinal degeneration. The prevalence is 2:100,000-4:100,000 newborn.	NM_001909.4	c.1155_1169dupGGGCGACGTCTTCAT;c.1149G>C;c.764dupA; c.1155_1169dupGGGCGACGTCTTCAT;c.1149G>C;c.764dupA;c.685T>A;c.446G>T;c.299C>T;c.268dupC	Neuronal ceroid lipofuscinosis, type 10 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSD gene located on chromosomal region 11p15.5. The age of onset is adult. This disease is characterized by dementia, seizures and loss of motor capacities, and sometimes associated with visual loss caused by retinal degeneration. The prevalence is 2:100,000-4:100,000 newborn.	Plus
CTSK	Pycnodysostosis Pycnodysostosis Descrição da doença: Pycnodysostosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSK gene located on chromosomal region 1q21. The age of onset is variable. This disease is characterized by osteosclerosis, short stature or dwarfism, acroosteolysis of the distal phalanges, fragile bones associated with spontaneous fractures and dysplasia of the clavicles. The prevalence is 1/1,000,000 to 9/1,000,000.	NM_000396.3	c.990A>G;c.934C>G;c.934C>T;c.926T>C;c.876G>A;c.784 c.990A>G;c.934C>G;c.934C>T;c.926T>C;c.876G>A;c.784+1G>A;c.721C>T;c.679_680insAA;c.669delG;c.648delC;c.618+1G>A;c.568C>T;c.436G>C;c.426delT;c.400-1G>C;c.395dupA;c.289_290delCT;c.236G>A;c.213T>A;c.154A>T;c.121-2A>G;c.120+1G>A;c.48delG;c.3G>A	Pycnodysostosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSK gene located on chromosomal region 1q21. The age of onset is variable. This disease is characterized by osteosclerosis, short stature or dwarfism, acroosteolysis of the distal phalanges, fragile bones associated with spontaneous fractures and dysplasia of the clavicles. The prevalence is 1/1,000,000 to 9/1,000,000.	Plus
CUBN	Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome) Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome) Descrição da doença: Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.	NM_001081.3	c.7955C>A;c.7906C>T;c.6928_6934delGAGGTTA;c.5549-2 c.7955C>A;c.7906C>T;c.6928_6934delGAGGTTA;c.5549-2A>C;c.5530C>T;c.5428C>T;c.4459C>T;c.4168G>A;c.3999C>A;c.3890C>T;c.3749C>T;c.3577T>G;c.3096delT;c.3056C>G;c.2949C>A;c.2673C>A;c.2614_2615delGA;c.1951C>T;c.1865delC;c.1838delG;c.1526delG;c.1506G>A;c.1436C>G;c.1230+1G>A;c.889C>T;c.673T>A;c.434G>A;c.382C>T;c.348+2T>C;c.252+1G>A;c.250C>T	Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.	Plus
CUL4B	Mental retardation, X-linked, syndromic, type 15 (Cabezas type) Mental retardation, X-linked, syndromic, type 15 (Cabezas type) Descrição da doença: This form of syndromic X-linked mental retardation is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).	NM_003588.3	c.2243_2244delTT;c.1736_1737delCA;c.1007_1011delTT c.2243_2244delTT;c.1736_1737delCA;c.1007_1011delTTATA;c.901-2A>G;c.811_812delCA;c.775C>T	This form of syndromic X-linked mental retardation is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).	Plus
CUL7	3-M syndrome 1 3-M syndrome 1 Descrição da doença: 3M syndrome 1 is an autosomal recessive disorder characterized by distinctive facial features, severe prenatal and postnatal growth retardation, and normal mental development. The main skeletal anomalies are long, slender tubular bones, reduced anteroposterior diameter of the vertebral bodies, and delayed bone age. Other skeletal manifestations include joint hypermobility, joint dislocation, winged scapulae, and pes planus (Badina et al., 2011).	NM_001168370.1	c.4969C>T;c.4833dupT;c.4781G>T;c.4703_4704delTG;c. c.4969C>T;c.4833dupT;c.4781G>T;c.4703_4704delTG;c.4643A>C;c.4585C>T;c.4570C>T;c.3688T>C;c.3631_3632delTG;c.3425-1G>C;c.3293T>G;c.3195_3196delCT;c.3100A>T;c.3039delC;c.2962C>T;c.2844T>G;c.2416C>T;c.2364G>A;c.1900C>T;c.419delT	3M syndrome 1 is an autosomal recessive disorder characterized by distinctive facial features, severe prenatal and postnatal growth retardation, and normal mental development. The main skeletal anomalies are long, slender tubular bones, reduced anteroposterior diameter of the vertebral bodies, and delayed bone age. Other skeletal manifestations include joint hypermobility, joint dislocation, winged scapulae, and pes planus (Badina et al., 2011).	Plus
CYB5A	46,XY disorder of sex development due to isolated 17,20-lyase deficiency 46,XY disorder of sex development due to isolated 17,20-lyase deficiency Descrição da doença: Methemoglobinemia and ambiguous genitalia is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012).Other autosomal recessive methemoglobinemias include types I and II (250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (124015.0016).	NM_148923.3	c.130-2A>G;c.81G>A c.130-2A>G;c.81G>A	Methemoglobinemia and ambiguous genitalia is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012).Other autosomal recessive methemoglobinemias include types I and II (250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (124015.0016).	Plus
CYB5R3	Methemoglobinemia, type 1; Methemoglobinemia, type 2 Methemoglobinemia, type 1; Methemoglobinemia, type 2 Descrição da doença: Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (Percy and Lappin, 2008).There are 2 types of methemoglobin reductase deficiency. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).	NM_001171660.1	c.833-1G>T;c.818A>G;c.754C>T;c.710G>A;c.577C>T;c.5 c.833-1G>T;c.818A>G;c.754C>T;c.710G>A;c.577C>T;c.563-2A>C;c.545T>C;c.481T>C;c.415G>A;c.349C>T;c.328C>T;c.317T>C	Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (Percy and Lappin, 2008).There are 2 types of methemoglobin reductase deficiency. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).	Plus
CYBA	Chronic granulomatous disease, autosomal recessive, due to deficiency of CYBA Chronic granulomatous disease, autosomal recessive, due to deficiency of CYBA Descrição da doença: Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the NADPH oxidase enzyme complex which generates the microbicidal 'respiratory burst.'	NM_000101.3	c.354C>A;c.7C>T c.354C>A;c.7C>T	Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the NADPH oxidase enzyme complex which generates the microbicidal 'respiratory burst.'	Plus
CYBB	Chronic granulomatous disease, X-linked Chronic granulomatous disease, X-linked Descrição da doença: Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the phagocyte NADPH oxidase (phox) complex, which generates the microbicidal 'respiratory burst' (Dinauer et al., 2001; Johnston, 2001).	NM_000397.3	c.23_26dupAGGG;c.80_83delTCTG;c.85delT;c.90_92delC c.23_26dupAGGG;c.80_83delTCTG;c.85delT;c.90_92delCCGinsGGT;c.141+1G>T;c.170C>A;c.210dupA;c.217C>T;c.271C>T;c.301C>T;c.302A>G;c.337+1G>T;c.343C>T;c.388delC;c.448G>T;c.469C>T;c.483+1G>T;c.484-2A>T;c.532A>C;c.565_568delATTA;c.607G>T;c.625C>T;c.626A>G;c.676C>T;c.731G>C;c.742dupA;c.781C>T;c.868C>T;c.898-2A>C;c.907C>A;c.907C>T;c.911C>G;c.960delA;c.1006G>T;c.1011G>A;c.1140dupG;c.1166G>C;c.1169C>T;c.1223G>A;c.1244C>A;c.1272G>A;c.1315-1G>A;c.1449G>A;c.1498G>C;c.1499A>G;c.1573delA;c.1609T>C;c.1618delG	Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the phagocyte NADPH oxidase (phox) complex, which generates the microbicidal 'respiratory burst' (Dinauer et al., 2001; Johnston, 2001).	Plus
CYP11A1	46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency Descrição da doença: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete is also known as P450scc deficiency and is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (Kim et al., 2008). Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; 201710), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (Sahakitrungruang et al., 2011).	NM_000781.2	c.1244T>A;c.835delA;c.425+1G>A;c.422T>G;c.358C>T c.1244T>A;c.835delA;c.425+1G>A;c.422T>G;c.358C>T	Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete is also known as P450scc deficiency and is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (Kim et al., 2008). Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; 201710), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (Sahakitrungruang et al., 2011).	Plus
CYP11B1	Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency Descrição da doença: Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991).CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991).	NM_000497.3	c.1398+2T>C;c.1343G>A;c.1331G>A;c.1269T>G;c.1205de c.1398+2T>C;c.1343G>A;c.1331G>A;c.1269T>G;c.1205delT;c.1181delA;c.1159dupA;c.1066C>T;c.955-1G>A;c.954G>A;c.841_842insACAGTACACCA;c.799+2T>C;c.799+1G>C;c.780G>A;c.779G>A;c.740G>A;c.595+1G>A;c.395+1G>C;c.372delG;c.347G>A;c.304C>T;c.281C>T;c.264G>A;c.168G>A;c.55C>T	Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991).CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991).	Plus
CYP11B2	Hypoaldosteronism, congenital, due to CMO I deficiency Hypoaldosteronism, congenital, due to CMO I deficiency Descrição da doença: CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).	NM_000498.3	c.1350C>A;c.814C>T;c.763G>T c.1350C>A;c.814C>T;c.763G>T	CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).	Plus
CYP17A1	17 alpha(Î±)-hydroxylase/17,20-lyase deficiency 17 alpha(Î±)-hydroxylase/17,20-lyase deficiency Descrição da doença: 17 alpha(Î±)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. 17Î±-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation. Hormone imbalances lead to the characteristic signs and symptoms of 17Î±-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development.	NM_000102.3	c.1435_1438dupATCC;c.1162A>T;c.715C>T;c.297+2T>C;c c.1435_1438dupATCC;c.1162A>T;c.715C>T;c.297+2T>C;c.286C>T;c.278T>G;c.81C>A;c.51G>A	17 alpha(Î±)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. 17Î±-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation. Hormone imbalances lead to the characteristic signs and symptoms of 17Î±-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development.	Plus
CYP19A1	Aromatase deficiency Aromatase deficiency Descrição da doença: Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. Affected females are usually diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females.	NM_000103.3	c.1310G>A;c.1303C>T;c.1224delC;c.1051C>T;c.743+2T> c.1310G>A;c.1303C>T;c.1224delC;c.1051C>T;c.743+2T>C;c.296+1G>A;c.201G>A	Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. Affected females are usually diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females.	Plus
CYP1B1	Glaucoma, primary congenital, type 3A Glaucoma, primary congenital, type 3A Descrição da doença: Primary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years of age), increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal edema, and optic nerve head cupping. Congenital glaucoma is a chronic disease and a serious cause of blindness worldwide (Azmanov et al., 2011).	NM_000104.3	c.1405C>T;c.1345delG;c.1330C>T;c.1302G>A;c.1200_12 c.1405C>T;c.1345delG;c.1330C>T;c.1302G>A;c.1200_1209dupTCATGCCACC;c.1159G>A;c.1064_1076delGAGTGCAGGCAGA;c.1063_1075delCGAGTGCAGGCAG;c.868dupC;c.830delT;c.535delG;c.171G>A;c.2T>C	Primary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years of age), increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal edema, and optic nerve head cupping. Congenital glaucoma is a chronic disease and a serious cause of blindness worldwide (Azmanov et al., 2011).	Plus
CYP21A2	Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Descrição da doença: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP21A2 gene located on chromosomal region 6p21.3. The age of onset is neonatal/infantile. This disease is characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females, and in both sexes with adrenal insufficiency with dehydration during the neonatal period, life threatening hypoglycemia and hyperandrogenia. The prevalence is 1/100,000 to 9/100,000. There is a common milder form of congenital adrenal hyperplasia (Nonclassic) characterized by a later onset of androgen excess symptoms seen in females and precocious pseudopuberty in both sexes. Cortisol and aldosterone levels are normal but there is an increased amount of androgens. Nonclassic form onset occurs in adolescence with variable degrees of postnatal androgen excess (precocious pubarche, hirsutism, acne, alopecia, anovulation and menstrual irregularies and in the post-pubertal period it can mimic polycystic ovary syndrome. It is also sometimes asymptomatic. The prevalence ranges from 1/1,000-1/500 in the general Caucasian population, but up to 1-2% among inbred populations, such as Eastern European (Ashkenazi) Jews.	NM_000500.9	CYP21A1P/CYP21A2 hybrid;CYP21A2 gene deletion;CYP2 CYP21A1P/CYP21A2 hybrid;CYP21A2 gene deletion;CYP21A2 gene duplication;NM_000500.9;c.1069C>T;c.1360C>T;c.293-13A/C>G;c.332_339delGAGACTAC;c.518T>A;c.710T>A;c.[710T>A;713T>A];c.[710T>A;713T>A;719T>A];c.713T>A;c.844G>T;c.923dupT;c.92C>T;c.955C>T	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP21A2 gene located on chromosomal region 6p21.3. The age of onset is neonatal/infantile. This disease is characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females, and in both sexes with adrenal insufficiency with dehydration during the neonatal period, life threatening hypoglycemia and hyperandrogenia. The prevalence is 1/100,000 to 9/100,000. There is a common milder form of congenital adrenal hyperplasia (Nonclassic) characterized by a later onset of androgen excess symptoms seen in females and precocious pseudopuberty in both sexes. Cortisol and aldosterone levels are normal but there is an increased amount of androgens. Nonclassic form onset occurs in adolescence with variable degrees of postnatal androgen excess (precocious pubarche, hirsutism, acne, alopecia, anovulation and menstrual irregularies and in the post-pubertal period it can mimic polycystic ovary syndrome. It is also sometimes asymptomatic. The prevalence ranges from 1/1,000-1/500 in the general Caucasian population, but up to 1-2% among inbred populations, such as Eastern European (Ashkenazi) Jews.	Plus
CYP24A1	Hypercalcemia, infantile, type 1 Hypercalcemia, infantile, type 1 Descrição da doença: Infantile hypercalcemia is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. An epidemic of idiopathic infantile hypercalcemia occurred in the United Kingdom in the 1950s after the implementation of an increased prophylactic dose of vitamin D supplementation; however, the fact that most infants receiving the prophylaxis remained unaffected suggested that an intrinsic hypersensitivity to vitamin D might be implicated in the pathogenesis (Schlingmann et al., 2011).	NM_000782.4	c.1426_1427delCT;c.1186C>T;c.1039C>T;c.451G>T c.1426_1427delCT;c.1186C>T;c.1039C>T;c.451G>T	Infantile hypercalcemia is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. An epidemic of idiopathic infantile hypercalcemia occurred in the United Kingdom in the 1950s after the implementation of an increased prophylactic dose of vitamin D supplementation; however, the fact that most infants receiving the prophylaxis remained unaffected suggested that an intrinsic hypersensitivity to vitamin D might be implicated in the pathogenesis (Schlingmann et al., 2011).	Plus
CYP27A1	Cerebrotendinous xanthomatosis Cerebrotendinous xanthomatosis Descrição da doença: Cerebrotendinous xanthomatosis is a rare inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients. Dotti et al. (2001) examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed.In a tabular presentation, Moghadasian et al. (2002) compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (143890) and sitosterolemia (210250).	NM_000784.3	c.11_20dupTGGGCTGCGC;c.5dupC;c.73delG;c.256-2A>G;c c.11_20dupTGGGCTGCGC;c.5dupC;c.73delG;c.256-2A>G;c.256-1G>T;c.305delC;c.355delC;c.373_379delCCAGTAC;c.380G>A;c.446+1G>A;c.446+1G>T;c.475C>T;c.526delG;c.583G>T;c.646+1G>C;c.646+2T>C;c.647-1G>T;c.666_678delCGAGAAACGCATT;c.691C>T;c.745C>T;c.752C>A;c.779G>A;c.808C>T;c.819delT;c.844+1G>A;c.845-2A>G;c.845-1G>A;c.847A>T;c.850A>T;c.863delA;c.886C>T;c.944_948delTGGCC;c.1072C>T;c.1180_1181delCT;c.1183C>T;c.1184G>A;c.1184+1G>A;c.1185-2A>C;c.1185-2A>T;c.1185-1G>A;c.1185-1G>T;c.1214G>A;c.1222G>T;c.1263+1G>A;c.1263+2T>C;c.1264-2A>G;c.1264-1G>A;c.1381C>T;c.1415G>C;c.1420C>T;c.1421G>A;c.1435C>G;c.1435C>T;c.1477-2A>C;c.1573C>T	Cerebrotendinous xanthomatosis is a rare inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients. Dotti et al. (2001) examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed.In a tabular presentation, Moghadasian et al. (2002) compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (143890) and sitosterolemia (210250).	Plus
CYP27B1	Vitamin D-dependent rickets, type 1 Vitamin D-dependent rickets, type 1 Descrição da doença: Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; 601769) (Koren, 2006; Liberman and Marx, 2001).In the liver, vitamin D 25-hydroxylase (CYP2R1; 608713) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; 609506) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (Takeyama et al., 1997). Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (Liberman and Marx, 2001).	NM_000785.3	c.1319_1325dupCCCACCC;c.1166G>A;c.693delC;c.631del c.1319_1325dupCCCACCC;c.1166G>A;c.693delC;c.631delG;c.589+1G>A;c.262delG	Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; 601769) (Koren, 2006; Liberman and Marx, 2001).In the liver, vitamin D 25-hydroxylase (CYP2R1; 608713) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; 609506) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (Takeyama et al., 1997). Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (Liberman and Marx, 2001).	Plus
CYP4F22	Ichthyosis, congenital, autosomal recessive, type 5 Ichthyosis, congenital, autosomal recessive, type 5 Descrição da doença: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	NM_173483.3	c.59dupG;c.367+1G>A;c.421+1G>A;c.429dupG;c.550-2A> c.59dupG;c.367+1G>A;c.421+1G>A;c.429dupG;c.550-2A>T;c.643_644delGT;c.720_723delTGTC;c.940-1G>A;c.976C>T;c.981delC;c.1007-2A>G;c.1084C>T;c.1138delG;c.1419-1G>A;c.1563G>A	Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).	Plus
CYP4V2	Bietti crystalline corneoretinal dystrophy Bietti crystalline corneoretinal dystrophy Descrição da doença: Bietti crystalline corneoretinal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP4V2 gene located on chromosomal region 4q35.2. The age of onset is adult. This disease is characterized by nightblindness, decreased vision, paracentral scotoma, and, in the end stages of the disease, legal blindness.	NM_207352.3	c.130T>A;c.327+1G>A;c.332T>C;c.335T>G;c.400G>T;c.7 c.130T>A;c.327+1G>A;c.332T>C;c.335T>G;c.400G>T;c.759dupA;c.958C>T;c.992A>C;c.1020G>A;c.1091-2A>G;c.1348C>T;c.1396A>G;c.1445C>A;c.1523G>A	Bietti crystalline corneoretinal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP4V2 gene located on chromosomal region 4q35.2. The age of onset is adult. This disease is characterized by nightblindness, decreased vision, paracentral scotoma, and, in the end stages of the disease, legal blindness.	Plus
CYP7B1	Spastic paraplegia type 5A, autosomal recessive Spastic paraplegia type 5A, autosomal recessive Descrição da doença: Spastic paraplegia type 5A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP7B1 gene located on chromosomal region 8q21.3. The age of onset is neonatal/infantile. This disease is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The prevalence is below 1,000,000.	NM_004820.4	c.1460dupT;c.1456C>T;c.1250G>A;c.1162C>T;c.914dupT c.1460dupT;c.1456C>T;c.1250G>A;c.1162C>T;c.914dupT;c.889A>G;c.825T>A;c.793C>T;c.525G>A;c.440G>A;c.334C>T;c.321_324delACAA;c.259+2T>C;c.187C>T	Spastic paraplegia type 5A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP7B1 gene located on chromosomal region 8q21.3. The age of onset is neonatal/infantile. This disease is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The prevalence is below 1,000,000.	Plus
D2HGDH	D-2-hydroxyglutaric aciduria D-2-hydroxyglutaric aciduria Descrição da doença: D-2-Hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the D2HGDH gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by extremely variable clinical manifestations, with severe cases characterized by neonatal or early infantile-onset epileptic encephalopathy, and marked hypotonia, and cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are also common in these cases. The prevalence is below 1,000,000.	NM_152783.4	c.325_326dupTC;c.440T>G;c.566C>T;c.642delT;c.685-2 c.325_326dupTC;c.440T>G;c.566C>T;c.642delT;c.685-2A>G;c.853+2T>C;c.1027delT;c.1123G>T;c.1306+2T>C;c.1315A>G;c.1331T>C;c.1333_1334delAC	D-2-Hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the D2HGDH gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by extremely variable clinical manifestations, with severe cases characterized by neonatal or early infantile-onset epileptic encephalopathy, and marked hypotonia, and cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are also common in these cases. The prevalence is below 1,000,000.	Plus
DAG1	Muscular dystrophy-dystroglycanopathy type A9; Muscular dystrophy-dystroglycanopathy type C9 Muscular dystrophy-dystroglycanopathy type A9; Muscular dystrophy-dystroglycanopathy type C9 Descrição da doença: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A9 is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, and congenital muscular dystrophy. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS), which is associated with death in infancy. The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1), collectively known as 'dystroglycanopathies' (Geis et al., 2013 and Riemersma et al., 2015). Mutation in the DAG1 gene can also cause the less severe disorder limb-girdle muscular dystrophy-dystroglycanopathy, type C9 (MDDGC9). MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (Hara et al., 2011).	NM_001165928.3	c.220G>A;c.575C>T;c.743delC;c.2006G>T c.220G>A;c.575C>T;c.743delC;c.2006G>T	Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A9 is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, and congenital muscular dystrophy. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS), which is associated with death in infancy. The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1), collectively known as 'dystroglycanopathies' (Geis et al., 2013 and Riemersma et al., 2015). Mutation in the DAG1 gene can also cause the less severe disorder limb-girdle muscular dystrophy-dystroglycanopathy, type C9 (MDDGC9). MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (Hara et al., 2011).	Plus
DARS2	Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation Descrição da doença: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline.	NM_018122.4	c.127+1G>A;c.223C>T;c.396+2T>G;c.492+2T>C;c.536G>A c.127+1G>A;c.223C>T;c.396+2T>G;c.492+2T>C;c.536G>A;c.787C>T;c.788G>A;c.948delT;c.1272_1273delGGinsC;c.1273G>T;c.1355T>G;c.1762C>G;c.1825C>T;c.1837C>T	Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline.	Plus
DBH	Dopamine beta-hydroxylase deficiency Dopamine beta-hydroxylase deficiency Descrição da doença: Dopamine beta (Î²)-hydroxylase deficiency is a condition that affects the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. Problems related to this disorder can first appear during infancy. Early signs and symptoms may include episodes of vomiting, dehydration, decreased blood pressure (hypotension), difficulty maintaining body temperature, and low blood sugar (hypoglycemia). Individuals with dopamine Î²-hydroxylase deficiency typically experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.	NM_000787.3	c.339+2T>C;c.617delA;c.806G>T;c.1033G>A;c.1085C>A c.339+2T>C;c.617delA;c.806G>T;c.1033G>A;c.1085C>A	Dopamine beta (Î²)-hydroxylase deficiency is a condition that affects the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. Problems related to this disorder can first appear during infancy. Early signs and symptoms may include episodes of vomiting, dehydration, decreased blood pressure (hypotension), difficulty maintaining body temperature, and low blood sugar (hypoglycemia). Individuals with dopamine Î²-hydroxylase deficiency typically experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.	Plus
DBT	Maple syrup urine disease, type 2 Maple syrup urine disease, type 2 Descrição da doença: Maple syrup urine disease, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DBT gene located on chromosomal region 1p21.2. The age of onset in neonatal/infantil. This disease is characterized by a maple syrup odor to the urine, deficient diet, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if not treated. The prevalence is 1-5/10,000.	NM_001918.3	c.1448G>T;c.1355A>G;c.1281+1G>A;c.1165_1166delAC;c c.1448G>T;c.1355A>G;c.1281+1G>A;c.1165_1166delAC;c.1033G>A;c.1017+1delG;c.939G>C;c.901C>T;c.871C>T;c.827T>G;c.773-2A>G;c.772+1G>A;c.731delC;c.725C>G;c.670G>T;c.634C>T;c.581C>G;c.555+1G>A;c.434-1G>A;c.360delA;c.360dupA;c.339_345delTTATGAT;c.294C>G;c.272_275delCAGT;c.251G>A;c.141_142delTA;c.126T>G;c.75_76delAT;c.51+1G>T	Maple syrup urine disease, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DBT gene located on chromosomal region 1p21.2. The age of onset in neonatal/infantil. This disease is characterized by a maple syrup odor to the urine, deficient diet, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if not treated. The prevalence is 1-5/10,000.	Plus
DCAF17	Woodhouse-Sakati syndrome Woodhouse-Sakati syndrome Descrição da doença: Woodhouse-Sakati syndrome is a multisystemic disorder characterized by hypogonadism, alopecia, diabetes mellitus, intellectual deficit and extrapyramidal signs with choreoathetoid movements and dystonia.	NM_025000.3	c.50delC;c.270delA;c.289dupA;c.341C>A;c.436delC;c. c.50delC;c.270delA;c.289dupA;c.341C>A;c.436delC;c.906G>A;c.982-2A>C	Woodhouse-Sakati syndrome is a multisystemic disorder characterized by hypogonadism, alopecia, diabetes mellitus, intellectual deficit and extrapyramidal signs with choreoathetoid movements and dystonia.	Plus
DCC	Gaze palsy, familial horizontal, with progressive scoliosis, type 2 Gaze palsy, familial horizontal, with progressive scoliosis, type 2 Descrição da doença: Gaze palsy, familial horizontal, with progressive scoliosis, 2 is an autosomal recessive neurologic disorder characterized by global developmental delay, delayed walking, intellectual disability, horizontal gaze palsy, and childhood-onset progressive scoliosis.	NM_005215.3	c.377C>A;c.571dupG;c.788_794delTTTCTGG;c.823C>T;c. c.377C>A;c.571dupG;c.788_794delTTTCTGG;c.823C>T;c.925delA;c.1140+1G>A;c.1336_1337insAGCC;c.1789C>T;c.1790G>C;c.1911+1G>C;c.2414G>A;c.2873_2877dupGGAAG;c.3836_3837delTC	Gaze palsy, familial horizontal, with progressive scoliosis, 2 is an autosomal recessive neurologic disorder characterized by global developmental delay, delayed walking, intellectual disability, horizontal gaze palsy, and childhood-onset progressive scoliosis.	Plus
DCDC2	Sclerosing cholangitis, neonatal; Nephronophthisis 19 Sclerosing cholangitis, neonatal; Nephronophthisis 19 Descrição da doença: Neonatal sclerosing cholangitis is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (Girard et al., 2016; Grammatikopoulos et al., 2016). Nephronophthisis 19 (NPHP19) is also caused by homozygous or compound heterozygous mutation in the DCDC2 gene. NPHP19 is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis resulting in end-stage renal disease. NPHP19 patients also manifest hepatosplenomegaly, hepatic fibrosis, destruction of the bile ducts, focal bile ductal proliferation, ductal plate malformation, and cholestasis.	NM_001195610.1	c.1271A>C;c.890T>A;c.649A>T;c.529dupA;c.383C>G;c.3 c.1271A>C;c.890T>A;c.649A>T;c.529dupA;c.383C>G;c.349-2A>G;c.123_124delGT;c.51G>C	Neonatal sclerosing cholangitis is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (Girard et al., 2016; Grammatikopoulos et al., 2016). Nephronophthisis 19 (NPHP19) is also caused by homozygous or compound heterozygous mutation in the DCDC2 gene. NPHP19 is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis resulting in end-stage renal disease. NPHP19 patients also manifest hepatosplenomegaly, hepatic fibrosis, destruction of the bile ducts, focal bile ductal proliferation, ductal plate malformation, and cholestasis.	Plus
DCLRE1C	Omenn syndrome; Severe combined immunodeficiency, Athabascan type Omenn syndrome; Severe combined immunodeficiency, Athabascan type Descrição da doença: Omenn syndrome and Athabascan type severe combined immunodeficiency follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the DCLRE1C gene located on chromosomal region 10p13. Omenn syndrome has an early age of onset and it is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency. The age of onset of Athabascan type severe combined immunodeficiency is neonatal/infantile and it is characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation. The prevalence is 1-9/1,000,000.	NM_001033855.2	c.1669dupA;c.1639G>T;c.1558dupA;c.1350_1356delAGAT c.1669dupA;c.1639G>T;c.1558dupA;c.1350_1356delAGATTGT;c.780+1delG;c.597C>A;c.403G>A;c.241C>T;c.194C>T;c.103C>G;c.2T>C	Omenn syndrome and Athabascan type severe combined immunodeficiency follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the DCLRE1C gene located on chromosomal region 10p13. Omenn syndrome has an early age of onset and it is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency. The age of onset of Athabascan type severe combined immunodeficiency is neonatal/infantile and it is characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation. The prevalence is 1-9/1,000,000.	Plus
DCX	Lissencephaly, X-linked Lissencephaly, X-linked Descrição da doença: Lissencephaly ('smooth brain') results from migrational arrest of cortical neurons short of their normal destination, and can result in profound mental retardation and seizures. In X-linked lissencephaly-1, affected males generally have more a severe phenotype compared to females. DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome (des Portes et al., 1997).There are several X-linked loci that affect neuronal migration, including the Aicardi locus (304050).	NM_000555.3;NM_178151.2	c.1270-2A>G;c.1150C>T;c.1118dupA;c.1096A>T;c.1057C c.1270-2A>G;c.1150C>T;c.1118dupA;c.1096A>T;c.1057C>T;c.1052-1G>A;c.1024C>T;c.1009A>T;c.1006G>T;c.994G>T;c.949-2A>G;c.913delG;c.909delC;c.894delC;c.871G>T;c.851C>A;c.851C>G;c.850A>G;c.839T>C;c.830G>A;c.821_828delAGGCTGTG;c.829C>A;c.829C>G;c.829C>T;c.817C>T;c.815C>G;c.800G>T;c.799C>T;c.787G>T;c.781A>G;c.776G>T;c.775C>T;c.771delT;c.763A>G;c.737_747delGCAACAGTGCA;c.748C>T;c.721_722delCA;c.721C>T;c.710dupT;c.694A>T;c.656A>G;c.655T>C;c.652G>T;c.629C>T;c.623G>A;c.620T>A;c.616T>C;c.582dupC;c.553A>T;c.548G>A;c.547C>G;c.547C>T;c.544G>A;c.542G>A;c.542G>T;c.533T>G;c.509G>C;c.508C>G;c.508C>T;c.476G>A;c.476G>T;c.475C>T;c.454G>T;c.453C>A;c.438C>A;c.435C>G;c.434A>G;c.433T>A;c.430C>T;c.428A>G;c.427G>A;c.425G>A;c.419G>A;c.419G>T;c.413T>G;c.410G>C;c.394_397delAAAG;c.382A>C;c.373C>T;c.371T>C;c.367delA;c.358C>T;c.324_328dupTAGCC;c.298C>T;c.273_274delAA;c.266_267delTT;c.2T>C	Lissencephaly ('smooth brain') results from migrational arrest of cortical neurons short of their normal destination, and can result in profound mental retardation and seizures. In X-linked lissencephaly-1, affected males generally have more a severe phenotype compared to females. DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome (des Portes et al., 1997).There are several X-linked loci that affect neuronal migration, including the Aicardi locus (304050).	Plus
DDB2	Xeroderma pigmentosum, complementation group E Xeroderma pigmentosum, complementation group E Descrição da doença: Xeroderma pigmentosum complementation group E follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDB2 gene located on chromosomal region 11p12-p11. The age of onset is variable. This disease is characterized by mild xeroderma pigmentosum symptoms and no neurological abnormalities. The prevalence is 1/1,000,000.	NM_000107.2	c.730A>G;c.818G>A;c.919G>T;c.937C>T c.730A>G;c.818G>A;c.919G>T;c.937C>T	Xeroderma pigmentosum complementation group E follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDB2 gene located on chromosomal region 11p12-p11. The age of onset is variable. This disease is characterized by mild xeroderma pigmentosum symptoms and no neurological abnormalities. The prevalence is 1/1,000,000.	Plus
DDC	Aromatic L-amino acid decarboxylase deficiency Aromatic L-amino acid decarboxylase deficiency Descrição da doença: Aromatic L-amino acid decarboxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDC gene located on chromosomal region 7p12.2. The age of onset is neonatal/infantile. This disease is characterized by severe developmental delay, weak muscle tone (hypotonia), muscle stiffness, difficulty moving, and involuntary writhing movements of the limbs (athetosis). The prevalence is below 1,000,000.	NM_000790.3	c.1073G>A;c.1040G>A;c.823G>A;c.749C>T;c.304G>A;c.2 c.1073G>A;c.1040G>A;c.823G>A;c.749C>T;c.304G>A;c.272C>T;c.100delG	Aromatic L-amino acid decarboxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDC gene located on chromosomal region 7p12.2. The age of onset is neonatal/infantile. This disease is characterized by severe developmental delay, weak muscle tone (hypotonia), muscle stiffness, difficulty moving, and involuntary writhing movements of the limbs (athetosis). The prevalence is below 1,000,000.	Plus
DDR2	Spondylometaepiphyseal dysplasia, short limb-hand type Spondylometaepiphyseal dysplasia, short limb-hand type Descrição da doença: Spondyloepimetaphyseal dysplasia short limb-hand type is a disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.	NM_001014796.1	c.337G>A;c.2138C>T;c.2177T>G;c.2254C>T c.337G>A;c.2138C>T;c.2177T>G;c.2254C>T	Spondyloepimetaphyseal dysplasia short limb-hand type is a disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.	Plus
DDX11	Warsaw breakage syndrome Warsaw breakage syndrome Descrição da doença: Warsaw breakage syndrome is a condition that can cause multiple abnormalities. People with Warsaw breakage syndrome have intellectual disability that varies from mild to severe. They also have impaired growth from birth leading to short stature and a small head size (microcephaly). Affected individuals have distinctive facial features that may include a small forehead, a short nose, a small lower jaw, a flat area between the nose and mouth (philtrum), and prominent cheeks. Other common features include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) and heart malformations.	NM_001257144.1	c.223C>T;c.484C>T;c.1763-1G>C;c.1949-1G>A;c.2271+2 c.223C>T;c.484C>T;c.1763-1G>C;c.1949-1G>A;c.2271+2T>C	Warsaw breakage syndrome is a condition that can cause multiple abnormalities. People with Warsaw breakage syndrome have intellectual disability that varies from mild to severe. They also have impaired growth from birth leading to short stature and a small head size (microcephaly). Affected individuals have distinctive facial features that may include a small forehead, a short nose, a small lower jaw, a flat area between the nose and mouth (philtrum), and prominent cheeks. Other common features include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) and heart malformations.	Plus
DDX3X	Mental retardation, X-linked, type 102 Mental retardation, X-linked, type 102 Descrição da doença: Mental retardation, X-linked, type 102 (MRX102) is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX102 features include mild to severe intellectual disability, hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Additionally, patients manifest variable non-neurologic features such as joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty.	NM_001356.4	c.372_373delCA;c.865-1G>C;c.869C>G;c.873C>A;c.874C c.372_373delCA;c.865-1G>C;c.869C>G;c.873C>A;c.874C>T;c.977G>A;c.1256delT;c.1334T>G;c.1423C>G;c.1423C>T;c.1438A>G;c.1462delC;c.1463G>A;c.1498-2A>G;c.1520T>C;c.1535_1536delAT;c.1541T>C;c.1769+1G>A	Mental retardation, X-linked, type 102 (MRX102) is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX102 features include mild to severe intellectual disability, hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Additionally, patients manifest variable non-neurologic features such as joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty.	Plus
DES	Myopathy, myofibrillar, type 1 Myopathy, myofibrillar, type 1 Descrição da doença: Myofibrillar myopathy, type 1 is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; 123590), dystrophin (300377), and myotilin (TTID; 604103).	NM_001927.3	c.347A>G;c.373A>T;c.380G>C;c.600delG;c.634C>T;c.73 c.347A>G;c.373A>T;c.380G>C;c.600delG;c.634C>T;c.735+1G>A;c.735+1G>C;c.735+1G>T;c.735+3A>G;c.985C>T;c.1049G>C;c.1064G>C;c.1213delT;c.1216C>T;c.1223delT;c.1237G>A;c.1255C>T;c.1285C>T;c.1289-2A>G;c.1333_1336delACGG;c.1346A>C;c.1360C>T;c.1371+1G>C	Myofibrillar myopathy, type 1 is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; 123590), dystrophin (300377), and myotilin (TTID; 604103).	Plus
DGUOK	DGUOK-related mitochondrial DNA depletion syndrome DGUOK-related mitochondrial DNA depletion syndrome Descrição da doença: Mitochondrial DNA depletion syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DGUOK gene located on chromosomal region 2p13. The age of onset is neonatal/infantile. This disease is characterized by progressive liver failure, hypoglycemia and neurologic abnormalities including hypotonia, encephalopathy and peripheral neuropathy	NM_080916.2	c.130G>A;c.137A>G;c.186C>A;c.195G>A;c.255delA;c.25 c.130G>A;c.137A>G;c.186C>A;c.195G>A;c.255delA;c.255+2T>A;c.313C>T;c.353G>A;c.425G>A;c.443+1G>A;c.444-11C>G;c.494A>T;c.591G>A;c.605_606delGA;c.609_610delGT;c.658G>T;c.679G>A;c.707+2T>G;c.763_766dupGATT;c.763G>T;c.797T>G	Mitochondrial DNA depletion syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DGUOK gene located on chromosomal region 2p13. The age of onset is neonatal/infantile. This disease is characterized by progressive liver failure, hypoglycemia and neurologic abnormalities including hypotonia, encephalopathy and peripheral neuropathy	Plus
DHCR24	Desmosterolosis Desmosterolosis Descrição da doença: Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (Waterham et al., 2001).	NM_014762.3	c.571G>A;c.307C>T;c.281G>A c.571G>A;c.307C>T;c.281G>A	Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (Waterham et al., 2001).	Plus
DHCR7	Smith-Lemli-Opitz syndrome Smith-Lemli-Opitz syndrome Descrição da doença: Smith-Lemli-Opitz syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHCR7 gene located on chromosomal region 11q13.4. The age of onset is neonatal/infantile. This disease is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems. The prevalence is 1/20,000 to 1/40,000 newborn.	NM_001163817.1	c.1426T>C;c.1396G>A;c.1342G>A;c.1337G>A;c.1328G>A; c.1426T>C;c.1396G>A;c.1342G>A;c.1337G>A;c.1328G>A;c.1228G>A;c.1222T>C;c.1210C>T;c.1139G>A;c.1138T>C;c.1057delG;c.1055G>A;c.1054C>T;c.976G>T;c.964-1G>C;c.964-1G>T;c.963+2T>G;c.963+1G>T;c.939G>A;c.934_935delGT;c.915C>G;c.907G>A;c.906C>G;c.894C>A;c.870G>A;c.866C>T;c.862G>A;c.858G>A;c.841G>A;c.839A>G;c.832-1G>C;c.831+2T>A;c.804delT;c.744G>T;c.740C>T;c.730G>A;c.725G>A;c.724C>T;c.627-1G>A;c.626+1G>C;c.626+1G>T;c.506C>T;c.470T>C;c.461C>G;c.461C>T;c.453G>A;c.452G>A;c.440G>A;c.413-1G>A;c.413-2A>G;c.356A>T;c.322-2A>G;c.292C>T;c.278C>T;c.151C>T;c.111G>A;c.99-1G>C;c.82C>T;c.16C>T;c.3G>A;c.1A>G	Smith-Lemli-Opitz syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHCR7 gene located on chromosomal region 11q13.4. The age of onset is neonatal/infantile. This disease is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems. The prevalence is 1/20,000 to 1/40,000 newborn.	Plus
DHDDS	Retinitis pigmentosa, type 59 Retinitis pigmentosa, type 59 Descrição da doença: Retinitis pigmentosa, type 59 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHDDS gene located on chromosomal region 1p36.11. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1/10,000 to 5/10,000.	NM_024887.3	c.124A>G;c.192G>A;c.330delA;c.998C>G c.124A>G;c.192G>A;c.330delA;c.998C>G	Retinitis pigmentosa, type 59 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHDDS gene located on chromosomal region 1p36.11. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1/10,000 to 5/10,000.	Plus
DHFR	Megaloblastic anemia due to dihydrofolate reductase deficiency Megaloblastic anemia due to dihydrofolate reductase deficiency Descrição da doença: Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.	NM_000791.3	c.238C>T c.238C>T	Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.	Plus
DHH	46,XY complete gonadal dysgenesis 46,XY complete gonadal dysgenesis Descrição da doença: 46,XY sex reversal 7 (SRXY7) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. SRXY7 patients have no functional gonads.	NM_021044.3	c.485T>C;c.371G>A;c.2T>C c.485T>C;c.371G>A;c.2T>C	46,XY sex reversal 7 (SRXY7) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. SRXY7 patients have no functional gonads.	Plus
DHODH	Miller syndrome Miller syndrome Descrição da doença: Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (Ng et al., 2010).	NM_001361.4	c.403C>T;c.454G>A;c.595C>T;c.605G>C;c.730C>T;c.103 c.403C>T;c.454G>A;c.595C>T;c.605G>C;c.730C>T;c.1036C>T	Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (Ng et al., 2010).	Plus
DIAPH1	Seizures, cortical blindness, microcephaly syndrome Seizures, cortical blindness, microcephaly syndrome Descrição da doença: Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (Ercan-Sencicek et al., 2015).	NM_005219.4	c.3624_3625delAG;c.3145C>T;c.2769delT;c.2332C>T c.3624_3625delAG;c.3145C>T;c.2769delT;c.2332C>T	Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (Ercan-Sencicek et al., 2015).	Plus
DIS3L2	Perlman syndrome Perlman syndrome Descrição da doença: Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (Astuti et al., 2012).	NM_152383.4	c.733C>T;c.2011-1G>C;c.2270delT c.733C>T;c.2011-1G>C;c.2270delT	Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (Astuti et al., 2012).	Plus
DKC1	Dyskeratosis congenita, X-linked Dyskeratosis congenita, X-linked Descrição da doença: X-linked dyskeratosis congenita follows an X-linked pattern of inheritance and is caused by pathogenic variants in the DKC1 gene located on chromosomal region Xq28. Tha age of onset is infantile. This disease is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features.	NM_001363.4	c.91C>A;c.91C>G;c.146C>T;c.194G>C;c.196A>G;c.200C> c.91C>A;c.91C>G;c.146C>T;c.194G>C;c.196A>G;c.200C>T;c.204C>A;c.214_215delCTinsTA;c.361A>G;c.911G>A;c.941A>G;c.949C>G;c.949C>T;c.961C>G;c.965G>A;c.1049T>C;c.1050G>A;c.1054A>G;c.1058C>T;c.1069A>G;c.1075G>A	X-linked dyskeratosis congenita follows an X-linked pattern of inheritance and is caused by pathogenic variants in the DKC1 gene located on chromosomal region Xq28. Tha age of onset is infantile. This disease is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features.	Plus
DLAT	Pyruvate dehydrogenase E2 deficiency Pyruvate dehydrogenase E2 deficiency Descrição da doença: Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In Pyruvate dehydrogenase E2 deficiency form episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.	NM_001931.4	c.848_849delAT;c.976-1G>A;c.1129+2T>C c.848_849delAT;c.976-1G>A;c.1129+2T>C	Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In Pyruvate dehydrogenase E2 deficiency form episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.	Plus
DLD	Dihydrolipoamide dehydrogenase deficiency Dihydrolipoamide dehydrogenase deficiency Descrição da doença: Dihydrolipoamide dehydrogenase deficiency E3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DLD gene located on chromosomal region 7q31-q32. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The prevalence is 1/1,000,000 to 9/1,000,000.	NM_000108.4	c.39+1G>A;c.82delT;c.104dupA;c.105delC;c.105_106in c.39+1G>A;c.82delT;c.104dupA;c.105delC;c.105_106insA;c.105C>G;c.112C>T;c.118+1G>T;c.140T>C;c.198+1G>A;c.199-1G>A;c.214A>G;c.223dupA;c.633dupA;c.685G>T;c.803_804delAG;c.865dupA;c.916_926delTGTGATGTACT;c.1081A>G;c.1123G>A;c.1178T>C;c.1236+1G>T;c.1429_1432delTGTG;c.1436A>T;c.1446_1447delAG;c.1463C>T;c.1483A>G	Dihydrolipoamide dehydrogenase deficiency E3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DLD gene located on chromosomal region 7q31-q32. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The prevalence is 1/1,000,000 to 9/1,000,000.	Plus
DLG3	Mental retardation, X-linked, type 90 Mental retardation, X-linked, type 90 Descrição da doença: Mental retardation, X-linked, type 90 (MRX90) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.	NM_021120.