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| Prepair 1000+ v1.2099 | RCBTB1 | Zornitza Stark Added comment: Comment when marking as ready: Currently, onset appears to mostly in adulthood. Demote and review in the future re new reports with earlier onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.2069 | RRM2B | Zornitza Stark Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075 (3) to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.2068 | RRM2B | Zornitza Stark reviewed gene: RRM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075, Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.2023 | NR0B1 | Zornitza Stark Phenotypes for gene: NR0B1 were changed from 46XY sex reversal 2, dosage-sensitive, 300018 (3) to Adrenal hypoplasia, congenital, MIM#300200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.2009 | MYD88 | Zornitza Stark Phenotypes for gene: MYD88 were changed from Pyogenic bacterial infections, recurrent, due to MYD88 deficiency, 612260 (3) to Immunodeficiency 68, MIM# 612260 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1944 | ITK | Zornitza Stark changed review comment from: Established gene-disease association characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, haemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinaemia. Autoimmune disorders, such as autoimmune haemolytic anemia or renal disease, may also occur.; to: Established gene-disease association characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, haemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinaemia. Autoimmune disorders, such as autoimmune haemolytic anaemia or renal disease, may also occur. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1899 | COL11A2 | Zornitza Stark Added comment: Comment when marking as ready: Deafness currently out of scope for this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1868 | PCSK1 |
Karina Sandoval changed review comment from: Unsure if severe enough to include in panel. MM- Tricky - Hyperphagia & obesity but associated metabolic problems can be severe includeing cases of death in childhood. PMID:27187081 - some patients displayed morbid obesity and severe hyperphagia, other subjects were only moderately obese. BMI rises from 2 years and patients became obese from early childhood. However, the extreme obesity of the index case at 3 years of age has not been reported in any subsequent patients. Presentation is severe malabsorptive diarrhea, becoming clinically evident within the first 3 months of life. This can be so severe as to lead to a metabolic acidosis. After the age of 2 years, the severity of the malabsorption appears to spontaneously improve, and many children can discontinue parenteral feeding. PMID: 27288825 - Nutrition significantly diminshed beyond 2 years and patients can thrive despite the presence of persistent diarrhea that is lifelong and malabsorption throughout life, and early in life will require intravenous support that may be tapered off as the child ages.; to: Unsure if severe enough to include in panel. MM- Tricky - Hyperphagia & obesity but associated metabolic problems can be severe includeing cases of death in childhood. PMID:27187081 - some patients displayed morbid obesity and severe hyperphagia, other subjects were only moderately obese. BMI rises from 2 years and patients became obese from early childhood. However, the extreme obesity of the index case at 3 years of age has not been reported in any subsequent patients. Presentation is severe malabsorptive diarrhea, becoming clinically evident within the first 3 months of life. This can be so severe as to lead to a metabolic acidosis. After the age of 2 years, the severity of the malabsorption appears to spontaneously improve, and many children can discontinue parenteral feeding. PMID: 27288825 - Nutrition significantly diminshed beyond 2 years and patients can thrive despite the presence of persistent diarrhea that is lifelong and malabsorption throughout life, and early in life will require intravenous support that may be tapered off as the child ages. |
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| Prepair 1000+ v1.1868 | FHL1 |
Melanie Marty changed review comment from: The FHL1 gene is associated with a diverse spectrum of X-linked diseases affecting skeletal and cardiac muscle (PMID: 21310615, 40017287). Well-established gene-disease association. FHL1 encodes 3 alternatively spliced isoforms - FHL1A, FHL1B, FHL1C composed of different LIM domains. FHL1A is predominant in muscle. Pathogenic variants affected isoform expression differently depending on location in alternatively spliced exons. Location of the variant appears to be related to severity of phenotype. Loss of function is the mechanism of disease. Reducing body myopathy (RBM) PMID: 18179901, 19716112, 18274675, 19181672, 25274776, 34366191 - XLD inheritance with clinical spectrum that includes severe early-onset to later-onset less progressive conditions including X-linked scapuloperoneal muscular dystrophy & X-linked myopathy with postural muscle atrophy. Pathogenic variants mainly located in more proximal exons (3-6). Fhl1 W122S knock-in mouse model has late-onset mild myopathy. XL-EDMD PMID: 19716112, 20186852, 20301609 - at least 7 families reported with XLD inheritance (female heterozygous carriers were asymptomatic or had mild myopathy and/or cardiomyopathy). EDMD-associated variants are localized in the distal exons (5-8) and associated with reduced function.; to: The FHL1 gene is associated with a diverse spectrum of X-linked diseases affecting skeletal and cardiac muscle (PMID: 21310615, 40017287). Well-established gene-disease association. FHL1 encodes 3 alternatively spliced isoforms - FHL1A, FHL1B, FHL1C composed of different LIM domains. FHL1A is predominant in muscle. Pathogenic variants affected isoform expression differently depending on location in alternatively spliced exons. Location of the variant appears to be related to severity of phenotype. Loss of function is the mechanism of disease. Reducing body myopathy (RBM) PMID: 18179901, 19716112, 18274675, 19181672, 25274776, 34366191 - XLD inheritance with clinical spectrum that includes severe early-onset to later-onset less progressive conditions including X-linked scapuloperoneal muscular dystrophy & X-linked myopathy with postural muscle atrophy. Pathogenic variants mainly located in more proximal exons (3-6). Fhl1 W122S knock-in mouse model has late-onset mild myopathy. Female carriers may experience mild proximal muscle weakness or be asymptomatic. XL-EDMD PMID: 19716112, 20186852, 20301609 - at least 7 families reported with XLD inheritance (female heterozygous carriers were asymptomatic or had mild myopathy and/or cardiomyopathy). EDMD-associated variants are localized in the distal exons (5-8) and associated with reduced function. |
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| Prepair 1000+ v1.1868 | POLE |
Andrew Coventry gene: POLE was added gene: POLE was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLE were set to 30503519; 23230001; 25948378; 36071887 Phenotypes for gene: POLE were set to IMAGE-I syndrome MIM#618336; FILS syndrome MIM#615139 Review for gene: POLE was set to GREEN Added comment: IMAGE-I Syndrome Autosomal recessive disorder characterised by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency. Patients exhibit distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. Well established gene-disease association. Reported in greater than 10 families. Note recurrent intronic variant, c.1686+32C-G (intron 15) in IMAGE-I, found in combination with multiple other variants. FILS syndrome FILS syndrome is characterised by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature. PMID: 23230001 - French consanguineoius kindred: 11 affected individuals displayed mild facial dysmorphism, immunodeficiency, livedo, and short stature. 3 additional members displayed two or three of these four features. Homozygous for splicing site variant: c.4444+3A>G. PMID: 25948378 - Palestinian girl, with same homozygous variant as reported in French family. PMID: 36071887 - 4y.o. Chinese boy with c.5811 + 2T > C and c.2006G > A variants. PMID: 32705701 - 6y.o. hispanic boy reported with homozygous c.100C>T(p.Arg34Cys Total of 14 affected individuals across 4 families. Sources: Literature |
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| Prepair 1000+ v1.1868 | POLR1D |
Andrew Coventry gene: POLR1D was added gene: POLR1D was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: POLR1D was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: POLR1D were set to 21131976; 24603435; 27448281; 25790162 Phenotypes for gene: POLR1D were set to Treacher Collins syndrome 2 MIM#613717 Review for gene: POLR1D was set to AMBER Added comment: Treacher Collins syndrome is a disorder of craniofacial development characterised by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. Currently, only one study reporting AR TCS, 1 pathogenic variant in 4 affected individuals, across 2 unrelated consanguineous families. PMID: 24603435. Adding gene, requiring further evidence in humans for consideration for inclusion in screening of AR TCS. Sources: Literature |
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| Prepair 1000+ v1.1868 | NR0B1 | Karina Sandoval reviewed gene: NR0B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19508677, 26030781; Phenotypes: Adrenal hypoplasia, congenital, MIM#300200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1845 | VPS33B | Zornitza Stark Phenotypes for gene: VPS33B were changed from Arthrogryposis, renal dysfunction, and cholestasis 1, 208085 (3) to Arthrogryposis, renal dysfunction, and cholestasis 1 MIM#208085; Cholestasis, progressive familial intrahepatic, 12 MIM#620010; Keratoderma-ichthyosis-deafness syndrome, autosomal recessive MIM#620009 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1826 | ABCB11 | Melanie Marty reviewed gene: ABCB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 16871584, 23141890, 9806540, 15300568, 11172067; Phenotypes: Cholestasis, progressive familial intrahepatic 2, MIM# 601847, Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1826 | VPS33B | Michelle Torres reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31479177, 30561130, 28017832; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1 MIM#208085, Cholestasis, progressive familial intrahepatic, 12 MIM#620010, Keratoderma-ichthyosis-deafness syndrome, autosomal recessive MIM#620009; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1822 | VIPAS39 | Michelle Torres reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 20190753, 35151346; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2 MIM#613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1811 | PEX19 |
Andrew Coventry gene: PEX19 was added gene: PEX19 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: PEX19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PEX19 were set to 10051604; 20683989; 39757991; 21031596; 30561787; 36931687 Phenotypes for gene: PEX19 were set to Peroxisome biogenesis disorder 12A (Zellweger) MIM#614886; Peroxisome biogenesis disorder MONDO:0019234 Review for gene: PEX19 was set to GREEN Added comment: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life. Functional studies and animal models are present. Reported in individuals across at least 4 unrelated families. Sources: Literature |
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| Prepair 1000+ v1.1811 | RBM8A |
Andrew Coventry gene: RBM8A was added gene: RBM8A was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: RBM8A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RBM8A were set to 22366785; 17236129; 26550033; 32227665 Phenotypes for gene: RBM8A were set to Thrombocytopenia-absent radius syndrome MIM#274000 Review for gene: RBM8A was set to AMBER Added comment: The thrombocytopenia-absent radius syndrome (TAR) is characterised by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia. Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee. Vast majority of cases include a recurrent 200kb deletion on one allele (although truncations are seen) and the presence of 1 of 2 SNPs in trans. The SNPs have a MAF of 3.05% and 0.42%. Cases have been reported with this phenotype without the 200kb deletion (PMID: 22366785, 32227665). Currently, the large CNV in majority of cases would not be detected. Sources: Literature |
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| Prepair 1000+ v1.1811 | AGTR1 |
Andrew Coventry gene: AGTR1 was added gene: AGTR1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGTR1 were set to 16116425; 22095942 Phenotypes for gene: AGTR1 were set to Renal tubular dysgenesis MIM#267430 Review for gene: AGTR1 was set to GREEN Added comment: Severe disorder of renal tubular development characterised by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Can cause stillbirth. Three unrelated families reported for AGTR1 variants. Other genes associated with this phenotype are included in 1000+. Sources: Literature |
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| Prepair 1000+ v1.1770 | TBX19 | Zornitza Stark Phenotypes for gene: TBX19 were changed from Adrenocorticotropic hormone deficiency, 201400 (3) to Adrenocorticotropic hormone deficiency, MIM# 201400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1744 | SLC4A4 | Zornitza Stark Phenotypes for gene: SLC4A4 were changed from Renal tubular acidosis, proximal, with ocular abnormalities, 604278 (3) to Renal tubular acidosis, proximal, with ocular abnormalities, MIM#604278 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1742 | SLC4A1 | Zornitza Stark Phenotypes for gene: SLC4A1 were changed from Distal renal tubular acidosis 4 with hemolytic anemia, MIM# 611590 to Distal renal tubular acidosis 4 with haemolytic anaemia, MIM# 611590 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1741 | SLC4A1 | Zornitza Stark Phenotypes for gene: SLC4A1 were changed from Renal tubular acidosis, distal, AR, 611590 (3) to Distal renal tubular acidosis 4 with hemolytic anemia, MIM# 611590 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1732 | SIL1 | Zornitza Stark Phenotypes for gene: SIL1 were changed from Marinesco-Sjogren syndrome, 248800 (3) to Marinesco-Sjogren syndrome MIM#248800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1676 | NEK8 | Zornitza Stark Phenotypes for gene: NEK8 were changed from Renal-hepatic-pancreatic dysplasia 2, 615415 (3), Autosomal recessive to Renal-hepatic-pancreatic dysplasia 2 MIM#615415 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1611 | TTC21B |
Kate Scarff changed review comment from: Short-rib thoracic dysplasia (SRTD) with or without polydactyly is a skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present. Nonskeletal involvement can include cleft lip/palate as well as anomalies of the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Homozygous null alleles in Ttc21b are embryonic lethal in mice and it is likely that biallelic truncating null variants are equally incompatible with survival in humans. Nephronophthisis 12: End stage kidney disease seen in multiple unrelated children <10 years. Patients harboring one truncating or splice site mutation in addition to a missense variant exhibit JATD or early onset NPHP with extra-renal features, whereas patients carrying homozygous p.Pro209Leu variants display a primarily kidney phenotype with NPHP and often with glomerular involvement (FSGS). However, liver and skeletal involvement as well as high myopia have also been described in patients with biallelic missense variants, including homozygous p.Pro209Leu carriers.; to: Short-rib thoracic dysplasia (SRTD) with or without polydactyly is a skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present. Nonskeletal involvement can include cleft lip/palate as well as anomalies of the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Homozygous null alleles in Ttc21b are embryonic lethal in mice and it is likely that biallelic truncating null variants are equally incompatible with survival in humans. Nephronophthisis 12: End stage kidney disease seen in multiple unrelated children <10 years. Patients harboring one truncating or splice site mutation in addition to a missense variant exhibit SRTD or early onset NPHP with extra-renal features, whereas patients carrying homozygous p.Pro209Leu variants display a primarily kidney phenotype with NPHP and often with glomerular involvement (FSGS). However, liver and skeletal involvement as well as high myopia have also been described in patients with biallelic missense variants, including homozygous p.Pro209Leu carriers. |
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| Prepair 1000+ v1.1611 | TTC21B |
Kate Scarff changed review comment from: Short-rib thoracic dysplasia (SRTD) with or without polydactyly is a skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present. Nonskeletal involvement can include cleft lip/palate as well as anomalies of the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Homozygous null alleles in Ttc21b are embryonic lethal in mice and it is likely that biallelic truncating null variants are equally incompatible with survival in humans.; to: Short-rib thoracic dysplasia (SRTD) with or without polydactyly is a skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present. Nonskeletal involvement can include cleft lip/palate as well as anomalies of the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Homozygous null alleles in Ttc21b are embryonic lethal in mice and it is likely that biallelic truncating null variants are equally incompatible with survival in humans. Nephronophthisis 12: End stage kidney disease seen in multiple unrelated children <10 years. Patients harboring one truncating or splice site mutation in addition to a missense variant exhibit JATD or early onset NPHP with extra-renal features, whereas patients carrying homozygous p.Pro209Leu variants display a primarily kidney phenotype with NPHP and often with glomerular involvement (FSGS). However, liver and skeletal involvement as well as high myopia have also been described in patients with biallelic missense variants, including homozygous p.Pro209Leu carriers. |
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| Prepair 1000+ v1.1600 | DNAAF4 | Lilian Downie Added comment: Comment when marking as ready: Primary ciliary dyskinesia-25 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have recurrent upper and lower airway disease, bronchiectasis, and decreased fertility. About half of patients show laterality defects, including situs inversus totalis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1596 | PEX1 |
Kate Scarff changed review comment from: Characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life. ~98% of variants detectable by sequencing. The PEX1 variants c.2097_2098insT/p.Ile700YfsX42 and c.2528GRA/p.Gly843Asp are the most common. Homozygosity for p.Ile700TyrfsTer42 is associated with a more severe phenotype. Homozygosity for p.Gly843Asp has to date been associated with a milder ZSD phenotype and sometimes with an intermediate phenotype. Other phenotypes: Peroxisome biogenesis disorder 1B (NALD/IRD), MIM #601539, characterised by overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum. Many children presenting as newborns, whereas others do not come to attention until later. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. Associated with p.Gly843Asp variant? Heimler syndrome-1 (MIM #234580) represents the mildest end of the peroxisomal biogenesis disorder spectrum, characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities. Not severe enough to report for P1000? See PMID: 26387595.; to: Characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life. ~98% of variants detectable by sequencing. The PEX1 variants c.2097_2098insT/p.Ile700YfsX42 and c.2528GRA/p.Gly843Asp are the most common. Homozygosity for p.Ile700TyrfsTer42 is associated with a more severe phenotype. Homozygosity for p.Gly843Asp has to date been associated with a milder ZSD phenotype and sometimes with an intermediate phenotype. Other phenotypes: Peroxisome biogenesis disorder 1B (NALD/IRD), MIM #601539, characterised by overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum. Many children presenting as newborns, whereas others do not come to attention until later. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. Associated with p.Gly843Asp variant? Heimler syndrome-1 (MIM #234580) represents the mildest end of the peroxisomal biogenesis disorder spectrum, characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities. Not severe enough to report for P1000? See PMID: 26387595. MONDO:0100259 - Any Zellweger spectrum disorder in which the cause of the disease is a mutation in the PEX1 gene. |
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| Prepair 1000+ v1.1596 | PEX1 |
Kate Scarff changed review comment from: Characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life. ~98% of variants detectable by sequencing. The PEX1 variants c.2097_2098insT/p.Ile700YfsX42 and c.2528GRA/p.Gly843Asp are the most common. Homozygosity for p.Ile700TyrfsTer42 is associated with a more severe phenotype. Homozygosity for p.Gly843Asp has to date been associated with a milder ZSD phenotype and sometimes with an intermediate phenotype. Other phenotypes: Peroxisome biogenesis disorder 1B (NALD/IRD), MIM #601539, characterised by overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum. Many children presenting as newborns, whereas others do not come to attention until later. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. Associated with p.Gly843Asp variant? Should this phenotype be included for P1000? Heimler syndrome-1 (MIM #234580) represents the mildest end of the peroxisomal biogenesis disorder spectrum, characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities. Not severe enough to report for P1000. See PMID: 26387595.; to: Characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life. ~98% of variants detectable by sequencing. The PEX1 variants c.2097_2098insT/p.Ile700YfsX42 and c.2528GRA/p.Gly843Asp are the most common. Homozygosity for p.Ile700TyrfsTer42 is associated with a more severe phenotype. Homozygosity for p.Gly843Asp has to date been associated with a milder ZSD phenotype and sometimes with an intermediate phenotype. Other phenotypes: Peroxisome biogenesis disorder 1B (NALD/IRD), MIM #601539, characterised by overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum. Many children presenting as newborns, whereas others do not come to attention until later. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. Associated with p.Gly843Asp variant? Heimler syndrome-1 (MIM #234580) represents the mildest end of the peroxisomal biogenesis disorder spectrum, characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities. Not severe enough to report for P1000? See PMID: 26387595. |
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| Prepair 1000+ v1.1568 | DLAT |
Andrew Coventry gene: DLAT was added gene: DLAT was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: DLAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DLAT were set to 34138529; 16049940; 20022530; 29093066 Phenotypes for gene: DLAT were set to Leigh syndrome MONDO:0009723; Pyruvate dehydrogenase E2 deficiency MIM#245348 Review for gene: DLAT was set to GREEN Added comment: Clinical presentation is in infancy. Pyruvate dehydrogenase E2 deficiency is a mitochondrial disorder, mostly affects the brain and leads to decreased ATP production and energy deficit. Can manifest as a syndrome of neurologic signs (congenital microcephaly, hypotonia, epilepsy, and/or ataxia), brain impacts (dysgenesis of the corpus callosum, Leigh syndrome) and metabolic abnormalities (increased plasma pyruvate, lactic acidemia, and/or metabolic acidosis). Biochemical function, expression data, and model systems available. 1-4% of total PDE2D cases are due to variants in DLAT - associated with phenotype w/survival into childhood/adulthood, milder than other genes involved with condition. PMID: 16049940 - 2 unrelated patients with Episodic dystonia. Hypotonia and ataxia, being less prominent. Neuroradiological evidence of discrete lesions restricted to the globus pallidus, Male patient 1 - dystonic movements of the facial muscles and of his hands and feet.Developmental delay (12 words at age 4). Treatment has improved condition. Male patient 2 - presented at 11 months of age with episodic dystonia (up to 3hrs duration). 8 years of age, developmental delay, cannot walk. PMID: 29093066 - 2 siblings (both homozygous for c.470T>G; p.Val157Gly). Male sibling reported with intellectual disability and exercise-induced gait abnormalities. IQ of 44 at 8 years of age. Female sibling noted to have global delays with intellectual disability. PMID: 20022530 - two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency. At least 6 cases, in 4 unrelated families as described in publications above. While reportedly milder than other presentations, appears severe presentation in absence of treatment. Other genes currently included: PDHA1, PDHB, PDP1. Sources: Literature |
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| Prepair 1000+ v1.1566 | TBX19 | Lauren Thomas reviewed gene: TBX19: Rating: GREEN; Mode of pathogenicity: None; Publications: 30086867; Phenotypes: Adrenocorticotropic hormone deficiency, MIM# 201400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1566 | SLC4A1 | Lauren Thomas reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31600044, 10926824; Phenotypes: Distal renal tubular acidosis 4 with hemolytic anemia, MIM# 611590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1566 | SIL1 | Andrew Coventry reviewed gene: SIL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24176978, 16282977, 20301371, 16282978; Phenotypes: Marinesco-Sjogren syndrome MIM#248800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1566 | NEK8 | Andrew Coventry reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 18199800, 26697755, 26862157, 26967905, 12421721, 18235101, 23274954, 23793029; Phenotypes: Renal-hepatic-pancreatic dysplasia 2 MIM#615415; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1528 | SLC4A4 | Cassandra Muller reviewed gene: SLC4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545938, 15085340, 15471865; Phenotypes: Proximal renal tubular acidosis-ocular anomaly syndrome, 604278 (3); Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1257 | TMEM138 |
Kate Scarff changed review comment from: Characterized by the molar tooth sign on brain imaging (cerebellar and brain stem malformation), oculomotor apraxia, variable coloboma, and rare kidney involvement, hypotonia and dev delay. Described in 8 consanguineous Arab families (6 different homozygous mutations).; to: Characterized by the molar tooth sign on brain imaging (cerebellar and brain stem malformation), oculomotor apraxia, variable coloboma, and rare kidney involvement, hypotonia and dev delay. Described in 8 consanguineous Arab families (6 different homozygous mutations). MIM #614465 |
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| Prepair 1000+ v1.1084 | SCARB2 | Zornitza Stark Phenotypes for gene: SCARB2 were changed from Epilepsy, progressive myoclonic 4, with or without renal failure, 254900 (3) to Epilepsy, progressive myoclonic 4, with or without renal failure, MIM#254900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | KIAA0586 | Ee Ming Wong reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: None; Publications: 26386044, 28125082, 36580738, 39063141; Phenotypes: Short-rib thoracic dysplasia 14 with polydactyly (MIM#616546), Joubert syndrome 23 (MIM#616490); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SYP | Ee Ming Wong reviewed gene: SYP: Rating: AMBER; Mode of pathogenicity: None; Publications: 23966691, 19377476; Phenotypes: Intellectual developmental disorder, X-linked 96 (MIM#300802); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | STIL | Ee Ming Wong reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157, 29352115, 24485834; Phenotypes: Microcephaly 7, primary, (MIM# 612703); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SLC25A46 | Ee Ming Wong reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27543974, 30178502; Phenotypes: Neuropathy, hereditary motor and sensory, type VIB (MIM# 616505), Pontocerebellar hypoplasia, type 1E (MIM# 619303); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SLC25A19 | Ee Ming Wong reviewed gene: SLC25A19: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301539, 31095747; Phenotypes: Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) (MIM#613710), Microcephaly, Amish type (MIM#607196); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SLC17A5 | Ee Ming Wong reviewed gene: SLC17A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 10947946, 5516337, 33862140; Phenotypes: Sialic acid storage disorder, infantile (MIM#269920); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SDCCAG8 | Ee Ming Wong reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 22819833, 20835237, 32432520, 22626039, 31534065, 26968886; Phenotypes: Bardet-Biedl syndrome 16 (MIM# 615993), Senior-Loken syndrome 7 (MIM# 613615); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SDCCAG8 | Ee Ming Wong reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bardet-Biedl syndrome 16 (MIM# 615993); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | CYB5R3 | Ee Ming Wong reviewed gene: CYB5R3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898843, 38303731; Phenotypes: Methemoglobinemia, type II (MIM# 250800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | UBE2T | Ee Ming Wong reviewed gene: UBE2T: Rating: GREEN; Mode of pathogenicity: None; Publications: 32646888, 26119737, 26046368, 26085575; Phenotypes: Fanconi anemia, complementation group T (MIM#616435); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | TBX22 | Ee Ming Wong reviewed gene: TBX22: Rating: AMBER; Mode of pathogenicity: None; Publications: 36901693, 22784330, 21375406; Phenotypes: Cleft palate with ankyloglossia (MIM# 303400); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | ELP1 |
Clare Hunt changed review comment from: From OMIM; Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by Morini et al., 2016). Gene previously referred to as IKBKAP gene (ELP1; 603722) located on chromosome 9q31. Also previously referred to as Riley-Day syndrome. From Mendeliome; AR dysautonomia: the condition is predominantly caused by homozygosity of c.2204+6T>C (major familial dysautonomia AJ haplotype - causes tissue-specific exon 20 skipping) in Ashkenazi Jewish individuals. Other variants have been reported in association with the disease.; to: From OMIM; Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by Morini et al., 2016). Gene previously referred to as IKBKAP gene (ELP1; 603722) located on chromosome 9q31. From Mendeliome; AR dysautonomia: the condition is predominantly caused by homozygosity of c.2204+6T>C (major familial dysautonomia AJ haplotype - causes tissue-specific exon 20 skipping) in Ashkenazi Jewish individuals. Other variants have been reported in association with the disease. |
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| Prepair 1000+ v1.992 | ELP1 |
Clare Hunt changed review comment from: From OMIM; Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by Morini et al., 2016). Gene previously referred to as IKBKAP gene (ELP1; 603722) located on chromosome 9q31. Also previously referred to as Riley-Day syndrome.; to: From OMIM; Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by Morini et al., 2016). Gene previously referred to as IKBKAP gene (ELP1; 603722) located on chromosome 9q31. Also previously referred to as Riley-Day syndrome. From Mendeliome; AR dysautonomia: the condition is predominantly caused by homozygosity of c.2204+6T>C (major familial dysautonomia AJ haplotype - causes tissue-specific exon 20 skipping) in Ashkenazi Jewish individuals. Other variants have been reported in association with the disease. |
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| Prepair 1000+ v1.992 | TAZ | Ee Ming Wong reviewed gene: TAZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 25299040; Phenotypes: Barth syndrome (MIM# 302060); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SUMF1 | Ee Ming Wong reviewed gene: SUMF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30896912; Phenotypes: Multiple sulfatase deficiency (MIM#272200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | SCARB2 | Ee Ming Wong reviewed gene: SCARB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26677510, 35346091; Phenotypes: Epilepsy, progressive myoclonic 4, with or without renal failure (MIM #254900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | RCBTB1 | Ee Ming Wong reviewed gene: RCBTB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486781, 33104391, 33624564; Phenotypes: Retinal dystrophy with or without extraocular anomalies (MIM#617175); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PTH1R | Ee Ming Wong reviewed gene: PTH1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: 15525660, 17164305, 39276366; Phenotypes: Chondrodysplasia, Blomstrand type (MIM#215045), Eiken syndrome (MIM#600002); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | POR | Ee Ming Wong reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 20301592, 35842891; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PYCR2 | Ee Ming Wong reviewed gene: PYCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25865492, 27130255; Phenotypes: Leukodystrophy, hypomyelinating 10 (MIM# 616420); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PMPCA | Ee Ming Wong reviewed gene: PMPCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25808372, 26657514, 33272776, 30617178; Phenotypes: Spinocerebellar ataxia 2 (MIM# 213200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PKLR | Ee Ming Wong reviewed gene: PKLR: Rating: GREEN; Mode of pathogenicity: None; Publications: 1896471, 9160692, 9057665, 16704447, 9090535, 32702739; Phenotypes: Pyruvate Kinase deficiency (MIM# 266200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PIGT | Ee Ming Wong reviewed gene: PIGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30976099, 25943031, 24906948, 24906948, 24906948, 28728837, 28728837, 28728837; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398, MONDO:0014165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PCNT | Ee Ming Wong reviewed gene: PCNT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18174396, 12210304, 30922925, 33460028, 32557621, 32267100; Phenotypes: Microcephalic osteodysplastic primordial dwarfism, type II, MIM# 210720, MONDO:0008872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PCDH12 | Ee Ming Wong reviewed gene: PCDH12: Rating: GREEN; Mode of pathogenicity: None; Publications: 27164683, 30178464; Phenotypes: Diencephalic-mesencephalic junction dysplasia syndrome 1 (MIM# 251280); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | PC |
Ee Ming Wong changed review comment from: - Well-established gene disease association - Age of onset: neonatal to early childhood - Severity: variable severity - three subtypes 1. Type A (infantile form aka North American form): characterized by infantile onset of metabolic and lactic acidosis, delayed motor development, intellectual disability, poor linear growth and/or weight gain, and neurologic findings. Brain anomalies can be noted. Most affected children die in infancy or early childhood. 2. Type B (severe neonatal form aka French form): characterized by neonatal or infantile onset of hypothermia, respiratory distress/failure, vomiting, severe lactic acidosis, hyperammonemia, and often hypoglycemia. Neurologic findings include brain abnormalities, lethargy, hypotonia, and pyramidal and extrapyramidal signs. Death typically occurs by age eight months. 3. Type C (intermittent/attenuated form aka Benign form): characterized by relatively normal or mildly delayed neurologic development, motor and/or gait abnormalities, (rarely) seizures, episodic movement disorders, and metabolic acidosis. Life span is unknown but survival into adulthood has been reported.; to: - Well-established gene disease association - Age of onset: neonatal to early childhood - Severity: variable severity - three subtypes 1. Type A (infantile form aka North American form): characterized by infantile onset of metabolic and lactic acidosis, delayed motor development, intellectual disability, poor linear growth and/or weight gain, and neurologic findings. Brain anomalies can be noted. Most affected children die in infancy or early childhood. 2. Type B (severe neonatal form aka French form): characterized by neonatal or infantile onset of hypothermia, respiratory distress/failure, vomiting, severe lactic acidosis, hyperammonemia, and often hypoglycemia. Neurologic findings include brain abnormalities, lethargy, hypotonia, and pyramidal and extrapyramidal signs. Death typically occurs by age eight months. 3. Type C (intermittent/attenuated form aka Benign form): characterized by relatively normal or mildly delayed neurologic development, motor and/or gait abnormalities, (rarely) seizures, episodic movement disorders, and metabolic acidosis. Life span is unknown but survival into adulthood has been reported. |
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| Prepair 1000+ v1.992 | PC | Ee Ming Wong reviewed gene: PC: Rating: GREEN; Mode of pathogenicity: None; Publications: 9585612, 12112657, 20301764; Phenotypes: Pyruvate carboxylase deficiency (MIM#266150); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NPR2 | Ee Ming Wong reviewed gene: NPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15146390; Phenotypes: Acromesomelic dysplasia, Maroteaux type (MIM#602875); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NMNAT1 |
Ee Ming Wong changed review comment from: Syndromic and non-syndromic causes of LCA are associated with bi-allelic variants in this gene. Non-syndromic LCA: multiple affected families reported, p.Glu257Lys is a common founder variant. Syndromic disorder: three families reported, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant. Green for non-syndromic LCA (MIM# added to review). No additional affected individuals in the literature (Amber? MIM# has not been added to review).; to: Syndromic and non-syndromic causes of LCA are associated with bi-allelic variants in this gene. Non-syndromic LCA: multiple affected families reported, p.Glu257Lys is a common founder variant. Syndromic disorder: three families reported, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant. Green for non-syndromic LCA (MIM# added to review). No additional affected individuals in the literature for syndromic LCA (Amber? MIM# has not been added to review). |
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| Prepair 1000+ v1.992 | NMNAT1 | Ee Ming Wong reviewed gene: NMNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32533184, 33668384, 22842230, 22842229; Phenotypes: Leber congenital amaurosis 9 (MIM#608553); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NFU1 | Ee Ming Wong reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21944046, 22077971, 32747156, 29441221, 36256512; Phenotypes: Multiple mitochondrial dysfunctions syndrome 1 (MIM# 605711), Spastic paraplegia 93 (MIM# 620938); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NEK1 | Ee Ming Wong reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21211617, 22499340, 25492405, 28123176; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly (MIM# 263520); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NDUFS6 | Ee Ming Wong reviewed gene: NDUFS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 15372108, 19259137, 30948790; Phenotypes: Mitochondrial complex I deficiency, nuclear type 9 (MIM#618232); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NBN | Ee Ming Wong reviewed gene: NBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33488600, 33082212; Phenotypes: Nijmegen breakage syndrome (MIM#251260); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NANS | Ee Ming Wong reviewed gene: NANS: Rating: GREEN; Mode of pathogenicity: None; Publications: 8152878, 15726110, 8723082, 27213289, 7551156; Phenotypes: Spondyloepimetaphyseal dysplasia, Camera-Genevieve type (MIM#610442); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NALCN | Ee Ming Wong reviewed gene: NALCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 23749988, 24075186, 3016785; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | NAA10 | Ee Ming Wong reviewed gene: NAA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 26522270, 34200686, 37130971, 30842225, 2443133134075687; Phenotypes: Ogden syndrome (MIM#300855), Syndromic microphthalmia 1 (MIM#309800); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | MTR | Ee Ming Wong reviewed gene: MTR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8968736, 8968737, 9683607, 12068375; Phenotypes: Homocystinuria-megaloblastic anaemia, cblG complementation type, MIM# 250940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | MOCS1 | Ee Ming Wong reviewed gene: MOCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 9731530; Phenotypes: Molybdenum cofactor deficiency A (MIM#252150); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.823 | CLDN19 | Zornitza Stark Phenotypes for gene: CLDN19 were changed from Hypomagnesemia 5, renal, with ocular involvement, 248190 (3) to Hypomagnesaemia 5, renal, with ocular involvement, MIM#248190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.813 | DOCK8 | Zornitza Stark Phenotypes for gene: DOCK8 were changed from Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700 (3) to Hyper-IgE recurrent infection syndrome, autosomal recessive, MIM#243700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.798 | LRPPRC | Zornitza Stark Phenotypes for gene: LRPPRC were changed from Leigh syndrome, French-Canadian type, 220111 (3) to Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.761 | TPRKB |
Lucy Spencer changed review comment from: Gene is red on Mackenzie's mission panel but the review itself is green and says "Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly." this is refering to 3 families all with homozygous missense, p.Lys65Met, p.Tyr149Cys, and p.Leu136Pro. There has been at least one more individual reported PMID: 38628357: a three-year-old male with developmental delay, regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. He also had relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. He was compound heterozygous for p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe). Severe early-onset and reported in at least 4 individuals (also green on mendeliome), upgrading to green here.; to: Gene is red on Mackenzie's mission panel but the review itself is green and says "Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly." this is refering to 3 families all with homozygous missense, p.Lys65Met, p.Tyr149Cys, and p.Leu136Pro (PMIDs: 28805828, 30053862). There has been at least one more individual reported PMID: 38628357: a three-year-old male with developmental delay, regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. He also had relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. He was compound heterozygous for p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe). Severe early-onset and reported in at least 4 individuals (also green on mendeliome), upgrading to green here. |
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| Prepair 1000+ v1.761 | CLDN19 |
Karina Sandoval changed review comment from: Dental anomalies on the AI spectrum are a feature of this primarily renal disorder. Macular coloboma is part of the phenotype. Variable age of onset of deafness, progressive, generally in the first decade. PMID 27530400 - 9 indiv from 6 families, age at onset of symtpoms ranging from 0-9 years with varying severity of symptoms ranging frrom FTT to polydipsia. Oldest age at CKD diagnosis was 15 years. PMID 17033971 - 12 patients affected with hypomagnesemia, renal failure, and severe ocular abnormalities. Age at onset of symptoms was 0-8 years. PMID 22422540 - 23 indiv with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, median age at onset 9.5years. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age; to: Dental anomalies on the AI spectrum are a feature of this primarily renal disorder. Macular coloboma is part of the phenotype. Variable age of onset of deafness, progressive, generally in the first decade. PMID 27530400 - 9 indiv from 6 families, age at onset of symtpoms ranging from 0-9 years with varying severity of symptoms ranging frrom FTT to polydipsia. Oldest age at CKD diagnosis was 15 years. PMID 17033971 - 12 patients affected with hypomagnesemia, renal failure, and severe ocular abnormalities. Age at onset of symptoms was 0-8 years. PMID 22422540 - 23 indiv with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, median age at onset 9.5years. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age |
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| Prepair 1000+ v1.730 | CLDN19 | Karina Sandoval reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 27530400, 17033971, 22422540; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM#248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.718 | DOCK8 | Melanie Marty reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive, MIM# 243700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.708 | LRPPRC | Cassandra Muller reviewed gene: LRPPRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 12529507, 12529507, 26510951, 21266382; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) 220111 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.692 | ATP6V0A4 | Lilian Downie Phenotypes for gene: ATP6V0A4 were changed from Renal tubular acidosis, distal, autosomal recessive, 602722 (3) to Distal renal tubular acidosis 3, with or without sensorineural hearing loss MIM#602722 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.691 | POMC | Zornitza Stark Phenotypes for gene: POMC were changed from Obesity, adrenal insufficiency, and red hair due to POMC deficiency, 609734 (3) to Obesity, adrenal insufficiency, and red hair due to POMC deficiency, MIM#609734 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.688 | ATP6V0A4 | Lilian Downie reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22872862, 12414817, 29311258; Phenotypes: Distal renal tubular acidosis 3, with or without sensorineural hearing loss MIM#602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.681 | LPIN1 | Zornitza Stark Phenotypes for gene: LPIN1 were changed from Myoglobinuria, acute recurrent, autosomal recessive, 268200 (3) to Myoglobinuria, acute recurrent, autosomal recessive, MIM#268200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.679 | SLC9A3 | Lilian Downie Added comment: Comment when marking as ready: Downgrade to RED for severity (mild, children thrive on normal diet) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | MMAA | Ee Ming Wong reviewed gene: MMAA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, vitamin B12-responsive, cblA type (MIM#251100); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | MERTK | Ee Ming Wong reviewed gene: MERTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 11062461, 17301963, 20300561, 22180149; Phenotypes: Retinitis pigmentosa 38 (MIM#613862); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | MARS | Ee Ming Wong reviewed gene: MARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24103465, 25913036; Phenotypes: Interstitial lung and liver disease, MIM#615486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | LHX3 | Ee Ming Wong reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30759489; Phenotypes: Pituitary hormone deficiency, combined, 3 (MIM# 221750); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | KY | Ee Ming Wong reviewed gene: KY: Rating: GREEN; Mode of pathogenicity: None; Publications: 27484770, 27485408, 30591934; Phenotypes: Myopathy, myofibrillar, 7 (MIM#617114); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | KLHL7 | Ee Ming Wong reviewed gene: KLHL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31953236, 30300710, 31856884; Phenotypes: PERCHING syndrome (MIM#617055); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | POMC | Crystle Lee reviewed gene: POMC: Rating: GREEN; Mode of pathogenicity: None; Publications: 34177811; Phenotypes: Obesity, adrenal insufficiency, and red hair due to POMC deficiency, MIM#609734; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | LPIN1 | Crystle Lee reviewed gene: LPIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18817903, 32549891; Phenotypes: Myoglobinuria, acute recurrent, autosomal recessive, MIM#268200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | JAGN1 | Ee Ming Wong reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144, 37528877; Phenotypes: Severe congenital neutropenia 6, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | IL10RA | Ee Ming Wong reviewed gene: IL10RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 19890111, 21519361, 22476154; Phenotypes: Early onset inflammatory bowel disease 28 (MIM# 613148); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | IFT140 | Ee Ming Wong reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: 22503633, 23418020, 28288023, 28724397; Phenotypes: Short-rib thoracic dysplasia 9 with of without polydactyly (MIM#266920); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | IDS | Ee Ming Wong reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301451; Phenotypes: Mucopolysaccharidosis II, MIM# 309900, Hunter syndrome, MONDO:0010674; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | HPRT1 | Ee Ming Wong reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301328; Phenotypes: Lesch-Nyhan syndrome (MIM#300322); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.631 | ESCO2 | Lilian Downie Added comment: Comment on phenotypes: ClinGen review for Roberts-SC phocolmelia MONDO:0100253 but no reference to Juberg-Hayward syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.596 | CA2 | Lilian Downie Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, 259730 (3) to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.592 | CA2 | Melanie Marty reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34624559, 33555497, 12566520, 7627193; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.592 | GCH1 | Lilian Downie Added comment: Comment when marking as ready: Biallelic variants in GCH1 typically result in severe deficiency of GTPCH activity, and result in hyperphenylalaninemia due to secondary PAH deficiency. This can be identified by newborn screening. However, patients with phenotypes that are intermediate between the classic DRD and severe GTPCH deficiency symptoms have been described, such those with severe DRD and additional neurological features but without hyperphenylalaninemia (for review, see Table in Brüggemann et al 2012, PMID 22473768). Because the mechanism of disease in both the monoallelic and biallelic cases is loss of function of GTPCH, and there is a range of GTPCH activity that can cause disease, the decision was made to curate GCH1 for GTPCH deficiency with semi-dominant inheritance. Note that heterozygous parents of biallelic individuals are usually reported as unaffected, although there are some exceptions (Furukawa et al, 1998, PMID 9667588; Bodzioch et al, 2010, PMID 20842687). Reduced penetrance has been reported for individuals with monoallelic GCH1 variants, with penetrance varying according to age and diagnostic criteria. In addition, some variants (e.g. p.Arg184His and p.Lys224Arg) have been reported in monallelic and biallelic individuals. This data was presented to the ClinGen Lumping and Splitting Working Group on November 3, 2020 and there was agreement that GTPCH deficiency should be curated as a semi-dominant trait, including individuals with monoallelic and biallelic GCH1 variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.553 | GUCY1A3 | Ee Ming Wong reviewed gene: GUCY1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36941667; Phenotypes: Moyamoya 6 with achalasia, MIM#615750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.553 | GTF2H5 | Ee Ming Wong reviewed gene: GTF2H5: Rating: GREEN; Mode of pathogenicity: None; Publications: 30359777, 24986372, 37356817; Phenotypes: Trichothiodystrophy 3, photosensitive, MIM# 616395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.553 | GRM1 | Ee Ming Wong reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223; Phenotypes: Spinocerebellar ataxia, autosomal recessive 13, 614831; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.553 | GPAA1 | Ee Ming Wong reviewed gene: GPAA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100095; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 15, MIM#617810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.553 | GNS | Ee Ming Wong reviewed gene: GNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31536183; Phenotypes: Mucopolysaccharidosis type IIID, MIM# 252940, Sanfilippo syndrome type D, MONDO:0009658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | GNPAT | Ee Ming Wong reviewed gene: GNPAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536089, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 2 (MIM# 222765); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | GNB5 | Ee Ming Wong reviewed gene: GNB5: Rating: GREEN; Mode of pathogenicity: None; Publications: 34436834; Phenotypes: Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia (MIM#617173), Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia (MIM#617182); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | G6PC | Ee Ming Wong reviewed gene: G6PC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease Ia (MIM# 232200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | ACE | Lauren Rogers reviewed gene: ACE: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | FOXP3 | Ee Ming Wong reviewed gene: FOXP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11295725, 11137993, 33668198, 33614561, 33330291, 32234571; Phenotypes: Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (MIM#304790); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | FLVCR1 | Ee Ming Wong reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39306721; Phenotypes: Neurodevelopmental disorder MONDO:0700092, FLVCR1-related, Ataxia, posterior column, with retinitis pigmentosa, MIM#609033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | FKRP | Ee Ming Wong reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38277301; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 (MIM#613153), Muscular dystrophy-dystroglycanopathy (congenital with or without intellectual development), type B, 5 (MIM#606612), Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 (MIM#607155); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | FARS2 | Ee Ming Wong reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30869852; Phenotypes: Combined oxidative phosphorylation deficiency 14 (MIM#614946), Spastic paraplegia 77 (MIM#617046); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.547 | F7 | Ee Ming Wong reviewed gene: F7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor VII deficiency, MIM# 227500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.516 | REN | Zornitza Stark Marked gene: REN as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.516 | REN | Zornitza Stark Gene: ren has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.516 | REN | Zornitza Stark Phenotypes for gene: REN were changed from Renal tubular dysgenesis, 267430 (3) to Renal tubular dysgenesis MIM#267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.486 | TANGO2 | Lucy Spencer reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration MIM#616878; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.486 | REN | Lucy Spencer reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular dysgenesis MIM#267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.434 | HSD3B2 | Lilian Downie Phenotypes for gene: HSD3B2 were changed from 3-beta-hydroxysteroid dehydrogenase, type II, deficiency, 201810 (3) to Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM#201810 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.420 | HSD3B2 | Lisa Norbart reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33757164, 1363812; Phenotypes: Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM#201810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.420 | AGT | Andrew Coventry reviewed gene: AGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425 34234805 33163725; Phenotypes: Renal tubular dysgenesis MIM#267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.420 | NPHP3 | Zornitza Stark Phenotypes for gene: NPHP3 were changed from Meckel syndrome 7, 267010 (3) to Renal-hepatic-pancreatic dysplasia 1 MIM#208540; Meckel syndrome 7 MIM#267010; Nephronophthisis 3 MIM#604387 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.390 | NPHP3 | Lucy Spencer reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal-hepatic-pancreatic dysplasia 1 MIM#208540, Meckel syndrome 7 MIM#267010, Nephronophthisis 3 MIM#604387; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.384 | SGPL1 | Lilian Downie reviewed gene: SGPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36050428, 30517686, 35748945; Phenotypes: RENI syndrome MIM#617575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.356 | SGPL1 | Ain Roesley Phenotypes for gene: SGPL1 were changed from Nephrotic syndrome 14, 617575 (3), Autosomal recessive to RENI syndrome (MIM#617575) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.348 | HK1 |
Lilian Downie Added comment: Comment when marking as ready: Caution mutliple phenotypes: AD phenotype Neurodevelopmental disorder with visual defects and brain anomalies MIM#618547 caused by recurrent variants likely causing gain-of-function c.1370C>T, c.1334C>T, c.1240G>A (PMID: 38617198) AR HMSNR Founder variant in the Roma, -3818-195G-C, AltT2 EXON in 5'UTR identified in multiple families. |
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| Prepair 1000+ v1.322 | STAR | Andrew Coventry reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608 8634702 9326645 8948562 9097960 11061515 11297612 14764819 16968793; Phenotypes: Lipoid adrenal hyperplasia MIM#201710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.322 | SARS2 | Andrew Coventry reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24034276 21255763 33751860 34407605 38326069 38264205; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.322 | PQBP1 | Andrew Coventry reviewed gene: PQBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31840929 14634649 20410308 19661183; Phenotypes: Renpenning syndrome MIM#309500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | ABCD1 | Crystle Lee reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983253; Phenotypes: Adrenoleukodystrophy, MIM#300100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | EVC | Ee Ming Wong reviewed gene: EVC: Rating: GREEN; Mode of pathogenicity: None; Publications: 23220543; Phenotypes: Ellis-van Creveld syndrome, MIM# 225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | ERCC2 | Ee Ming Wong reviewed gene: ERCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301571, 32047639, 33369099; Phenotypes: Cerebrooculofacioskeletal syndrome 2, MIM# 610756, Trichothiodystrophy 1, photosensitive, MIM# 601675, Xeroderma pigmentosum, group D, MIM# 278730; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | EPCAM | Ee Ming Wong reviewed gene: EPCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340; Phenotypes: Diarrhea 5, with tufting enteropathy, congenital, MIM# 613217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | DYNC2LI1 | Ee Ming Wong reviewed gene: DYNC2LI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33030252; Phenotypes: Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.287 | LCAT |
Lauren Rogers changed review comment from: Well established gene-disease association. A disorder of lipoprotein metabolism that causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure. Onset is generally in adulthood; to: Well established gene-disease association. A disorder of lipoprotein metabolism that causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure. Onset/diagnosis is generally in adulthood |
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| Prepair 1000+ v1.262 | CFH |
Lilian Downie Added comment: Comment when marking as ready: This deficiency, with biallelic form can cause atypical hemolytic uremic syndrome (HUS), type II or III membranoproliferative glomerulonephritis (MPGN) and increased susceptibility to meningicoccal infection. Can be early onset and severe requiring renal transplant. Variable expression Gene also known as HF1 |
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| Prepair 1000+ v1.256 | FREM1 | Lilian Downie Phenotypes for gene: FREM1 were changed from Bifid nose with or without anorectal and renal anomalies, 608980 (3) to Manitoba oculotrichoanal syndrome MIM# 248450; Bifid nose with or without anorectal and renal anomalies, MIM# 608980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.248 | FREM1 | Marta Cifuentes Ochoa reviewed gene: FREM1: Rating: ; Mode of pathogenicity: None; Publications: 32016392, 21931569, 21507892, 19732862, 20301721, 28111185, 19732862; Phenotypes: Manitoba oculotrichoanal syndrome MIM# 248450, Bifid nose with or without anorectal and renal anomalies, MIM# 608980, oculotrichoanal syndrome MONDO:0009560, BNAR syndrome MONDO:0012165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.248 | GNE |
Andrew Coventry changed review comment from: Nonaka myopathy - Well established gene disease relationship. However, age of onset of myopathy reported to usually occur between age 20 and 40. Marginal for childhood onset condition. Thrombocytopenia - well reported association of affected individuals experiencing bleeding episodes that commence from neonatal to early childhood. Myopathy variably reported in those affected - possibly due to young age of individuals presenting with bleeding symptoms. Myopathy, when reported, occurs at similar age of onset to Nonaka. Publication (25257349) indicates myopathy onset in affected sibs at mid-late teens. Also reported renal complications at age 7. Mouse model for GNE knockout shows renal involvement (PMID: 17549255). Condition reported to have caused cerebral haemorrhages in neonatal period (PMID:29941673). Unsure if phenotypic variability of condition, and isolated bleeding phenotype (as in ClinGen) suitable or adequate for screening context.; to: Nonaka myopathy - Well established gene disease relationship. However, age of onset of myopathy reported to usually occur between age 20 and 40. Myopathy then progresses, usually over ~10 year period to then require wheelchair assistance for mobility. Severe condition but onset is marginal for childhood onset screening context. Thrombocytopenia - well reported association of affected individuals experiencing bleeding episodes that commence from neonatal to early childhood. Myopathy variably reported in those affected - possibly due to young age of individuals presenting with bleeding symptoms. Myopathy, when reported, occurs at similar age of onset to Nonaka. Publication (25257349) indicates myopathy onset in affected sibs at mid-late teens. Also reported renal complications at age 7. Mouse model for GNE knockout shows renal involvement (PMID: 17549255). Condition reported to have caused cerebral haemorrhages in neonatal period (PMID:29941673). Unsure if phenotypic variability of condition, and isolated bleeding phenotype (as in ClinGen) suitable or adequate for screening context. |
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| Prepair 1000+ v1.236 | CRTAP | Ee Ming Wong reviewed gene: CRTAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21955071, 19846465, 17192541; Phenotypes: Osteogenesis imperfecta, type VII MIM#610682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.236 | COQ8A | Ee Ming Wong reviewed gene: COQ8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32337771; Phenotypes: Coenzyme Q10 deficiency, primary, 4 MIM#612016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.236 | COQ6 | Ee Ming Wong reviewed gene: COQ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28125198; Phenotypes: Coenzyme Q10 deficiency, primary, 6 MIM#614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.236 | CHRNG | Ee Ming Wong reviewed gene: CHRNG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826520, 16826531, 22167768; Phenotypes: Escobar syndrome (MIM# 265000), Multiple pterygium syndrome, lethal type, (MIM# 253290); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.236 | CCDC8 | Ee Ming Wong reviewed gene: CCDC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21737058; Phenotypes: 3-M syndrome 3, MIM#614205; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.236 | CCDC114 | Ee Ming Wong reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.187 | CEP152 |
Marta Cifuentes Ochoa changed review comment from: Primary microcephaly (head circumference more than 3 standard deviations below the age- and sex-matched population mean). Causes Intellectual disability. Seckel syndrome is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical “bird-head” facial appearance. Established gene-disease association. Congenital onset, severe disorder HGNC approved symbol/name: CEP152 Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges? N Gene reported in >3 independent families; to: Primary microcephaly (head circumference more than 3 standard deviations below the age- and sex-matched population mean). Causes Intellectual disability. Seckel syndrome is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, facial dysmorphic features. Established gene-disease association. Congenital onset, severe disorder HGNC approved symbol/name: CEP152 Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges? N Gene reported in >3 independent families |
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| Prepair 1000+ v1.159 | HBA2 |
Andrew Coventry changed review comment from: Well established and strong gene-disease association. Alpha-thalassemia result in anaemias from early childhood when fetal haemoglobin expression is diminished. Haemoglobinopathies of alpha-globin can result from variants at either of the 2 alpha-globin loci, HBA1 or HBA2. Subtypes: Haemoglobin H disease is a subtype of alpha-thalassemia: Deletional' Hb H disease is caused by the combination of alpha(0)-thalassemia with deletional alpha(+)-thalassemia. Deletional Haemoglobin H - phenotypic variability ranging from asymptomatic, to needing periodic transfusions, to severe anaemia with haemolysis and hepatosplenomegaly, to fatal hydrops fetalis in utero. Variable age of onset and features - see PMID: 21345100 'Nondeletional' Hb H disease is caused by an alpha(0)-thalassemia plus an alpha(+)-thalassemia point mutation or small insertion/deletion. Disease phenotype is usually are greater levels of anaemia, more symptomatic, more likely to have significant hepatosplenomegaly, and greater likelihood to require transfusions. Note: Deletions are well known and frequent cause of these alpha thalassemia phenotypes and subtypes. Diverse range of non-deletional HBA2 variants also described. Possible technological challenge due to deletions which are prevalent.; to: Well established gene-disease association. The alpha-thalassemia phenotype ranges from asymptomatic to lethal. The severity of the disorder is usually well correlated with the number of non-functional copies of the alpha-globin genes (HBA1/HBA2). Gene function can be lost by deletion, or by SNVs (total loss or partial).The clinically relevant forms of alpha-thalassemia usually involve alpha(0)-thalassemia, either coinherited with alpha(+)-thalassemia and resulting in HbH disease, or inherited from both parents and resulting in haemoglobin Bart hydrops fetalis. Note: Deletions are well known and frequent cause of these alpha thalassemia phenotypes and subtypes. Diverse range of non-deletional HBA2 variants also described. Possible technological challenge due to deletions which are prevalent. |
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| Prepair 1000+ v1.143 | CSMD1 |
Krithika Murali gene: CSMD1 was added gene: CSMD1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD1 were set to PMID:38816421 Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: CSMD1 was set to GREEN Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected. Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP. Sources: Literature |
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| Prepair 1000+ v1.123 | ARMC4 | Lilian Downie Added comment: Comment when marking as ready: Primary ciliary dyskinesia-23 is an autosomal recessive disorder resulting from defective ciliary motility. Affected individuals have respiratory distress and recurrent upper and lower airway infections, and they often develop bronchiectasis. About 50% of patients have situs inversus or laterality defects. Ultrastructural analysis of respiratory cilia shows defects in the outer dynein arm | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | ATP8A2 | Ee Ming Wong reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 31612321; Phenotypes: Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4 (MIM#615268); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | ATOH7 | Ee Ming Wong reviewed gene: ATOH7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22068589, 22645276, 31696227, 11493566, 11493566; Phenotypes: Persistent hyperplastic primary vitreous, autosomal recessive, MIM# 221900, microphthalmia, cataract, glaucoma, congenital retinal nonattachment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | ATAD1 | Ee Ming Wong reviewed gene: ATAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28180185, 29390050, 29659736; Phenotypes: Hyperekplexia 4, MIM#618011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | ARSA | Ee Ming Wong reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25987178, 23348427, 33195324; Phenotypes: Metachromatic leukodystrophy, MIM# 250100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | AKR1D1 | Ee Ming Wong reviewed gene: AKR1D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12970144, 20522910, 30373615; Phenotypes: Bile acid synthesis defect, congenital, 2, MIM# 235555; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | ADAMTS2 | Ee Ming Wong reviewed gene: ADAMTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 26765342, 28306229; Phenotypes: Ehlers-Danlos syndrome, dermatosparaxis type (MIM# 225410); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | CYP17A1 | Andrew Coventry changed review comment from: Established gene-disease association. Congenital onset. More than 100 families reported. Mechanism impacts hormone production in gonads and adrenal glands. Phenotype typically includes hypertension, low blood potassium, and abnormal development of sexual characteristics including genitalia (disorder of sexual development) in both males and females. Phenotypic spectrum for those affected is variable.; to: Established gene-disease association. Congenital onset. More than 100 families reported. Mechanism impacts hormone production in gonads and adrenal glands. Phenotype typically includes hypertension, low blood potassium, and abnormal development of sexual characteristics including genitalia (disorder of sexual development) in both males and females. Phenotypic spectrum of severity for those affected is variable. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.76 | CYP11A1 | Andrew Coventry reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12161514 16705068 18182448 28425981; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete MIM#613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.76 | ADAT3 |
Cassandra Muller changed review comment from: 20+ unrelated Arab families reported in the literature with the same homozygous missense variant in this gene causing intellectual disability (p.(Val128Met)) Other features can include microcephaly, growth failure, epilepsy.; to: 20+ unrelated Arab families reported in the literature with the same homozygous missense variant in this gene causing intellectual disability (p.(Val128Met)). One known family with a different variant in the same gene. Other features can include microcephaly, growth failure, epilepsy. |
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| Prepair 1000+ v1.65 | CLCNKB |
Lucy Spencer changed review comment from: Is the phenotype(s) severe and onset <18yo? YES. CLCNKB mutations cause Bartter syndrome type 3 also called classic Bartter syndrome with renal salt wasting, hypokalemia, metabolic alkalosis, polyuria, polydipsia, and failure to thrive. It typically manifests in early childhood but late childhood or adulthood onset cases have been reported. Classic Bartter syndrome has a heterogeneous presentation from severe to very mild (PMIDs: 25810436, 24965226) There is also a digenic inheritance known for this gene with variants in CLCNKA causing Bartter syndrome type 4b.; to: Is the phenotype(s) severe and onset <18yo? YES. CLCNKB mutations cause Bartter syndrome type 3 also called classic Bartter syndrome with renal salt wasting, hypokalemia, metabolic alkalosis, polyuria, polydipsia, and failure to thrive. It typically manifests in early childhood but late childhood or adulthood onset cases have been reported. Classic Bartter syndrome has a heterogeneous presentation from severe to very mild (PMIDs: 25810436, 24965226) There is also a digenic inheritance known for this gene with variants in CLCNKA causing Bartter syndrome type 4b. |
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| Prepair 1000+ v1.61 | ALDH3A2 | Zornitza Stark Phenotypes for gene: ALDH3A2 were changed from Sjogren-Larsson syndrome, 270200 (3) to Sjogren-Larsson syndrome (MIM#270200) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.60 | ALDH3A2 | Zornitza Stark reviewed gene: ALDH3A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Sjogren-Larsson syndrome (MIM#270200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.35 | ATP6V1B1 | Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from Renal tubular acidosis with deafness, 267300 (3) to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.10 | IL1RN | Zornitza Stark Phenotypes for gene: IL1RN were changed from Interleukin 1 receptor antagonist deficiency, 612852 (3) to Interleukin 1 receptor antagonist deficiency, MIM# 612852; Chronic recurrent multifocal osteomyelitis 2, with periostitis and pustulosis, MIM# 61285 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.9 | AGL | Marta Cifuentes Ochoa commented on gene: AGL: Current Treatment high-fat, high-protein and low-carbohydrate diet with cornstarch supplementation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.9 | IL1RN | Lauren Rogers reviewed gene: IL1RN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Interleukin 1 receptor antagonist deficiency, MIM# 612852, Chronic recurrent multifocal osteomyelitis 2, with periostitis and pustulosis, MIM# 61285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.9 | ALDH3A2 | Lucy Spencer reviewed gene: ALDH3A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Sjogren-Larsson syndrome (MIM#270200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.7 | ACY1 | Marta Cifuentes Ochoa reviewed gene: ACY1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16274666, 16465618, 17562838, 24117009, 37523070, 29653693, 26686503; Phenotypes: Aminoacylase 1 deficiency, MIM# 609924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.7 | ATP6V1B1 | Lauren Rogers reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | TANGO2 | Seb Lunke Added phenotypes Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration for gene: TANGO2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | STAR | Seb Lunke Added phenotypes Lipoid adrenal hyperplasia, 201710 (3) for gene: STAR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | PQBP1 | Seb Lunke Added phenotypes Renpenning syndrome, 309500 (3) for gene: PQBP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | LRPPRC | Seb Lunke Added phenotypes Leigh syndrome, French-Canadian type, 220111 (3) for gene: LRPPRC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | CYP11A1 | Seb Lunke Added phenotypes Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743 (3) for gene: CYP11A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | ATP6V1B1 | Seb Lunke Added phenotypes Renal tubular acidosis with deafness, 267300 (3) for gene: ATP6V1B1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | ALDH3A2 | Seb Lunke Added phenotypes Sjogren-Larsson syndrome, 270200 (3) for gene: ALDH3A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | ABCD1 | Seb Lunke Added phenotypes Adrenoleukodystrophy, 300100 (3) for gene: ABCD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1 | AMN |
Crystle Lee gene: AMN was added gene: AMN was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: AMN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AMN were set to Imerslund-Grasbeck syndrome 2 (MIM#618882) Review for gene: AMN was set to AMBER Added comment: Well established gene-disease association. Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anaemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Clinical features include failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Sources: Literature |
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| Prepair 1000+ v1.0 | BRIP1 |
Himanshu Goel gene: BRIP1 was added gene: BRIP1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: BRIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BRIP1 were set to 16116423 Phenotypes for gene: BRIP1 were set to Fanconi Anaemia Penetrance for gene: BRIP1 were set to Complete Mode of pathogenicity for gene: BRIP1 was set to Other Review for gene: BRIP1 was set to GREEN gene: BRIP1 was marked as current diagnostic Added comment: Sources: Literature |
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| Prepair 1000+ v0.168 | HERC2 |
Crystle Lee edited their review of gene: HERC2: Added comment: Mapping issues reviewed: Majority of exons in this gene are well covered and there is no evidence of any recurrent variants. Insufficient mapping issues to exclude gene. Note: most SNVs reported as VUS. Lots of multigenic CNVs reported.; Changed rating: GREEN |
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| Prepair 1000+ v0.145 | CYP21A2 | Zornitza Stark reviewed gene: CYP21A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (MIM#201910); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v0.144 | CYP11B1 | Zornitza Stark reviewed gene: CYP11B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency (MIM#202010); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v0.85 | SLC12A3 |
Crystle Lee gene: SLC12A3 was added gene: SLC12A3 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: SLC12A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC12A3 were set to 8528245; 11102542 Phenotypes for gene: SLC12A3 were set to Gitelman syndrome (MIM#263800) Review for gene: SLC12A3 was set to AMBER Added comment: Gitelman syndrome is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most individuals have onset of symptoms as adults, but some can present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis. Well established gene-disease association. Sources: Literature |
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| Prepair 1000+ v0.85 | PYGM |
Crystle Lee gene: PYGM was added gene: PYGM was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: PYGM was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PYGM were set to McArdle disease (MIM#232600) Review for gene: PYGM was set to AMBER Added comment: Gene-disease association for bi-allelic variants is well established. McCardle disease: glycogen storage disease type V (GSD5), characterized by onset of exercise intolerance and muscle cramps in childhood or adolescence. Transient myoglobinuria may occur after exercise, due to rhabdomyolysis. Severe myoglobinuria may lead to acute renal failure. Patients may report muscle weakness, myalgia, and lack of endurance since childhood or adolescence. Later in adult life, there is persistent and progressive muscle weakness and atrophy with fatty replacement. McArdle disease is a relatively benign disorder, except for possible renal failure as a complication of myoglobinuria Clinical heterogeneity exists; about 10% of all affected individuals have mild manifestations (e.g., fatigue or poor stamina without contractures) and remain virtually asymptomatic during daily activities of living(Gene Reviews) Sources: Literature |
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| Prepair 1000+ v0.61 | GJB1 |
Crystle Lee gene: GJB1 was added gene: GJB1 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: GJB1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: GJB1 were set to Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 (MIM#302800) Review for gene: GJB1 was set to AMBER Added comment: CMTX has both demyelinating and axonal features. Well established gene-disease association, over 100 families reported. Variable phenotype with incomplete penetrance (OMIM) PMID 31842800: Three unrelated males with GJB1 variants and recurrent episodes of reversible posterior leukoencephalopathy reported. Sources: Literature |
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| Prepair 1000+ v0.61 | CYP21A2 |
Crystle Lee gene: CYP21A2 was added gene: CYP21A2 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: CYP21A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP21A2 were set to Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (MIM#201910) Review for gene: CYP21A2 was set to RED Added comment: Well established gene-disease association. Pseudogene and structural variants make NGS data difficult to interpret. Not suitable for inclusion in a carrier screening panel due to technical reasons Sources: Literature |
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| Prepair 1000+ v0.61 | CYP11B1 |
Crystle Lee gene: CYP11B1 was added gene: CYP11B1 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: CYP11B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP11B1 were set to 8768848 Phenotypes for gene: CYP11B1 were set to Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency (MIM#202010) Review for gene: CYP11B1 was set to AMBER Added comment: CAH due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. Well established gene-disease association. Sources: Literature |
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| Prepair 1000+ v0.61 | CERKL |
Crystle Lee changed review comment from: More than 20 families reported, though some variants are recurrent (founder). This gene causes nonsyndromic retinal disease. Highly variable age of onset (7-45 years) and severity. There is also evidence of phenotypic intra- and inter-familial variability between patients with the same genotype. Sources: Literature; to: More than 20 families reported, though some variants are recurrent (founder). This gene causes nonsyndromic retinal disease. Highly variable age of onset (7-45 years) and severity. There is also evidence of phenotypic intra- and inter-familial variability between patients with the same genotype. Sources: Literature |
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| Prepair 1000+ v0.61 | CERKL |
Crystle Lee gene: CERKL was added gene: CERKL was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: CERKL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CERKL were set to 33322828 Phenotypes for gene: CERKL were set to Retinitis pigmentosa 26 (MIM#608380) Review for gene: CERKL was set to RED Added comment: More than 20 families reported, though some variants are recurrent (founder). This gene causes nonsyndromic retinal disease. Highly variable age of onset (7-45 years) and severity. There is also evidence of phenotypic intra- and inter-familial variability between patients with the same genotype. Sources: Literature |
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| Prepair 1000+ v0.50 | PROC |
Crystle Lee changed review comment from: Gene is associated AD and AR thrombophilia 3 due to protein C deficiency AR form of condition is associated with variable severity and occasional late-onset of symptoms with homozygosity Heterozygous 'carriers' of pathogenic variants in the PROC gene are said to have mild protein C deficiency which is often asymptomatic, but may involve recurrent venous thrombosis. Difficult to define penetrance as represents risk factor for thrombophilia. Challenge in interpretation and reporting in a carrier screening context; to: Gene is associated AD and AR thrombophilia 3 due to protein C deficiency AR form of condition is associated with variable severity and occasional late-onset of symptoms with homozygosity Heterozygous 'carriers' of pathogenic variants in the PROC gene are said to have mild protein C deficiency which is often asymptomatic, but may involve recurrent venous thrombosis. Difficult to define penetrance as represents risk factor for thrombophilia. Challenge in interpretation and reporting in a carrier screening context |
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| Prepair 1000+ v0.0 | VPS33B |
Zornitza Stark gene: VPS33B was added gene: VPS33B was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: VPS33B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VPS33B were set to Arthrogryposis, renal dysfunction, and cholestasis 1, 208085 (3) |
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| Prepair 1000+ v0.0 | VIPAS39 |
Zornitza Stark gene: VIPAS39 was added gene: VIPAS39 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction, and cholestasis 2, 613404 (3) |
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| Prepair 1000+ v0.0 | TBX19 |
Zornitza Stark gene: TBX19 was added gene: TBX19 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: TBX19 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBX19 were set to Adrenocorticotropic hormone deficiency, 201400 (3) |
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| Prepair 1000+ v0.0 | TANGO2 |
Zornitza Stark gene: TANGO2 was added gene: TANGO2 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration |
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| Prepair 1000+ v0.0 | STAR |
Zornitza Stark gene: STAR was added gene: STAR was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STAR were set to Lipoid adrenal hyperplasia, 201710 (3) |
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| Prepair 1000+ v0.0 | SLC4A4 |
Zornitza Stark gene: SLC4A4 was added gene: SLC4A4 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SLC4A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC4A4 were set to Renal tubular acidosis, proximal, with ocular abnormalities, 604278 (3) |
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| Prepair 1000+ v0.0 | SLC4A1 |
Zornitza Stark gene: SLC4A1 was added gene: SLC4A1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SLC4A1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC4A1 were set to Renal tubular acidosis, distal, AR, 611590 (3) |
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| Prepair 1000+ v0.0 | SIL1 |
Zornitza Stark gene: SIL1 was added gene: SIL1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SIL1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SIL1 were set to Marinesco-Sjogren syndrome, 248800 (3) |
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| Prepair 1000+ v0.0 | SCARB2 |
Zornitza Stark gene: SCARB2 was added gene: SCARB2 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure, 254900 (3) |
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| Prepair 1000+ v0.0 | SARS2 |
Zornitza Stark gene: SARS2 was added gene: SARS2 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, 613845 (3) |
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| Prepair 1000+ v0.0 | RRM2B |
Zornitza Stark gene: RRM2B was added gene: RRM2B was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: RRM2B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RRM2B were set to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075 (3) |
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| Prepair 1000+ v0.0 | REN |
Zornitza Stark gene: REN was added gene: REN was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: REN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: REN were set to Renal tubular dysgenesis, 267430 (3) |
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| Prepair 1000+ v0.0 | PQBP1 |
Zornitza Stark gene: PQBP1 was added gene: PQBP1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: PQBP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: PQBP1 were set to Renpenning syndrome, 309500 (3) |
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| Prepair 1000+ v0.0 | POMC |
Zornitza Stark gene: POMC was added gene: POMC was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: POMC was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POMC were set to Obesity, adrenal insufficiency, and red hair due to POMC deficiency, 609734 (3) |
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| Prepair 1000+ v0.0 | NEK8 |
Zornitza Stark gene: NEK8 was added gene: NEK8 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: NEK8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NEK8 were set to Renal-hepatic-pancreatic dysplasia 2, 615415 (3), Autosomal recessive |
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| Prepair 1000+ v0.0 | MYD88 |
Zornitza Stark gene: MYD88 was added gene: MYD88 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: MYD88 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MYD88 were set to Pyogenic bacterial infections, recurrent, due to MYD88 deficiency, 612260 (3) |
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| Prepair 1000+ v0.0 | LRPPRC |
Zornitza Stark gene: LRPPRC was added gene: LRPPRC was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: LRPPRC was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LRPPRC were set to Leigh syndrome, French-Canadian type, 220111 (3) |
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| Prepair 1000+ v0.0 | LPIN1 |
Zornitza Stark gene: LPIN1 was added gene: LPIN1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: LPIN1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LPIN1 were set to Myoglobinuria, acute recurrent, autosomal recessive, 268200 (3) |
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| Prepair 1000+ v0.0 | FREM1 |
Zornitza Stark gene: FREM1 was added gene: FREM1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: FREM1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FREM1 were set to Bifid nose with or without anorectal and renal anomalies, 608980 (3) |
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| Prepair 1000+ v0.0 | DOCK8 |
Zornitza Stark gene: DOCK8 was added gene: DOCK8 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: DOCK8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DOCK8 were set to Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700 (3) |
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| Prepair 1000+ v0.0 | CYP11A1 |
Zornitza Stark gene: CYP11A1 was added gene: CYP11A1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: CYP11A1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP11A1 were set to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743 (3) |
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| Prepair 1000+ v0.0 | CLDN19 |
Zornitza Stark gene: CLDN19 was added gene: CLDN19 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: CLDN19 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CLDN19 were set to Hypomagnesemia 5, renal, with ocular involvement, 248190 (3) |
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| Prepair 1000+ v0.0 | CA2 |
Zornitza Stark gene: CA2 was added gene: CA2 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, 259730 (3) |
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| Prepair 1000+ v0.0 | ATP6V1B1 |
Zornitza Stark gene: ATP6V1B1 was added gene: ATP6V1B1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ATP6V1B1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP6V1B1 were set to Renal tubular acidosis with deafness, 267300 (3) |
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| Prepair 1000+ v0.0 | ATP6V0A4 |
Zornitza Stark gene: ATP6V0A4 was added gene: ATP6V0A4 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ATP6V0A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP6V0A4 were set to Renal tubular acidosis, distal, autosomal recessive, 602722 (3) |
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| Prepair 1000+ v0.0 | ALDH3A2 |
Zornitza Stark gene: ALDH3A2 was added gene: ALDH3A2 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome, 270200 (3) |
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| Prepair 1000+ v0.0 | AGT |
Zornitza Stark gene: AGT was added gene: AGT was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AGT were set to Renal tubular dysgenesis, 267430 (3) |
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| Prepair 1000+ v0.0 | ACE |
Zornitza Stark gene: ACE was added gene: ACE was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACE were set to Renal tubular dysgenesis, 267430 (3) |
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| Prepair 1000+ v0.0 | ABCD1 |
Zornitza Stark gene: ABCD1 was added gene: ABCD1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ABCD1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: ABCD1 were set to Adrenoleukodystrophy, 300100 (3) |
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