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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+ v1.2032 | LRSAM1 | Lilian Downie Added comment: Comment when marking as ready: Only single AR family reported, insufficient evidence, downgrade to RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1956 | VKORC1 | Lilian Downie Added comment: Comment when marking as ready: Single homozygous missense variant, Arg98Trp reported to cause the AR phenotype (PMID: 12704386). (ClinGen 2023) This phenotype causes intracranial haemmorhage in the first weeks of life and ongoing bleeding predisposition but this is reversed with vit K administration so highly treatable. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | SEC23A |
Melanie Marty changed review comment from: SEC23A is an essential component of coat protein complex II (COPII)-coated vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex. Boyadjiev et al 2006 (PMID:16980979): One family was reported with a homozygous missense variant and craniolenticulosutural dysplasia (CLSD), with some functional studies supporting pathogenicity. Boyadjiev et al 2011 (PMID: 21039434): The same authors as above later reported another individual with similar phenotype with a paternally inherited heterozygous missense variant, this variant has 91 hets in gnomAD and the father was unaffected. They suggest digenic inheritance but found no other variants in 3 candidate genes. Wang et al 2023 (PMID: 37828500): 2 x compound heterozygous missense variants were identified in a patient with CLSD. Cisarova et al 2022 (PMID: 34580982) 1 x patient with het missense variant inherited from his affected father. Shown to be de novo in the father. Minale et al 2024 (PMID: 38275611): 1 x patient with de novo het missense variant Zebrafish models lend some support to the gene-disease association (PMID:16980979, 16980978) Summary: 2 reports of AR inheritance, 2 reports of AD inheritance, 1 uncertain; to: SEC23A is an essential component of coat protein complex II (COPII)-coated vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex. Boyadjiev et al 2006 (PMID:16980979): One family was reported with a homozygous missense variant and craniolenticulosutural dysplasia (CLSD), with some functional studies supporting pathogenicity. Boyadjiev et al 2011 (PMID: 21039434): The same authors as above later reported another individual with similar phenotype with a paternally inherited heterozygous missense variant, this variant has 91 hets in gnomAD and the father was unaffected. They suggest digenic inheritance but found no other variants in 3 candidate genes. Wang et al 2023 (PMID: 37828500): 2 x compound heterozygous missense variants were identified in a patient with CLSD. Cisarova et al 2022 (PMID: 34580982) 1 x patient with CLSD and a het missense variant inherited from his affected father. Shown to be de novo in the father. Minale et al 2024 (PMID: 38275611): 1 x patient with CLSD and a de novo het missense variant Zebrafish models lend some support to the gene-disease association (PMID:16980979, 16980978) Summary: 2 reports of AR inheritance, 2 reports of AD inheritance, 1 uncertain |
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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 | CHMP1A |
Andrew Coventry gene: CHMP1A was added gene: CHMP1A was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: CHMP1A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHMP1A were set to 23023333; 37789895 Phenotypes for gene: CHMP1A were set to Pontocerebellar hypoplasia, type 8 MIM#614961 Review for gene: CHMP1A was set to AMBER Added comment: Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterised by severe psychomotor impediment, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum. Zebrafish model present. PMID: 23023333 - Three families reported, 2 variants; two families likely with founder effect. PMID: 37789895 - describe novel variants in an affected individual, one is deletion of exon 1, other is c.53 T > C (p.Leu18Pro). Total 4 families now reported with 4 variants. 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 | COL11A2 |
Melanie Marty changed review comment from: The gene-disease association with otospondylomegaepiphyseal dysplasia is well established (DEFINITIVE) by ClinGen, and deafness is part of the phenotype, both mono-allelic and bi-allelic variants are reported. Otospondylomegaepiphyseal dysplasia AD (OSMED, MIM#184840) is also known as non-ocular Stickler syndrome or Type III Stickler syndrome. There are also a number of reports of mono-allelic and bi-allelic variants associated with isolated deafness (PMIDs: 10581026;25633957;16033917), and rated as MODERATE by ClinGen for AR and DEFINITIVE for AD. Bi-allelic variants are associated with severe pre lingual deafness. Fibrochondrogenesis 2 a severe skeletal dysplasia is associated with AD and AR.; to: The gene-disease association with otospondylomegaepiphyseal dysplasia is well established (DEFINITIVE) by ClinGen, and deafness is part of the phenotype, both mono-allelic and bi-allelic variants are reported. Otospondylomegaepiphyseal dysplasia AD (OSMED, MIM#184840) is also known as non-ocular Stickler syndrome or Type III Stickler syndrome. There are also a number of reports of mono-allelic and bi-allelic variants associated with isolated deafness (PMIDs: 10581026;25633957;16033917), and rated as MODERATE by ClinGen for AR and DEFINITIVE for AD. Bi-allelic variants are associated with severe pre lingual deafness. Fibrochondrogenesis 2 a severe skeletal dysplasia is associated with AD and AR. Only including the AR phenotypes for this screening panel. |
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| Prepair 1000+ v1.1826 | LRSAM1 |
Melanie Marty changed review comment from: Only a single family reported with recessive inheritance. Over 30 families reported with dominant disease. Age of onset typically between the second and fifth decades of life. Marking as red for carrier screening due to age of onset and limited evidence for recessive disease.; to: Only a single family reported with recessive inheritance. Over 30 families reported with dominant disease. Age of onset typically between the second and fifth decades of life. Peak age of onset in second decade (range childhood to 76 years) (OMIM). Marking as red for carrier screening due to age of onset and limited evidence for recessive disease. |
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| Prepair 1000+ v1.1826 | LRSAM1 |
Melanie Marty changed review comment from: Only a single family reported with recessive inheritance. Over 30 families reported with dominant disease. Age of onset typically between the second and fifth decades of life.; to: Only a single family reported with recessive inheritance. Over 30 families reported with dominant disease. Age of onset typically between the second and fifth decades of life. Marking as red for carrier screening due to age of onset and limited evidence for recessive disease. |
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| Prepair 1000+ v1.1822 | CLN3 | Lilian Downie Added comment: Comment when marking as ready: Consider exclusion (Amber) as we will miss a high proportion of cases due to the founder variant being a 1kb deletion | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | SCO1 |
Andrew Coventry changed review comment from: Four unrelated families reported, typically presenting with lactatic acidosis and encephalopathy in infancy. SCO1 pathogenic variants were first described in an infant with respiratory distress, metabolic acidosis, hepatic failure, and encephalopathy in the setting of profound complex IV deficiency in muscle and liver. Further reports have shown phenotypic spectrum to include cardiomyopathy, encephalopathy, and lactic acidosis without cardiac or hepatic involvement. Many cases are fatal in the first few months of life. Functional studies and model organisms also present. ClinGen: While various names have been given to the constellation of features seen in those with SCO1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SCO1 phenotype has been lumped into one disease entity. Sources: Literature; to: Six unrelated families reported. Typically presenting with lactatic acidosis and encephalopathy in infancy. SCO1 pathogenic variants were first described in an infant with respiratory distress, metabolic acidosis, hepatic failure, and encephalopathy in the setting of profound complex IV deficiency in muscle and liver. Further reports have shown phenotypic spectrum to include cardiomyopathy, encephalopathy, and lactic acidosis without cardiac or hepatic involvement. Many cases are fatal in the first few months of life. Functional studies and model organisms also present. ClinGen: While various names have been given to the constellation of features seen in those with SCO1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SCO1 phenotype has been lumped into one disease entity. PMID: 39214134: 3 cases from 2 unrelated families, with developmental and epileptic encephalopathy, hypopituitarism. |
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| Prepair 1000+ v1.1811 | SCO1 |
Andrew Coventry gene: SCO1 was added gene: SCO1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: SCO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCO1 were set to 11013136; 19295170; 31352446; 23878101 Phenotypes for gene: SCO1 were set to Mitochondrial disease MONDO:0044970; Mitochondrial complex IV deficiency, nuclear type 4 MIM#619048 Review for gene: SCO1 was set to GREEN Added comment: Four unrelated families reported, typically presenting with lactatic acidosis and encephalopathy in infancy. SCO1 pathogenic variants were first described in an infant with respiratory distress, metabolic acidosis, hepatic failure, and encephalopathy in the setting of profound complex IV deficiency in muscle and liver. Further reports have shown phenotypic spectrum to include cardiomyopathy, encephalopathy, and lactic acidosis without cardiac or hepatic involvement. Many cases are fatal in the first few months of life. Functional studies and model organisms also present. ClinGen: While various names have been given to the constellation of features seen in those with SCO1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SCO1 phenotype has been lumped into one disease entity. 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 | MTPAP |
Andrew Coventry gene: MTPAP was added gene: MTPAP was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: MTPAP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTPAP were set to 20970105; 33340416; 32376682; 15769737; 31779033; 35235001; 27391121 Phenotypes for gene: MTPAP were set to Mitochondrial disease MONDO:0044970 Review for gene: MTPAP was set to GREEN Added comment: Definitive disease-gene classification by ClinGen - "Identified in five individuals from four publications (PMIDs: 20970105, 31779033, 35235001, 27391121). Supported by a biochemical function (mitochondrial translation) shared with other genes associated with primary mitochondrial disease, early embryonic lethality and failure of developmental progression in a knockout mouse model, and disrupted expression of mitochondrial proteins and mitochondrial dysfunction following gene knockdown in HeLa cells (PMIDs: 33340416, 32376682, 15769737)." Note that 6 individuals with spastic ataxia all had same founder variant and were traced as distantly related (Amish community - c.1432A>G (p.Asn478Asp). Further additional families reported with a much more severe phenotype of lethal encephalopathy. Phenotypes previous reported to be associated with MTPAP are likely to represent a continuum of severity associated with a mitochondrial disorder. Clingen "While various names have been given to the constellation of features seen in those with MTPAP-related disease, including autosomal recessive spastic ataxia 4 (SPAX4) (MIM 613672) in additional to other mitochondrial disorders, pathogenic variants in this gene cause a primary mitochondrial disease.... lumped into one disease entity..." 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+ v1.1656 | LRP5 | Zornitza Stark Phenotypes for gene: LRP5 were changed from Osteoporosis-pseudoglioma syndrome, 259770 (3) to Exudative vitreoretinopathy 4 MIM#601813; Osteoporosis-pseudoglioma syndrome MIM#259770 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1644 | LAMA1 | Zornitza Stark Phenotypes for gene: LAMA1 were changed from Poretti-Boltshauser syndrome, 615960 (3) to Poretti-Boltshauser syndrome, MIM #615960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1598 | TRIP11 |
Kate Scarff changed review comment from: Characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death. In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Described in >10 unrelated families Knockout mouse model PMID: 20089971 Deep intronic variants have been described PMID: 34057271, 34014608; to: ACG1A: Characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death. In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Described in >10 unrelated families Knockout mouse model PMID: 20089971 Deep intronic variants have been described PMID: 34057271, 34014608 Odontochondrodysplasia 1: non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. Variable severity. Null mutations of TRIP11 lead to ACG1A, while splicing/hypomorphic mutations cause ODCD (PMID: 34111908, 30728324). |
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| Prepair 1000+ v1.1598 | TMEM107 |
Kate Scarff changed review comment from: Ciliopathy 26518474: one patient with bilateral postaxial polydactyly in hands and feet, multiple tongue cysts, and several facial dysmorphic features including frontal narrowing, short palpebral fissures, flat nasal bridge, retrognathia, and low-set ears. Mutation was del Phe106. 26595381: one patient with OFD had homozygous missense variant, another patient with Joubert syndrome comp het for del Phe106 and a frameshift deletion. 26123494: Meckel–Gruber syndrome cases in this paper were defined on the basis of occipital encephalocele, perinatal lethality and either polydactyly or polycystic kidneys. Two individuals had a homozygous p.Ser92Cysfs*7 variant were identified. Unclear if we should also be reporting other phenotypes: ?Joubert syndrome 29/Meckel syndrome 13, MIM #617562; to: Ciliopathy 26518474: one patient with bilateral postaxial polydactyly in hands and feet, multiple tongue cysts, and several facial dysmorphic features including frontal narrowing, short palpebral fissures, flat nasal bridge, retrognathia, and low-set ears. Mutation was del Phe106. 26595381: one patient with OFD had homozygous missense variant, another patient with Joubert syndrome comp het for del Phe106 and a frameshift deletion. 26123494: Meckel–Gruber syndrome cases in this paper were defined on the basis of occipital encephalocele, perinatal lethality and either polydactyly or polycystic kidneys. Two individuals had a homozygous p.Ser92Cysfs*7 variant identified. OMIM denotes with a ? that for Joubert syndrome 29, MIM #617562, it indicates that the relationship between the phenotype and gene is provisional. |
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| Prepair 1000+ v1.1596 | RAB39B |
Kate Scarff changed review comment from: Characterised by intellectual disability with additional clinical features ranging from ASD, macrocephaly, seizures and/or early-onset parkinsonism. One family had ~45kb deletion encompassing RAB39B gene and the last three coding exons of CLIC2 (PMID 25434005). Unsure if Waisman syndrome 311510 is a distinct phenotype that should be reported, causes ID and Parkinson's (some juvenile PD).; to: Intellectual developmental disorder, X-linked 72; Characterised by intellectual disability with additional clinical features ranging from ASD, macrocephaly, seizures and/or early-onset parkinsonism. One family had ~45kb deletion encompassing RAB39B gene and the last three coding exons of CLIC2 (PMID 25434005). Waisman syndrome: neurologic disorder characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease (some juvenile PD). |
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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? 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+ v1.1596 | LARGE1 |
Kate Scarff changed review comment from: Condition includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), involves characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. Described in >4 unrelated families. Intragenic deletions have been reported (PMID: 17436019), as has an intragenic insertion/deletion (PMID: 21248746) Should other phenotype for this gene be included? Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, MIM #608840, causes muscle weakness, brain abnormalities, and intellectual disability but does not affect the eyes. Phenotype described in Mendeliome.; to: Muscular dystrophy with impaired intellectual development and structural brain abnormalities type A, 6, MIM #613154: Condition includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), involves characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. Described in >4 unrelated families. Intragenic deletions have been reported (PMID: 17436019), as has an intragenic insertion/deletion (PMID: 21248746) Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, MIM #608840: causes muscle weakness, structural brain abnormalities, and intellectual disability. |
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| Prepair 1000+ v1.1593 | EIF2AK4 | Lilian Downie Added comment: Comment when marking as ready: Downgrade to orange, onset is usually not until adulthood, teenage onset reported but usually 20's or later | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v1.1568 | IQSEC2 |
Karina Sandoval changed review comment from: De novo variants and PTCs in females are severe, while inherited missense are milder. Females with these missense may be asymptomatic or show mild intellectual disability (PMID: 31415821). Autistic features are common. Missense can be both GOF or LOF. More than 20 unrelated families reported.; to: De novo variants and PTCs in females are severe, while inherited missense are milder. Females with these missense may be asymptomatic or show mild intellectual disability (PMID: 31415821). Autistic features are common. Missense can be both GOF or LOF. More than 20 unrelated families reported. ClinGen: Definitive gene-disease association - The affected individuals, including both males and females, typically have intellectual disability with variable seizures, autistic traits, and psychiatric problems. Males are generally more severely affected compared with females. |
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| Prepair 1000+ v1.1568 | EIF2AK4 |
Karina Sandoval changed review comment from: Slowly progressive and ultimately fatal without a lung transplant. Age of onset in 3rd decade. Pulmonary hypertension is a feature of the condition Severe; yes. Early onset; ? PMID:24135949 - 2 affected sibs, aged 19y & 33y at diagnosis. And 2x sporadic cases at 22y & 15y PMID: 24292273 - 13 families with 19 affected individuals. Age of PVOD diagnosis 3x 2nd decade (aged 11, 15 & 19), 9x 3rd decade, 4x 4th decade, 2x 5th decade, 1x 6th decade; to: Slowly progressive and ultimately fatal without a lung transplant. Age of onset in 3rd decade. Pulmonary hypertension is a feature of the condition Well established gene-disease assoc. Severe; yes. Early onset; varies PMID:24135949 - 2 affected sibs, aged 19y & 33y at diagnosis. And 2x sporadic cases at 22y & 15y PMID: 24292273 - 13 families with 19 affected individuals. Age of PVOD diagnosis 3x 2nd decade (aged 11, 15 & 19), 9x 3rd decade, 4x 4th decade, 2x 5th decade, 1x 6th decade |
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| Prepair 1000+ v1.1566 | LAMA1 | Kate Scarff reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24013853, 25105227, 26932191; Phenotypes: Poretti-Boltshauser syndrome, MIM #615960; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1566 | SCNN1A |
Lauren Thomas changed review comment from: Well established gene-disease association. Childhood onset, potentially lethal salt wasting condition characterised by excess loss of salt in the urine and high concentrations of sodium in sweat, stool, and saliva. Treatment for this condition involves aggressive salt replacement and control of hyperkalemia. HGNC approved symbol/name: SCNN1A Is the phenotype(s) severe and onset <18yo? Yes Treatments available: Yes, supplementary sodium, but not mineralocorticoids Known technical challenges? No Gene reported in 3 independent families: Yes; to: Well established gene-disease association. Childhood onset, potentially lethal salt wasting condition characterised by excess loss of salt in the urine and high concentrations of sodium in sweat, stool, and saliva. Treatment for this condition involves aggressive salt replacement and control of hyperkalemia. HGNC approved symbol/name: SCNN1A Is the phenotype(s) severe and onset <18yo? Yes Treatments available: Yes, supplementary sodium, but not mineralocorticoids Known technical challenges? No Gene reported in 3 independent families: Yes NOTE: Limited evidence for association between mono-allelic variants and disease (bronchiectasis with or without elevated sweat chloride 2, MIM# 613021; Liddle syndrome 3, MIM# 618126) |
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| Prepair 1000+ v1.1566 | PLEC |
Lauren Thomas changed review comment from: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950; to: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950 |
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| Prepair 1000+ v1.1566 | PLEC |
Lauren Thomas changed review comment from: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950; to: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950 |
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| Prepair 1000+ v1.1566 | SLC6A5 |
Andrew Coventry changed review comment from: Affected individuals cab present with neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. In some cases, symptoms resolved in the first year of life (PMID: 16751771). Well established gene-disease association, especially for bi-allelic variants, including animal model. AD association also reported, however, limited evidence in literature for mono-allelic cause of disease.; to: Affected individuals can present with neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. In some cases, symptoms resolved in the first year of life (PMID: 16751771). Well established gene-disease association, especially for bi-allelic variants, including animal model. AD association also reported, however, limited evidence in literature for mono-allelic cause of disease. |
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| Prepair 1000+ v1.1480 | UROS | Zornitza Stark Phenotypes for gene: UROS were changed from Porphyria, congenital erythropoietic, 263700 (3) to Porphyria, congenital erythropoietic MIM#263700, cutaneous porphyria MONDO:0009902 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1460 | MED23 | Andrew Coventry changed review comment from: Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy is a syndromic intellectual disability, including early onset epilepsy, spasticity, microcephaly and, less frequently, delayed myelination and thin corpus callosum. Variants in MED23 have been reported in at least 11 affected individuals from at least 6 unrelated families. Congenital/early onset. Functional studies and animal models present.; to: Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy is a syndromic intellectual disability, including early onset epilepsy, spasticity, microcephaly and, less frequently, delayed myelination and thin corpus callosum. Variants in MED23 have been reported in at least 11 affected individuals from at least 6 unrelated families. Congenital/early onset. Functional studies and animal models present. Variants reported include nonsense and missense. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1460 | UROS | Marta Cifuentes Ochoa reviewed gene: UROS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30685241, 24027798, 28334762, 27512208, 34187847, 34828434, 15065102; Phenotypes: Porphyria, congenital erythropoietic MIM#263700, cutaneous porphyria MONDO:0009902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1460 | TRMU |
Marta Cifuentes Ochoa commented on gene: TRMU: Acute infantile liver failure resulting from variants in TRMU is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. HGNC approved symbol/name: TRMU Is the phenotype(s) severe and onset <18yo? Y Known technical challenges? N Gene reported in >3 independent families Yemenite Jewish founder variant, p.Tyr77His. |
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| Prepair 1000+ v1.1457 | MTHFR |
Lauren Thomas changed review comment from: Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. HGNC approved symbol/name: MTHFR Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes ; to: Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. HGNC approved symbol/name: MTHFR Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes NOTE: there are two very common variants in this gene that are not associated with severe disease (665C>T & 1286A>C) |
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| Prepair 1000+ v1.1456 | UGT1A1 | Zornitza Stark Phenotypes for gene: UGT1A1 were changed from Crigler-Najjar syndrome, type I, 218800 (3) to Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport); Crigler-Najjar syndrome, type I MIM#218800; Crigler-Najjar syndrome, type II MIM#606785 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1397 | UGT1A1 | Clare Hunt reviewed gene: UGT1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12983120, 37585628, 1734381, 5411133, 9413009; Phenotypes: Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport), Crigler-Najjar syndrome, type I MIM#218800, Crigler-Najjar syndrome, type II MIM#606785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1367 | MUT |
Lauren Thomas changed review comment from: Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. Variable severity and age of onset: • Infantile completely deficient (mut0) or non-B12-responsive (clbB) is the most common phenotype and presents during infancy. Infants are normal at birth, but develop lethargy, vomiting, and dehydration within the first few months of life. They may also exhibit hepatomegaly, hypotonia, encephalopathy, metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia. • Partially deficient (mut-) or B12-responsive (cblA, cblD, rarely cblB) is an intermediate phenotype that can occur in the first few months or years of life. Symptoms include feeding problems, failure to thrive, hypotonia, and developmental delay. Some have protein aversion and vomiting, and lethargy after protein intake. HGNC approved symbol/name: MMUT * Is the phenotype(s) severe and onset <18yo? Yes Treatments available: cobalamin, N-carbamylglutamate, carnitine, diet, liver transplant Known technical challenges? No Gene reported in 3 independent families: Yes * NOTE: gene previously called MUT; to: Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. Variable severity and age of onset: • Infantile completely deficient (mut0) or non-B12-responsive (clbB) is the most common phenotype and presents during infancy. Infants are normal at birth, but develop lethargy, vomiting, and dehydration within the first few months of life. They may also exhibit hepatomegaly, hypotonia, encephalopathy, metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia. • Partially deficient (mut-) or B12-responsive (cblA, cblD, rarely cblB) is an intermediate phenotype that can occur in the first few months or years of life. Symptoms include feeding problems, failure to thrive, hypotonia, and developmental delay. Some have protein aversion and vomiting, and lethargy after protein intake. HGNC approved symbol/name: MMUT * Is the phenotype(s) severe and onset <18yo? Yes Treatments available: cobalamin, N-carbamylglutamate, carnitine, diet, liver transplant Known technical challenges? No Gene reported in 3 independent families: Yes * NOTE: gene previously called MUT |
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| Prepair 1000+ v1.1367 | MTHFR |
Lauren Thomas changed review comment from: Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. HGNC approved symbol/name: MTHFR Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes NOTE: common variants not associated with severe disease are not reported; to: Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. HGNC approved symbol/name: MTHFR Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes |
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| Prepair 1000+ v1.1357 | DCLRE1C |
Lauren Thomas changed review comment from: The majority of individuals present within the first months of life with oral thrush, diarrhea, fever, pneumonia, and/or failure to thrive as well as hypogammmaglobulinaemia, absent T and B lymphocytes and increased radiosensitivity. Homozygous and compound heterozygous (missense, in-frame indel, nonsense, frameshift, and large deletion) variants have been reported; with the most common being gross deletions exons 1-3. *c.597C>A p.Tyr199X founder variant (Athabascan/ European Origin) HGNC approved symbol/name: DCLRE1C Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges: ?most common variant is a deletion Gene reported in 3 independent families: Yes Note: ClinGen groups the 2 OMIM phenotypes into "severe combined immunodeficiency due to DCLRE1C deficiency"; to: The majority of individuals present within the first months of life with oral thrush, diarrhea, fever, pneumonia, and/or failure to thrive as well as hypogammmaglobulinaemia, absent T and B lymphocytes and increased radiosensitivity. Homozygous and compound heterozygous (missense, in-frame indel, nonsense, frameshift, and large deletion) variants have been reported; with the most common being gross deletions exons 1-3 (~59%) *c.597C>A p.Tyr199X founder variant (Athabascan/ European Origin) HGNC approved symbol/name: DCLRE1C Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges: ?most common variant is a deletion Gene reported in 3 independent families: Yes Note: ClinGen groups the 2 OMIM phenotypes into "severe combined immunodeficiency due to DCLRE1C deficiency" |
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| Prepair 1000+ v1.1326 | COL4A5 | Zornitza Stark Phenotypes for gene: COL4A5 were changed from Alport syndrome 1, X-linked to Alport syndrome 1, X-linked, MIM#301050 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1268 | GJA1 |
Michelle Torres changed review comment from: The GJA1 gene is associated with both AD & AR conditions (OMIM). For carrier screening testing, the only relevant conditions are the AR disorders: Craniometaphyseal dysplasia MIM#218400; Oculodentodigital dysplasia MIM#257850. Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. Characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with CMD (PMID: 23951358). Reports are rare and individuals are homozygous for the p.(Arg239Gln), located in the C-terminus of the GJA1 gene; at least 4x families reported (PMID: 23951358). Oculodentodigital dysplasia (ODDD) is a rare condition characterised by a typical facial appearance and variable findings of the eyes, teeth, and fingers (PMID: 29902798). ODDD is generally AD (DN and GoF suggested), but rare AR cases have been identified. LoF is associated with AR ODDD (PMID: 29902798), and most variants reported are PTV within the connexin domain (PMID: 34035645). NB: the association with Hypoplastic left heart syndrome 1, MIM#241550 isn't listed in OMIM anymore, variants associated have been re-classified VUS (OMIM). Pfitzer C 2024 concludes that researchers must move beyond the expectation that a single disease-causing variant can be found (PMID 38884762).; to: The GJA1 gene is associated with both AD & AR conditions (OMIM). For carrier screening testing, the only relevant conditions are the AR disorders: Craniometaphyseal dysplasia MIM#218400; Oculodentodigital dysplasia MIM#257850. Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. Characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with CMD (PMID: 23951358). Reports are rare and individuals are homozygous for the p.(Arg239Gln), located in the C-terminus of the GJA1 gene; at least 4x families reported (PMID: 23951358). Oculodentodigital dysplasia (ODDD) is a rare condition characterised by a typical facial appearance and variable findings of the eyes, teeth, and fingers (PMID: 29902798). ODDD is generally AD (DN and GoF suggested), but rare AR cases have been identified. LoF is associated with AR ODDD (PMID: 29902798), and most variants reported are PTV within the connexin domain (PMID: 34035645). NB: the association with Hypoplastic left heart syndrome 1, MIM#241550 isn't listed in OMIM anymore, variants associated have been re-classified VUS (OMIM; PMID 38884762). |
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| Prepair 1000+ v1.1268 | COL7A1 |
Michelle Torres changed review comment from: The COL7A1 gene is associated with dystrophic epidermolysis bullosa (DEB), a genetic skin disorder affecting skin and nails that usually presents at birth. There are 2 main subtypes: dominant (DDEB) and recessive (RDEB), both with many clinical subtypes. For carrier screening testing, the only relevant subtypes are AR. Genotype-phenotype correlation is unclear (PMID: 31670143), but variants resulting in complete absence of protein are usually associated with the most severe RDEB (PMID: 32506467). The recessive exon skipping variants are scattered throughout the gene (PMID: 31670143). NB: Transient bullous of the newborn MIM#131705 is predominantly AD, but AR cases have been reported (PMID: 25639640 Table 1). It has onset at birth, but skin lesions resolve between 6 months and 2 years of age. Some patients have milder persistent blistering.; to: The COL7A1 gene is associated with dystrophic epidermolysis bullosa (DEB), a genetic skin disorder affecting skin and nails that usually presents at birth. There are 2 main subtypes: dominant (DDEB) and recessive (RDEB), both with many clinical subtypes. For carrier screening testing, the only relevant subtypes are AR. Genotype-phenotype correlation is unclear (PMID: 31670143), but variants resulting in complete absence of protein are usually associated with the most severe RDEB (PMID: 32506467). The recessive exon skipping variants are scattered throughout the gene (PMID: 31670143). NB: Transient bullous of the newborn MIM#131705 is predominantly AD, but AR cases have been reported (PMID: 25639640 Table 1). It has onset at birth, but skin lesions resolve between 6 months and 2 years of age. Some patients have milder persistent blistering. As noted above, genotype-phenotype correlation is unclear. |
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| Prepair 1000+ v1.1268 | COL7A1 |
Michelle Torres changed review comment from: The COL7A1 gene is associated with dystrophic epidermolysis bullosa (DEB), a genetic skin disorder affecting skin and nails that usually presents at birth. There are 2 main subtypes: dominant (DDEB) and recessive (RDEB), both with many clinical subtypes. For carrier screening testing, the only relevant subtypes are AR. Genotype-phenotype correlation is unclear (PMID: 31670143), but variants resulting in complete absence of protein are usually associated with the most severe RDEB (PMID: 32506467). The recessive exon skipping variants are scattered throughout the gene (PMID: 31670143). NB: Transient bullous of the newborn MIM#131705 is predominantly AD, but AR cases have been reported (PMID: 25639640 Table 1). It has onset at birth, but skin lesions resolve between 6 months and 2 years of age. Some patients have milder persistent blistering. Relevance for Prepair requires discussion.; to: The COL7A1 gene is associated with dystrophic epidermolysis bullosa (DEB), a genetic skin disorder affecting skin and nails that usually presents at birth. There are 2 main subtypes: dominant (DDEB) and recessive (RDEB), both with many clinical subtypes. For carrier screening testing, the only relevant subtypes are AR. Genotype-phenotype correlation is unclear (PMID: 31670143), but variants resulting in complete absence of protein are usually associated with the most severe RDEB (PMID: 32506467). The recessive exon skipping variants are scattered throughout the gene (PMID: 31670143). NB: Transient bullous of the newborn MIM#131705 is predominantly AD, but AR cases have been reported (PMID: 25639640 Table 1). It has onset at birth, but skin lesions resolve between 6 months and 2 years of age. Some patients have milder persistent blistering. |
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| Prepair 1000+ v1.1257 | COL4A5 | Crystle Lee reviewed gene: COL4A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36531881, 19965530, 36341250; Phenotypes: Alport syndrome 1, X-linked, MIM#301050; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1257 | TWNK |
Crystle Lee changed review comment from: Gene also know as C10ORF2. MTDPS7 is characterized by primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy (OMIM) PMID: 35035228: Reported an 11yo girl with delayed gonadal development, sensorineural hearing loss, and neurologic manifestations Allelic conditions, Perrault syndrome is less severe than MTDPS7.; to: Gene also know as C10ORF2. MTDPS7 is characterized by primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy (OMIM) PMID: 35035228: Reported an 11yo girl with delayed gonadal development, sensorineural hearing loss, and neurologic manifestations Allelic conditions, Perrault syndrome is less severe than MTDPS7. |
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| Prepair 1000+ v1.1105 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1105 | POR | Zornitza Stark Gene: por has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.1105 | POR | Zornitza Stark Publications for gene: POR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | STIL |
Ee Ming Wong changed review comment from: - More than 10 unrelated families reported. - Onset at birth - PMID: 24485834; 29352115: Complete loss of STIL is not compatible with life. Genetic mutations in human STIL result in 1. residual expression or 2. stabilization of STIL: PTCs that delete of the critical C-terminal KEN Box domain involved in Anaphase-Promoting-Complex/Cyclosome (APC/C)-mediated degradation of STIL5 were shown to result in mutant STIL stabilization and accumulation and subsequent centriole amplification. Demonstrated for p.(Val1219X) and p.(Gln1239X), suggested gain of function.; to: - More than 10 unrelated families reported. - Onset at birth - PMID: 24485834; 29352115: Complete loss of STIL is not compatible with life. Genetic mutations in human STIL result in 1. residual expression or 2. stabilization of mutant STIL: PTCs that delete of the critical C-terminal KEN Box domain involved in Anaphase-Promoting-Complex/Cyclosome (APC/C)-mediated degradation of STIL5 were shown to result in mutant STIL stabilization and accumulation and subsequent centriole amplification. Demonstrated for p.(Val1219X) and p.(Gln1239X), suggested gain of function. |
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| Prepair 1000+ v1.992 | TBX22 |
Ee Ming Wong changed review comment from: 1. Cleft palate with ankyloglossia (MIM# 303400) - More than 10 families reported with cleft palate/ankyloglossia and variants in this gene. - PMID:36901693 - Characterised by a cleft palate phenotype that is most often present in males and ranges from a high-arched palate, bifid uvula, submucous cleft palate, soft cleft palate, to complete cleft palate - OMIM, PMID:36901693 - Ankyloglossia/ bifid uvula/cleft palate reported in heterozygous females - Overall mild phenotype although PMID: 21375406 describes 1x TBX22 hemizygous individual with unilateral complete cleft lip and palate, ankyloglossia, hypodontia of the left maxillary second premolar, carpal bone anomalies, and hypoplastic thumb of the right hand. No other genes were tested. 2. Abruzzo-Erickson syndrome, MIM# 302905 PMID:22784330 - Single family reported with Abruzzo-Erickson syndrome, a syndromic form of cleft palate. Did not find additional reports on this phenotype; to: 1. Cleft palate with ankyloglossia (MIM# 303400) - More than 10 families reported with cleft palate/ankyloglossia and variants in this gene. - PMID:36901693 - Characterised by a cleft palate phenotype that is most often present in males and ranges from a high-arched palate, bifid uvula, submucous cleft palate, soft cleft palate, to complete cleft palate - OMIM, PMID:36901693 - Ankyloglossia/ bifid uvula/cleft palate reported in heterozygous females - Overall mild phenotype although PMID: 21375406 describes 1x TBX22 hemizygous individual with unilateral complete cleft lip and palate, ankyloglossia, hypodontia of the left maxillary second premolar, carpal bone anomalies, and hypoplastic thumb of the right hand. No other genes were tested. 2. Abruzzo-Erickson syndrome, MIM# 302905 PMID:22784330 - Single family reported with Abruzzo-Erickson syndrome, a syndromic form of cleft palate. Did not find additional reports on this phenotype |
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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. 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 | ISCA1 |
Lauren Thomas changed review comment from: Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood. HGNC approved symbol/name: ISCA1 Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes; to: Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood. HGNC approved symbol/name: ISCA1 Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes Most recent case report: PMID 32092383 (4th independent family) |
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| Prepair 1000+ v1.992 | ISCA1 |
Lauren Thomas changed review comment from: Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood. HGNC approved symbol/name: ISCA1 Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes; to: Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood. HGNC approved symbol/name: ISCA1 Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? No Gene reported in 3 independent families: Yes |
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| Prepair 1000+ v1.992 | DGUOK | Clare Hunt reviewed gene: DGUOK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12874104, 15887277, 23043144; Phenotypes: Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880, Portal hypertension, noncirrhotic, 1, MIM# 617068, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.992 | POR |
Ee Ming Wong changed review comment from: - PORD (P450 oxidoreductase deficiency) is associated with disorders of sex development in both sexes, where Antley-Bixler (ABS) syndrome is the name given to the severe form - Skeletal abnormalities of the ABS phenotype are frequently observed in individuals with PORD, characterised by craniosynostosis, brachycephaly, radio-ulnar or radio-humeral synostosis, bowed femora, arachnodactyly, midface hypoplasia, proptosis, and choanal stenosis. The severity of malformations varies from mild to moderate and severe. NB: Only the more severe MIM# has been added to this gene list.; to: - PORD (P450 oxidoreductase deficiency) is associated with disorders of sex development in both sexes, where Antley-Bixler (ABS) syndrome is the name given to the severe form - Skeletal abnormalities of the ABS phenotype are frequently observed in individuals with PORD, characterised by craniosynostosis, brachycephaly, radio-ulnar or radio-humeral synostosis, bowed femora, arachnodactyly, midface hypoplasia, proptosis, and choanal stenosis. The severity of malformations varies from mild to moderate and severe. - Congenital onset NB: Only the more severe MIM# has been added to this gene list. |
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| 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 | 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 | 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 | CHST14 |
Michelle Torres edited their review of gene: CHST14: Added comment: Musculocontractural EDS type 1 (mcEDS) is a rare type of EDS caused by biallelic loss-of-function variants in CHST14 (PMID: 34815299). Major features are: congenital multiple contractures and characteristic craniofacial features at birth or in early infancy; congenital multiple contractures and characteristic cutaneous features in adolescence and in adulthood (PMID: 34815299). The CHST14 gene has only 1 exon, therefore PTV variants escape NMD. Missense and in-frame deletion have also been reported with a similar phenotype to that caused by PTV (PMID: 34815299).; Changed rating: GREEN |
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| Prepair 1000+ v1.992 | TCAP |
Crystle Lee changed review comment from: Established for LGMD. Rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. Mean age at onset 12.5 years (range 2 to 15 years). Progression to wheelchair in fourth decade (OMIM) PMID: 37216648: Onset range from 6-35. PMID: 25724973: Onset in teens. Wheelchair bound by 44. PMID: 25055047: Reported PTCs in 2 families. In at least one family, with 3 affected family members, one was wheelchair bound state at 21 years of age. Other similar/more severe LDMG phenotypes included in panel.; to: Established for LGMD. Rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. Mean age at onset 12.5 years (range 2 to 15 years). Progression to wheelchair in fourth decade (OMIM) PMID: 37216648: Onset range from 6-35. PMID: 25724973: Onset in teens. Wheelchair bound by 44. PMID: 25055047: Reported PTCs in 2 families. In at least one family, with 3 affected family members, one was wheelchair bound state at 21 years of age. Other similar/more severe LGMD phenotypes included in panel. |
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| Prepair 1000+ v1.992 | TCAP |
Crystle Lee changed review comment from: Established for LGMD. Rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. Mean age at onset 12.5 years (range 2 to 15 years). Progression to wheelchair in fourth decade (OMIM) PMID: 37216648: Onset range from 6-35. PMID: 25724973: Onset in teens. Wheelchair bound by 44. PMID: 25055047: Reported PTCs in 2 families. In at least one family, with 3 affected family members, one was wheelchair bound state at 21 years of age. Other similar/more severe LDMG phenotypes included in panel.; to: Established for LGMD. Rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. Mean age at onset 12.5 years (range 2 to 15 years). Progression to wheelchair in fourth decade (OMIM) PMID: 37216648: Onset range from 6-35. PMID: 25724973: Onset in teens. Wheelchair bound by 44. PMID: 25055047: Reported PTCs in 2 families. In at least one family, with 3 affected family members, one was wheelchair bound state at 21 years of age. Other similar/more severe LDMG phenotypes included in panel. |
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| Prepair 1000+ v1.978 | PGAP2 | Shakira Heerah changed review comment from: Strong gene-disease association, multiple unrelated families reported severe intellectual disability.; to: Strong gene-disease association, multiple unrelated families reported severe intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.978 | PGAP2 | Shakira Heerah changed review comment from: Strong gene-disease association, multiple unrelated families reported severe intellectual disability..; to: Strong gene-disease association, multiple unrelated families reported severe intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.978 | NSDHL |
Kate Scarff changed review comment from: X-linked recessive disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. 25 affected males from three unrelated families have been reported. Heterozygous females are typically unaffected; however, some may experience mild behavior problems such as irritability or aggression. The NSDHL pathogenic variants c.455G>A, c.696_698delGAA, and c.1098dupT have been consistently associated with CK syndrome. Other phenotype associated with this gene is CHILD syndrome (MIM #308050) not reportable for Prepair1000 as is X-linked dominant, only affects females, lethal before birth in hemizygous males.; to: X-linked recessive disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. 25 affected males from three unrelated families have been reported. Heterozygous females are typically unaffected; however, some may experience mild behavior problems such as irritability or aggression. The NSDHL pathogenic variants c.455G>A, c.696_698delGAA, and c.1098dupT have been consistently associated with CK syndrome. Other phenotype associated with this gene is CHILD syndrome (MIM #308050) not reportable for Prepair1000 as is X-linked dominant, only affects females, lethal before birth in hemizygous males. See also GeneReviews PMID: 21290788 |
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| Prepair 1000+ v1.836 | GUCY2D |
Kate Scarff changed review comment from: LCA1 is a congenital eye disorder that primarily affects the retina and causes vision loss, nystagmus, and severe retinal dysfunction. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time. Cone-rod dystrophy 6, MIM #601777 is a dominant condition due to heterozygous mutations in GUCY2D, not reportable for Prepair1000+. Autosomal recessive GUCY2D mutations may cause congenital night blindness with normal acuity and refraction, and unique electroretinography. Progression to mild retinitis pigmentosa may occur. See PMID: 29559409. Not reportable for Prepair1000+ (severity).; to: LCA1 is a congenital eye disorder that primarily affects the retina and causes vision loss, nystagmus, and severe retinal dysfunction. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time. Cone-rod dystrophy 6, MIM #601777 is a dominant condition due to heterozygous mutations in GUCY2D, not reportable for Prepair1000+. See PMID: 35205358 Autosomal recessive GUCY2D mutations may cause congenital night blindness with normal acuity and refraction, and unique electroretinography. Progression to mild retinitis pigmentosa may occur. See PMID: 29559409. Not reportable for Prepair1000+ (severity). |
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| 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+ v1.745 | SLC16A1 | Zornitza Stark Phenotypes for gene: SLC16A1 were changed from Monocarboxylate transporter 1 deficiency, 616095 (3) to Monocarboxylate transporter 1 deficiency, MIM#616095 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | SLC9A6 |
Andrew Coventry changed review comment from: Established gene-disease association. Childhood onset, multi-system, Angelman-like disorder. Characterised by microcephaly, impaired ocular movements, progressive severe global developmental delay, developmental regression, hypotonia, abnormal movements, and early-onset seizures of variable types. Female carriers may be either asymptomatic, or more mildly affected than males. PMID 31192222: describes 20 female carriers from 9 families. Presentations included impairments in visuospatial function, attention, and executive function. Cohort features: Intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). PMID 35198730: Japanese family where SLC9A6 variant in female carriers segregated with atypical parkinsonism and intellectual disability. More than 20 unrelated families reported. Functional data including mouse model.; to: Established gene-disease association. Childhood onset, multi-system, Angelman-like disorder in affected males - characterised by microcephaly, impaired ocular movements, progressive severe global developmental delay, developmental regression, hypotonia, abnormal movements, and early-onset seizures of variable types. Female carriers may be either asymptomatic, or more mildly affected than males. PMID 31192222: describes 20 female carriers from 9 families. Presentations included impairments in visuospatial function, attention, and executive function. Cohort features: Intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). PMID 35198730: Japanese family where SLC9A6 variant in female carriers segregated with atypical parkinsonism and intellectual disability. More than 20 unrelated families reported. Functional data including mouse model. |
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| Prepair 1000+ v1.633 | SLC26A2 |
Andrew Coventry changed review comment from: Well established gene disease association causing skeletal abnormalities of varying severity. Variants in this gene have been shown to cause achondrogenesis type 1B, atelosteogenesis type 2, diastrophic dysplasia, and recessive multiple epiphyseal dysplasia, which comprise a spectrum of phenotypes (depending on level of residual sulfate transport). Onset/features can often be observed neonatally. Mouse models present for some phenotypes, and functional studies are present. Homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type IB, whereas other structural or regulatory mutations usually result in one of the less severe phenotypes (PMID: 8723100) Unsure of phenotypes to list under condition. Clingen includes curations for: diastrophic dysplasia MONDO:0009107 multiple epiphyseal dysplasia MONDO:0016648 atelosteogenesis type II MONDO:0009727 achondrogenesis type IB MONDO:0010966 OMIM phenotypes (6) listed above.; to: Well established gene disease association causing skeletal abnormalities of varying severity. Variants in this gene have been shown to cause achondrogenesis type 1B, atelosteogenesis type 2, diastrophic dysplasia, and recessive multiple epiphyseal dysplasia, which comprise a spectrum of phenotypes (depending on level of residual sulfate transport). Onset/features can often be observed neonatally. Mouse models present for some phenotypes, and functional studies are present. Homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type IB, whereas other structural or regulatory variants usually result in one of the less severe phenotypes (PMID: 8723100) Unsure of phenotypes to list under condition. Clingen includes curations for: diastrophic dysplasia MONDO:0009107 multiple epiphyseal dysplasia MONDO:0016648 atelosteogenesis type II MONDO:0009727 achondrogenesis type IB MONDO:0010966 OMIM phenotypes (6) listed above. |
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| Prepair 1000+ v1.633 | SLC26A2 |
Andrew Coventry changed review comment from: Well established gene disease association causing skeletal abnormalities of varying severity. Variants in this gene have been shown to cause achondrogenesis type 1B, atelosteogenesis type 2, diastrophic dysplasia, and recessive multiple epiphyseal dysplasia, which comprise a spectrum of phenotypes (depending on level of residual sulfate transport). Onset can be neonatal. Mouse models present for some phenotypes, and functional studies are present. Homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type IB, whereas other structural or regulatory mutations usually result in one of the less severe phenotypes (PMID: 8723100) Unsure of phenotypes to list under condition. Clingen includes curations for: diastrophic dysplasia MONDO:0009107 multiple epiphyseal dysplasia MONDO:0016648 atelosteogenesis type II MONDO:0009727 achondrogenesis type IB MONDO:0010966 OMIM phenotypes (6) listed above.; to: Well established gene disease association causing skeletal abnormalities of varying severity. Variants in this gene have been shown to cause achondrogenesis type 1B, atelosteogenesis type 2, diastrophic dysplasia, and recessive multiple epiphyseal dysplasia, which comprise a spectrum of phenotypes (depending on level of residual sulfate transport). Onset/features can often be observed neonatally. Mouse models present for some phenotypes, and functional studies are present. Homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type IB, whereas other structural or regulatory mutations usually result in one of the less severe phenotypes (PMID: 8723100) Unsure of phenotypes to list under condition. Clingen includes curations for: diastrophic dysplasia MONDO:0009107 multiple epiphyseal dysplasia MONDO:0016648 atelosteogenesis type II MONDO:0009727 achondrogenesis type IB MONDO:0010966 OMIM phenotypes (6) listed above. |
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| Prepair 1000+ v1.633 | SLC16A1 | Andrew Coventry reviewed gene: SLC16A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25390740, 20301549, 36082648, 35729663; Phenotypes: Monocarboxylate transporter 1 deficiency MIM#616095; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | L2HGDH |
Crystle Lee changed review comment from: Well established gene-disease association. Onset typically in infancy or early childhood, however, reports of milder, adult onset cases have been reported. Patients may present with a wide variety of clinical manifestations.; to: Well established gene-disease association. Onset typically in infancy or early childhood, however, reports of milder, adult onset cases have been reported. Patients may present with a wide variety of clinical manifestations. |
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| 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+ v1.546 | IFNGR1 |
Andrew Coventry changed review comment from: Multiple families with recessive disease reported, reviewed in PMID 15589309. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. The disorder can thus be categorized as a form of mendelian susceptibility to mycobacterial disease (MSMD). Bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Recessive deficiency is thought to result in complete loss of cellular response to IFNG and absence of surface IFNGR1 expression. Animal models present. Note: AD condition associated with this gene - Immunodeficiency 27B, mycobacteriosis, MIM#615978. Dominant deficiency is typically due to cytoplasmic domain truncations resulting in accumulation of non-functional IFNGR1 proteins that may impede the function of molecules encoded by the wildtype allele, thereby leading to diminished but not absent responsiveness to IFNG. Common deletions at and around nucleotide 818. (PMID: 10192386); to: Multiple families with recessive disease reported, reviewed in PMID 15589309. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. The disorder can thus be categorized as a form of mendelian susceptibility to mycobacterial disease (MSMD). Bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Recessive deficiency is thought to result in complete loss of cellular response to IFNG and absence of surface IFNGR1 expression. Animal models present. Note: AD condition associated with this gene - Immunodeficiency 27B, mycobacteriosis, MIM#615978. Dominant deficiency is typically due to cytoplasmic domain truncations resulting in accumulation of non-functional IFNGR1 proteins that may impede the function of molecules encoded by the wildtype allele, thereby leading to diminished but not absent responsiveness to IFNG. Deletions including nucleotide 818 reported. (PMID: 10192386) |
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| Prepair 1000+ v1.503 | FOLR1 | Zornitza Stark Phenotypes for gene: FOLR1 were changed from Neurodegeneration due to cerebral folate transport deficiency, 613068 (3) to Neurodegeneration due to cerebral folate transport deficiency, MIM#613068 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.486 | FOLR1 | Andrew Coventry reviewed gene: FOLR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19732866 30420205 27743887; Phenotypes: Neurodegeneration due to cerebral folate transport deficiency MIM#613068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.384 | TSPYL1 |
Lilian Downie Added comment: Comment when marking as ready: Originally reported only in Amish community, founder variant subsequently reported in 3 unrelated families, non amish - GREEN AT UPGRADE 2 cohort studies looking for variants in this gene in SIDS cohorts but it's very rare and presents with more of a progressive neurological phenotype in the non Amish families |
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| Prepair 1000+ v1.371 | PNKP | Lilian Downie Added comment: Comment on phenotypes: CMT phenotype is usually onset in 30's but childhood onset has been reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.322 | AARS2 |
Clare Hunt edited their review of gene: AARS2: Added comment: At least 6 families presenting with a severe COXPD phenotype in infancy, primarily with cardiac, muscle and neurological features in addition to lactic acidosis. Further 6 reported with a progressive neurodegenerative disorder characterised by loss of motor and cognitive skills, usually with onset in young adulthood. Some had a history of delayed motor development or learning difficulties in early childhood. Neurologic decline was severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most individuals lost speech and become wheelchair-bound or bedridden. Brain MRI showed progressive white matter signal abnormalities in the deep white matter. Affected females developed premature ovarian failure. These likely represent a spectrum of severity of a single mitochondrial disorder. Created: 29 Aug 2020, 4:55 a.m. | Last Modified: 29 Aug 2020, 4:55 a.m. Panel Version: 0.3999; Changed publications: 27839525 |
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| Prepair 1000+ v1.322 | ALAD | Lauren Thomas reviewed gene: ALAD: Rating: GREEN; Mode of pathogenicity: None; Publications: 16343966, 30724374, 2063868, 1569184, 15303011; Phenotypes: Porphyria, acute hepatic, MIM#612740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.304 | ERCC2 |
Ee Ming Wong changed review comment from: - Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. - Severe, early onset of all three phenotypes have been reported - Variable expressivity has been reported for Xeroderma pigmentosum, group D, MIM# 278730 where individuals can present with or without mild or severe neurologic abnormalities (GeneReviews) - OMIM: The location of variants (mutagenic pattern) is consistent in determining the phenotype. Variants shared by both phenotypes are functionally null alleles, and the second / compound heterozygous variant then determines the phenotype. Changes at p.Arg683 are clearly associated with XP, whereas p.Arg112His, p.Arg722Trp, and changes at p.Arg658 are associated with TTD.; to: - Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. - Severe, early onset of all three phenotypes have been reported - Variable expressivity has been reported for Xeroderma pigmentosum, group D, MIM# 278730 where individuals can present with or without mild or severe neurologic abnormalities (GeneReviews) - OMIM: The location of variants (mutagenic pattern) is consistent in determining the phenotype. Variants shared by both phenotypes are functionally null alleles, and the second / compound heterozygous variant then determines the phenotype. Changes at p.Arg683 are clearly associated with XP, whereas p.Arg112His, p.Arg722Trp, and changes at p.Arg658 are associated with TTD. |
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| Prepair 1000+ v1.287 | LRP5 | Andrew Coventry reviewed gene: LRP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9056564 9831343 11719191 15346351 18602879; Phenotypes: Exudative vitreoretinopathy 4 MIM#601813, Osteoporosis-pseudoglioma syndrome MIM#259770; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.258 | COL4A4 | Kate Scarff reviewed gene: COL4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301386; Phenotypes: Alport syndrome 2, autosomal recessive MIM# 203780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.248 | F2 |
Marta Cifuentes Ochoa changed review comment from: Prothrombin deficiency type I, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. HGNC approved symbol/name: F2 Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges? N Gene reported in >3 independent families Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein; to: Prothrombin deficiency type I, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. HGNC approved symbol/name: F2 Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges? N Gene reported in >3 independent families Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein AD forms and multifactorial conditions described for this gene not reportable in screening context |
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| 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+ v1.229 | DYSF |
Marta Cifuentes Ochoa commented on gene: DYSF: Miyoshi myopathy (MM) is the most common form of recessive distal myopathy in populations with founder mutations such as Libyan and Israeli Jewish population, Italian and Spanish populations.The typical age of onset of MM lies between 15 and 30 years Autosomal recessive limb-girdle muscular dystrophy type 2B (LGMD2B) is a subtype of autosomal recessive limb-girdle muscular dystrophy characterized by an onset in late adolescence or early adulthood of slowly progressive, proximal weakness and atrophy of shoulder and pelvic girdle muscles. Cardiac and respiratory muscles are not involved. Hypertrophy of the calf muscles and highly elevated serum creatine kinase levels are frequently observed. Myopathy, distal, with anterior tibial onset is a rare genetic neuromuscular disease with characteristics of a progressive muscle weakness starting in the anterior tibial muscles, later involving lower and upper limb muscles, associated with an increased serum creatine kinase levels and absence of dysferlin on muscle biopsy. Patients become wheelchair dependent. HGNC approved symbol/name: DYSF Is the phenotype(s) severe and onset <18yo ? ? chidhood, early adulthood to late onset Known technical challenges? N but large‐scale copy number variants have been identified. Gene reported in >3 independent families Unsure due genotype/phenotype correlation and onset |
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| Prepair 1000+ v1.219 | COL4A3 | Zornitza Stark Phenotypes for gene: COL4A3 were changed from Alport syndrome, autosomal recessive, 203780 (3) to Alport syndrome 3b, autosomal recessive MIM#620536; MONDO:0957811 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v1.187 | COLQ |
Marta Cifuentes Ochoa changed review comment from: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood. Well established gene-disease association, more than 10 families reported. HGNC approved symbol/name: COLQ Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges?N; to: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood. Presentations: -neonatal: respiratory insufficiency, multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero. Feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness.In some individuals, long face, narrow jaw, and a high-arched palate have been reported -childhood: delayed motr milestones, fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids. Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.Spinal deformity or muscle atrophy may occur -limb-girdle Well established gene-disease association, more than 10 families reported. HGNC approved symbol/name: COLQ Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges?N |
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| Prepair 1000+ v1.187 | COL4A3 | Marta Cifuentes Ochoa reviewed gene: COL4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24052634, 35419377, 39071776; Phenotypes: Alport syndrome 3b, autosomal recessive MIM#620536, MONDO:0957811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.187 | CLN3 |
Marta Cifuentes Ochoa commented on gene: CLN3: Well established gene disease association. Severe neurodegenerative disorder. HGNC approved symbol/name: CLN3 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+ v1.168 | YIF1B | Zornitza Stark edited their review of gene: YIF1B: Added comment: DEFINITIVE gene-disease association by ClinGen. Over 20 individuals now reported in the literature.; Changed publications: 33103737, 32006098, 36948290, 34373908 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v1.142 | MFRP |
Zornitza Stark gene: MFRP was added gene: MFRP was added to Prepair 1000+. Sources: Expert Review Mode of inheritance for gene: MFRP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MFRP were set to 17167404; 18554571; 20361016 Phenotypes for gene: MFRP were set to Microphthalmia, isolated 5, MIM# 611040 Review for gene: MFRP was set to GREEN Added comment: More than 10 unrelated families reported with bi-allelic variants in this gene associated with posterior microphthalmia with retinitis pigmentosa, foveoschisis, and optic disc drusen. Causes congenital visual impairment. Sources: Expert Review |
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| Prepair 1000+ v1.88 | RMRP | Lilian Downie Added comment: Comment when marking as ready: A range of phenotypes from mild skeletal dysplasia to a severe (anauxetic dysplasia), there is not a clear genotype phenotype correlation, however loss of function variants are more often reported in the severe phenotypes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.82 | AKR1D1 |
Ee Ming Wong changed review comment from: Well established gene-disease association. Inborn error of bile acid metabolism. At least 6 cases (with 5 variants) in 5 families reported. Severe condition with congenital onset, leads to liver failure.; to: Well established gene-disease association. Inborn error of bile acid metabolism. At least 6 cases (with 5 variants) in 5 families reported. Severe condition with congenital onset, leads to liver failure. |
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| 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 | CLCNKB | Lilian Downie Added comment: Comment when marking as ready: The digenic inheritance is not clearly proven, patients with variants in both genes also had biallelic variants in this gene which is just as likely to have been the cause. Not enough evidence to report in carrier screening as a digenic condition. PMID: 18310267 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v1.67 | ATM | Lilian Downie Added comment: Comment when marking as ready: NB for reporting carrier mother may need additional breast cancer surveillance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.65 | MMADHC | Lauren Rogers reviewed gene: MMADHC: Rating: ; Mode of pathogenicity: None; Publications: 33552904; Phenotypes: Homocystinuria, cblD type, variant 1 MIM#277410, Methylmalonic aciduria and homocystinuria, cblD type MIM#277410, Methylmalonic aciduria, cblD type, variant 2 MIM#277410, Disorders of cobalamin absorption, transport and metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v1.43 | COQ4 |
Lauren Rogers changed review comment from: At least 9 unrelated families reported. Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.; to: At least 9 unrelated families reported. Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations. |
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| Prepair 1000+ v1.43 | COQ4 |
Lauren Rogers changed review comment from: At least 9 unrelated families reported. Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.; to: At least 9 unrelated families reported. Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations. |
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| Prepair 1000+ v1.7 | ABCB7 |
Andrew Coventry changed review comment from: HGNC approved symbol/name: ABCB7 Reported cases of ataxia are typically childhood onset and progressive, anaemia reported to be mostly mild.; to: HGNC approved symbol/name: ABCB7 Reported cases of ataxia are typically childhood onset and progressive, anaemia reported to be mostly mild. |
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| Prepair 1000+ v1.5 | ADPRHL2 |
Zornitza Stark changed review comment from: Fourteen unrelated families reported with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS), an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. The disorder is characterised by cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some individuals develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy. New HGNC approved name is ADPRS.; to: Fourteen unrelated families reported with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS), an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. The disorder is characterised by cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some individuals develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy. New HGNC approved name is ADPRS. To be upgraded to GREEN in next version of panel. |
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| Prepair 1000+ v1.4 | PIEZO1 |
Crystle Lee gene: PIEZO1 was added gene: PIEZO1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: PIEZO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIEZO1 were set to PMID: 26333996 Phenotypes for gene: PIEZO1 were set to Lymphatic malformation 6, MIM#616843 Review for gene: PIEZO1 was set to GREEN Added comment: Biallelic mutations in PIEZO1 reported in 10 patients from 6 families with generalized lymphatic dysplasia (GLD) This is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. Sources: Literature |
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| Prepair 1000+ v1.3 | POR | Seb Lunke Added phenotypes Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, 201750 (3) for gene: POR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | COL4A5 | Seb Lunke Added phenotypes Alport syndrome 1, X-linked for gene: COL4A5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | COL4A4 | Seb Lunke Added phenotypes Alport syndrome, autosomal recessive, 203780 (3) for gene: COL4A4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.3 | COL4A3 | Seb Lunke Added phenotypes Alport syndrome, autosomal recessive, 203780 (3) for gene: COL4A3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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+ v0.164 | RYR1 | Zornitza Stark commented on gene: RYR1: Hard to predict outcome in a screening context. However, multiple reports of severe perinatal outcomes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v0.135 | PRKRA |
Zornitza Stark changed review comment from: Founder variant but multiple other families reported. Pseudogene is a processed pseudogene and therefore false positives can be identified on manual inspection.; to: Founder variant but multiple other families reported. Pseudogene is a processed pseudogene and therefore false positives can be identified on manual inspection. Risk of false negatives is low. |
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| Prepair 1000+ v0.126 | MPZ | Zornitza Stark changed review comment from: More than 3 families reported with biallelic variants.; to: More than 3 families reported with biallelic variants. Childhood/congenital onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v0.85 | TECPR2 |
Crystle Lee gene: TECPR2 was added gene: TECPR2 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TECPR2 were set to 23176824; 26542466; 35130874 Phenotypes for gene: TECPR2 were set to Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, MIM#615031 Review for gene: TECPR2 was set to GREEN Added comment: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent Sources: Literature |
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| Prepair 1000+ v0.85 | RS1 |
Crystle Lee gene: RS1 was added gene: RS1 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: RS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: RS1 were set to 15932525; 23453514; 23847049 Phenotypes for gene: RS1 were set to Retinoschisis (MIM#312700) Review for gene: RS1 was set to AMBER Added comment: - This gene is known to be associated with X-linked recessive disease, however, some affected females have been reported (OMIM). - May not clinically manifest until middle life (OMIM) - Many PTCs and missense reported. All result in same XLRS phenotype (although expression can be variable). Also a knockout mouse with similar phenotype. - PTCs and missense involving cysteines tend to result in a more severe phenotype, whereas other missense can vary widely in severity (PMID: 23847049). 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+ v0.85 | MCCC2 |
Crystle Lee gene: MCCC2 was added gene: MCCC2 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: MCCC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MCCC2 were set to 3-Methylcrotonyl-CoA carboxylase 2 deficiency (MIM#210210) Review for gene: MCCC2 was set to RED Added comment: Variants in this gene cause a biochemical defect. Relationship to clinical features is less certain. Variants in this gene have been reported in multiple individuals with ID/regression/neurological phenotypes. However, ascertainment through NBS programs indicates most individuals remain asymptomatic and therefore caution should be applied in interpreting the clinical significance of variants in this gene (though they undoubtedly cause a biochemical phenotype). Sources: Literature |
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| Prepair 1000+ v0.61 | HYAL1 |
Crystle Lee gene: HYAL1 was added gene: HYAL1 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: HYAL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HYAL1 were set to 10339581; 18344557; 21559944 Phenotypes for gene: HYAL1 were set to Mucopolysaccharidosis type IX (MIM#601492) Review for gene: HYAL1 was set to RED Added comment: Two families reported: in one, multiple soft tissue masses were the predominant clinical manifestation, and in the second, juvenile arthritis. Mouse model. >15 pLoF variants reported as pathogenic in ClinVar. All submitted by a single lab and evidence suggests that the variant has not been previously reported. Insufficient gene disease association. Not suitable for inclusion in a carrier screening panel Sources: Literature |
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| Prepair 1000+ v0.61 | GRHPR |
Crystle Lee gene: GRHPR was added gene: GRHPR was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: GRHPR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GRHPR were set to 28569194; 10484776; 10484776; 24116921 Phenotypes for gene: GRHPR were set to Hyperoxaluria, primary, type II (MIM#260000) Review for gene: GRHPR was set to AMBER Added comment: Well established gene-disease association, more than 10 families reported. Onset usually in infancy or early childhood, variable severity and some patients may be asymptomatic (OMIM; Gene Reviews) Sources: Literature |
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| Prepair 1000+ v0.61 | GP9 |
Crystle Lee gene: GP9 was added gene: GP9 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: GP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GP9 were set to 8049428; 33553065; 32030720; 31484196 Phenotypes for gene: GP9 were set to Bernard-Soulier syndrome, type C (MIM#231200) Review for gene: GP9 was set to AMBER Added comment: Bernard-Soulier syndrome is a bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5. At least 3 unrelated families reported, animal model. 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 | G6PD |
Crystle Lee gene: G6PD was added gene: G6PD was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: G6PD 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: G6PD were set to Hemolytic anemia, G6PD deficient (favism) (MIM#300908) Review for gene: G6PD was set to AMBER Added comment: Well established gene disease association. Most G6PD-deficient patients are asymptomatic throughout their life, but G6PD deficiency can be life-threatening Note: OMIM states this is XLD, however it is males that a repeatedly reported affected and just carrier females; females are affected when HOMOZYGOUS, meaning this is primarily an XLR condition Sources: Literature |
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| Prepair 1000+ v0.61 | F11 |
Crystle Lee gene: F11 was added gene: F11 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: F11 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: F11 were set to 18446632; 15026311; 27723456 Phenotypes for gene: F11 were set to Factor XI deficiency, autosomal dominant (MIM#612416); Factor XI deficiency, autosomal recessive, (MIM#612416) Review for gene: F11 was set to AMBER Added comment: Recessive cases are more severe than heterozygous carriers, who may be asymptomatic despite having FXI deficiency (PMID:18446632). Dominant negative missense tend to have dominant inheritance patterns (PMID:15026311), while PTCs are generally recessive, though symptomatic carriers have been reported (OMIM). PMID: 27723456 - "Bleeding due to FXI deficiency is variable and does not correlate with the plasma FXI level or FXI coagulant activity1" 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+ v0.61 | AIRE |
Crystle Lee gene: AIRE was added gene: AIRE was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: AIRE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIRE were set to 35521792; 28323927 Phenotypes for gene: AIRE were set to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia (MIM#240300) Review for gene: AIRE was set to AMBER Added comment: Well established gene disease association. Onset in childhood however phenotype can vary even between siblings with the same genotype. Therefore, it may be difficult (?impossible) to predict the severity/age of onset from the genotype Most reported individuals have bi-allelic variants. AD inheritance has been reported in a single family (OMIM) p.G228W has been shown to have a dominant-negative effect by binding to WT AIRE (OMIM) 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+ v0.31 | ALG2 |
Crystle Lee commented on gene: ALG2: One additional variant reported in association with CDG on top of the previously reviewed patients reported with CDG/congenital myasthenia PMID: 33644825: R251L reported in 3 probands from 2 families with CDG (same patients in PMID: 30397276) |
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| Prepair 1000+ v0.0 | SEC23A |
Crystle Lee changed review comment from: Amber in Mendeliome. Insufficient evidence for inclusion. There is only one family reported with convincing evidence for gene-disease association, and we have downgraded this gene on other panels.; to: Amber in Mendeliome. Insufficient evidence for inclusion. There is only one family reported with convincing evidence for gene-disease association, and we have downgraded this gene on other panels. |
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| Prepair 1000+ v0.0 | PIBF1 |
Crystle Lee gene: PIBF1 was added gene: PIBF1 was added to Reproductive Carrier Screen_VCGS. Sources: Literature Mode of inheritance for gene: PIBF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIBF1 were set to 26167768; 30858804; 29695797; 33004012 Phenotypes for gene: PIBF1 were set to Joubert syndrome 33 (MIM#617767) Review for gene: PIBF1 was set to AMBER Added comment: Green gene to be considered for inclusion Three unrelated families plus three Hutterite families reported with bi-allelic variants in this gene. Sources: Literature |
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| Prepair 1000+ v0.0 | UROS |
Zornitza Stark gene: UROS was added gene: UROS was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: UROS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: UROS were set to Porphyria, congenital erythropoietic, 263700 (3) |
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| Prepair 1000+ v0.0 | SLC16A1 |
Zornitza Stark gene: SLC16A1 was added gene: SLC16A1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: SLC16A1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC16A1 were set to Monocarboxylate transporter 1 deficiency, 616095 (3) |
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| Prepair 1000+ v0.0 | POR |
Zornitza Stark gene: POR was added gene: POR was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POR were set to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, 201750 (3) |
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| Prepair 1000+ v0.0 | LRP5 |
Zornitza Stark gene: LRP5 was added gene: LRP5 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: LRP5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LRP5 were set to Osteoporosis-pseudoglioma syndrome, 259770 (3) |
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| Prepair 1000+ v0.0 | LAMA1 |
Zornitza Stark gene: LAMA1 was added gene: LAMA1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LAMA1 were set to Poretti-Boltshauser syndrome, 615960 (3) |
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| Prepair 1000+ v0.0 | FOLR1 |
Zornitza Stark gene: FOLR1 was added gene: FOLR1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, 613068 (3) |
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| Prepair 1000+ v0.0 | COL4A5 |
Zornitza Stark gene: COL4A5 was added gene: COL4A5 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: COL4A5 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: COL4A5 were set to Alport syndrome 1, X-linked |
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| Prepair 1000+ v0.0 | COL4A4 |
Zornitza Stark gene: COL4A4 was added gene: COL4A4 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: COL4A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: COL4A4 were set to Alport syndrome, autosomal recessive, 203780 (3) |
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| Prepair 1000+ v0.0 | COL4A3 |
Zornitza Stark gene: COL4A3 was added gene: COL4A3 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: COL4A3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: COL4A3 were set to Alport syndrome, autosomal recessive, 203780 (3) |
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| Prepair 1000+ v0.0 | ALAD |
Zornitza Stark gene: ALAD was added gene: ALAD was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ALAD was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ALAD were set to Porphyria, acute hepatic, 612740 (3) |
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| Prepair 1000+ v0.0 | ACTA1 |
Zornitza Stark gene: ACTA1 was added gene: ACTA1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: ACTA1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACTA1 were set to Myopathy, congenital, with fiber-type disproportion 1, 255310 (3) |
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