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| Mendeliome v1.2489 | AFF2_FRAXE_GCC |
Bryony Thompson STR: AFF2_FRAXE_GCC was added STR: AFF2_FRAXE_GCC was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: AFF2_FRAXE_GCC was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for STR: AFF2_FRAXE_GCC were set to 8334699; 8673085; 11388762 Phenotypes for STR: AFF2_FRAXE_GCC were set to Intellectual developmental disorder, X-linked 109 MIM#309548 Review for STR: AFF2_FRAXE_GCC was set to GREEN STR: AFF2_FRAXE_GCC was marked as clinically relevant STR: AFF2_FRAXE_GCC was marked as current diagnostic Added comment: NM_001169122.1(AFF2):c.-460_-458GCC(6_25) Loss of function through methylation silencing is the mechanism of disease Normal - 5-44 repeats Inconclusive - 45-54 repeats Premutation - 55-200 repeats Abnormal - >200 or >230 repeats Sources: Expert list |
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| Mendeliome v1.2479 | PCNA |
Sangavi Sivagnanasundram gene: PCNA was added gene: PCNA was added to Mendeliome. Sources: ClinGen Mode of inheritance for gene: PCNA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCNA were set to 24911150, 33426167, 36990216 Phenotypes for gene: PCNA were set to hereditary ataxia MONDO:0100309 Review for gene: PCNA was set to AMBER Added comment: Classified as Limited by Cerebellar Ataxia GCEP on 09/04/2025 - https://search.clinicalgenome.org/CCID:008778 Two missense variants have been reported across 5 families. Both the missense variants are present in gnomAD (rare enough for AR gene). Method of pathogenicity is still unknown. Affected individuals reported with ataxia, photosensitivity, telangiectasias, and some degree of intellectual disability. Sources: ClinGen |
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| Mendeliome v1.2452 | EFNA4 |
Bryony Thompson changed review comment from: Supporting animal models, but no compelling evidence in human cases. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease. PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent. PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls. PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4.; to: Supporting animal models, but no compelling evidence in human cases has been reported since 2006. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease. PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent. PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls. PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4. |
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| Mendeliome v1.2432 | CDC20 |
Zornitza Stark gene: CDC20 was added gene: CDC20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDC20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDC20 were set to 32666501; 33683667; 33898437; 34218387 Phenotypes for gene: CDC20 were set to Oocyte/zygote/embryo maturation arrest 14, MIM# 620276 Review for gene: CDC20 was set to GREEN Added comment: i) PMID: 32666501- Biallelic (homozygous/compound heterozygous) variants in 5 unrelated Chinese women with infertility due to oocyte maturation arrest. Knocked down mouse oocytes showed an metaphase I (MI) arrest phenotype that could be rescued by injection of wildtype human CDC20 cRNA; all of the variants significantly reduced the ability of CDC20 to rescue the phenotype. ii) PMID: 33683667- a compound heterozygous (missense and nonsense) variant in a Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest. iii) PMID: 33898437- 4 patients from 3 Chinese families with homozygous or compound heterozygous variants with infertility due to oocyte maturation arrest, fertilization failure, and early embryonic arrest. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that the homozygous and compound heterozygous variants significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest). iv) PMID: 34218387- homozygous missense variant in a Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of MII oocytes. Sources: Literature |
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| Mendeliome v1.2430 | CCNB3 |
Zornitza Stark gene: CCNB3 was added gene: CCNB3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CCNB3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCNB3 were set to 35722368; 32938693; 34021051; 30770433; 34850816 Phenotypes for gene: CCNB3 were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CCNB3-related Review for gene: CCNB3 was set to GREEN Added comment: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29) ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II. iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I. Supporting mouse evidence: iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos. v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development). Sources: Expert Review |
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| Mendeliome v1.2396 | HEPHL1 |
Sangavi Sivagnanasundram changed review comment from: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755 Reported in a proband with chet variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism; to: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755 Reported in a proband with biallelic variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism |
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| Mendeliome v1.2396 | HEPHL1 |
Sangavi Sivagnanasundram changed review comment from: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755 Reported in a proband with chet variants. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism; to: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755 Reported in a proband with chet variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism |
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| Mendeliome v1.2386 | CRMP1 |
Achchuthan Shanmugasundram changed review comment from: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants. PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID. There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence. Sources: Literature; to: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants. PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID. Summary: There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence. Sources: Literature |
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| Mendeliome v1.2386 | CRMP1 |
Achchuthan Shanmugasundram gene: CRMP1 was added gene: CRMP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRMP1 were set to 36511780; 39758889 Phenotypes for gene: CRMP1 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: CRMP1 was set to AMBER Added comment: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants. PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID. There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence. Sources: Literature |
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| Mendeliome v1.2289 | PTPMT1 |
Bryony Thompson gene: PTPMT1 was added gene: PTPMT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPMT1 were set to 39279645; 37672386 Phenotypes for gene: PTPMT1 were set to inborn mitochondrial metabolism disorder MONDO:0004069 Review for gene: PTPMT1 was set to GREEN Added comment: 6 cases from 3 independent families with biallelic variants in PTPMT1 (a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis). All cases presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome including developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Supporting knockout zebrafish and mouse models. Sources: Literature |
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| Mendeliome v1.2274 | PPA1 |
Zornitza Stark gene: PPA1 was added gene: PPA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPA1 were set to 37999237 Phenotypes for gene: PPA1 were set to Galactosaemia, MONDO:0018116 Review for gene: PPA1 was set to RED Added comment: Homozygous missense variant detected in two siblings with increased galactose and galactose-related metabolites ascertained in neonatal screening. Some supportive functional data. Sources: Literature |
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| Mendeliome v1.2248 | DAP3 |
Zornitza Stark gene: DAP3 was added gene: DAP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DAP3 were set to 39701103 Phenotypes for gene: DAP3 were set to Mitochondrial disease MONDO:0044970, DAP3-related Review for gene: DAP3 was set to GREEN Added comment: DAP3 encodes the mitoribosomal small subunit 29 (MRPS29). Five unrelated individuals reported with bi-allelic variants in DAP3 and variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Sources: Literature |
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| Mendeliome v1.2237 | LRRC8C |
Sangavi Sivagnanasundram changed review comment from: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy. Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome. Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF. Sources: Literature; to: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy. Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome. Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF. Supporting in vitro functional assay was conducted however further evidence is required to upgrade the gene classification. Sources: Literature |
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| Mendeliome v1.2235 | LRRC8C |
Sangavi Sivagnanasundram gene: LRRC8C was added gene: LRRC8C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LRRC8C were set to 39623139 Phenotypes for gene: LRRC8C were set to TIMES syndrome MIM#621056 Mode of pathogenicity for gene: LRRC8C was set to Other Review for gene: LRRC8C was set to RED Added comment: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy. Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome. Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF. Sources: Literature |
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| Mendeliome v1.2199 | PDE12 |
Chirag Patel gene: PDE12 was added gene: PDE12 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE12 were set to PMID: 39567835 Phenotypes for gene: PDE12 were set to Mitochondrial disease MONDO:0044970 Review for gene: PDE12 was set to GREEN Added comment: 3 families (2 consanguineous) with 5 affected individuals with early onset mitochondrial disease presentation (3 liveborn, 2 intrauterine death). -Family 1: 1 x infant death @3mths (no clinical information), 1 x 7yr old with neonatal respiratory and lactic acidosis, developmental delay, and mitochondrial respiratory chain deficiencies, and marked cytochrome c oxidase (COX) deficiency in muscle. -Family 2: 1 x neonatal death @2days with metabolic acidosis and lactic acidosis, respiratory failure, lissencephaly, dysgenesis of the corpus callosum and extensive periventricular and subcortical cysts. Normal pyruvate dehydrogenase complex and electron transfer chain activities in fibroblasts. -Family 3: 2 x fetuses (13wks and 22wks) with increase nuchal translucency and reduced fetal movements. One had intra-uterine growth retardation, hydrops and cystic hygroma. The other had permanent flexion contractures of four limbs). Western blotting in fetal skeletal muscle showed absent respiratory chain complexes (I, IV, and V). WES in all 3 families identified 3 different homozygous missense variants in PDE12 gene (p.Tyr155Cys, p.Gly372Glu, and p.Arg41Pro). All variants segregated with disease, were rare in gnomAD, and in silico pathogenicity prediction tools pointed towards a high likelihood of pathogenicity. PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Sources: Literature |
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| Mendeliome v1.2178 | CTGF | Bryony Thompson Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to Kyphomelic dysplasia MONDO:0008881; Spondyloepimetaphyseal dysplasia MONDO:0100510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2175 | CTGF | Bryony Thompson reviewed gene: CTGF: Rating: RED; Mode of pathogenicity: None; Publications: 39414788; Phenotypes: Spondyloepimetaphyseal dysplasia MONDO:0100510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2164 | RAB35 |
Bryony Thompson changed review comment from: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays. PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6). Sources: Literature; to: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays. PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6). Cosegergation in 1 affected relative also reported. Sources: Literature |
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| Mendeliome v1.2164 | RAB35 |
Bryony Thompson gene: RAB35 was added gene: RAB35 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB35 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: RAB35 were set to 38432637; 36928819 Phenotypes for gene: RAB35 were set to familial hypercholesterolemia MONDO:0005439; neurodevelopmental disorder MONDO:0700092 Review for gene: RAB35 was set to RED Added comment: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays. PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6). Sources: Literature |
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| Mendeliome v1.2162 | ARPC3 |
Bryony Thompson gene: ARPC3 was added gene: ARPC3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARPC3 were set to 36928819; 26166300 Phenotypes for gene: ARPC3 were set to Charcot-Marie-Tooth disease MONDO:0015626 Review for gene: ARPC3 was set to AMBER Added comment: Posterior probability association (PPA) 0.995 for Charcot-Marie Tooth disease under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 549 CMT cases and 54,856 controls used in BeviMed analysis. 5 rare variants (missense, splice region, a splice acceptor site) enriched in the CMT cohort (n=14). Additionally, ArpC3 conditional knockout mice fail to ensheath axons causing axon dysfunction. Sources: Literature |
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| Mendeliome v1.2161 | USP33 |
Bryony Thompson changed review comment from: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6). Sources: Literature; to: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 182 early-onset hypertension cases and 55,305 controls used in BeviMed analysis. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6). Sources: Literature |
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| Mendeliome v1.2161 | FMN1 | Bryony Thompson changed review comment from: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); to: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 510 CHI cases assessed and 54,738 controls in BeviMed analysis. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2159 | USP33 |
Bryony Thompson gene: USP33 was added gene: USP33 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: USP33 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: USP33 were set to 36928819 Phenotypes for gene: USP33 were set to Renal hypertension MONDO:0001105 Review for gene: USP33 was set to AMBER Added comment: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6). Sources: Literature |
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| Mendeliome v1.2154 | FMN1 | Bryony Thompson edited their review of gene: FMN1: Added comment: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); Changed publications: 20610440, 19383632, 15202026, 36928819; Changed phenotypes: Hearing loss disorder MONDO:0005365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2129 | APOA4 |
Zornitza Stark gene: APOA4 was added gene: APOA4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: APOA4 were set to 38096951 Phenotypes for gene: APOA4 were set to Hereditary amyloidosis, MONDO:0018634, APOA4-related Review for gene: APOA4 was set to GREEN Added comment: 5 families with autosomal dominant medullary amyloidosis. WGS/WES identified 2 different variants in the APOA4 gene (p.D33N in 3 families and p.L66V in 2 families). The variants were absent in gnomAD, located at the structurally flexible N-terminal domain of APOA4, and segregated with disease. There were 48 genotype +ve individuals with 44/48 having an eGFR <60. All clinically affected individuals presented with a bland urinary sediment, CKD, and no clinical evidence of systemic amyloidosis. Mean age of dialysis/transplantation was 58+/-11yrs. Routine kidney biopsies limited to the kidney cortex showed tubulointerstitial fibrosis and secondary glomerulosclerosis and no amyloid deposition. Four affected individuals were shown to have isolated medullary deposition of amyloid, with mass spectrometry showing the mutated Apoa4 as the primary constituent in 3 available cases. Plasma total ApoA4 levels were increased for patients (n=15) with ApoA4 mutations versus controls (n=49). They hypothesize that the amino acid substitutions alter the tertiary or quaternary structure of the mutated ApoA4, leading to increased plasma and primary urine concentrations and isolated medullary amyloid deposition. Sources: Literature |
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| Mendeliome v1.2113 | ME2 |
Bryony Thompson gene: ME2 was added gene: ME2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ME2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ME2 were set to 39401966 Phenotypes for gene: ME2 were set to inborn disorder of energy metabolism MONDO:0019243 Review for gene: ME2 was set to RED Added comment: A single individual with a homozygous frameshift variant from a consanguineous family. The phenotype included developmental delay, microcephaly, mild brain atrophy, peripheral hypotonia, subtle dysmorphic features, ectopic kidney, and mild lactate elevation. Deletion of yeast ortholog of the gene resulted in growth arrest (which could be rescued). Sources: Literature |
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| Mendeliome v1.2106 | GON4L |
Bryony Thompson gene: GON4L was added gene: GON4L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GON4L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GON4L were set to 39500882; 21937992; 31785789; 34011629; 33077954 Phenotypes for gene: GON4L were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: GON4L was set to GREEN Added comment: 2 LoF variants in 4 cases from 3 unrelated consanguineous families, and supporting null zebrafish model PMID: 39500882 - 2 homozygous truncating GON4L variants [NM_001282860.2: c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in 3 patients from 2 consanguineous families with prenatal-onset growth impairment, developmental delay, mild intellectual disability, speech impairment, progressive and disproportionate microcephaly, facial asymmetry, congenital heart anomaly, and brain structure abnormalities. Null zebrafish model had distinct morphological and size abnormalities in the craniofacial cartilage of zebrafish larvae Heterozygous carriers in biallelic families were unaffected PMID: 21937992 - a case from Iran from a consanguineous family homozygous for c.5517+1G>A with syndromic ID. No other clinical details provided Limited evidence for AD gene-disease association - heterozygous de novo variants identified in autism studies and a congenital hydrocephalus study. But, heterozygous carriers in families with biallelic LoF variants are healthy PMID: 31785789 - 4 (3 NS & 1 Silent) de novo GON4L variants in cases with autism (n=3) & neurodevelopmental disorder PMID: 34011629 - 2 cases with autism spectrum disorder and de novo missense PMID: 33077954 - a de novo splice site variant identified in a single case with congenital hydrocephalus Sources: Literature |
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| Mendeliome v1.2028 | ZDHHC16 |
Ain Roesley gene: ZDHHC16 was added gene: ZDHHC16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZDHHC16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZDHHC16 were set to 39313616 Phenotypes for gene: ZDHHC16 were set to neurodevelopmental disorder MONDO:0700092, ZDHHC16-related Review for gene: ZDHHC16 was set to AMBER gene: ZDHHC16 was marked as current diagnostic Added comment: 6 families including a pair of siblings Amber because 5 of the families had non specific phenotypes listed Abnormality of: the nervous system, metabolism/homeostasis, head/neck, immune system, the integument, the digestive system, the respiratory system, the endocrine system, Growth abnormality the skeletal system, the musculature, the eye Specific HPOs were provided for one individual (homoyzygous for a canonical splice) Abnormality of the face; Cerebellar hypoplasia; Developmental regression; Encephalopathy; Hyperreflexia; Hypertonia; Hypotonia; Inguinal hernia; Laryngomalacia; Microcephaly; Motor delay; Optic atrophy; Seizure; Spastic paraparesis; Spasticity; Talipes equinovarus; Umbilical hernia Sources: Literature |
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| Mendeliome v1.2014 | THAP11 | Zornitza Stark Phenotypes for gene: THAP11 were changed from Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2013 | THAP11 | Zornitza Stark edited their review of gene: THAP11: Changed phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1998 | SGMS1 |
Mark Cleghorn gene: SGMS1 was added gene: SGMS1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: SGMS1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SGMS1 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: SGMS1 was set to AMBER Added comment: SGMS1 Johannes Kopp, Charite Berlin ESHG presentation 4/6/24, unpublished Biallelic SGMS1 with novel metabolic disorder Only 2 families (3 cases) reported NDD, AbN cerebral myelination, SNHL, ichthyosis Homozygous or compound het SGMS1 missense Functional work to support role of SGMS1 in sphingolipid metabolism Sources: Other |
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| Mendeliome v1.1915 | SYCP2L | Zornitza Stark changed review comment from: PMID: 38521400 - A homozygous nonsense variant segregated with POI in a pedigree with two affected sisters (c.1528C>T, p.(Gln510Ter)) PMID: 32303603 - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L. Concordant mouse model.; to: PMID: 38521400 - A homozygous nonsense variant segregated with POI in a pedigree with two affected sisters c.1528C>T, p.(Gln510Ter) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1888 | SLC7A5 |
Sangavi Sivagnanasundram gene: SLC7A5 was added gene: SLC7A5 was added to Mendeliome. Sources: Other Mode of inheritance for gene: SLC7A5 was set to Unknown Publications for gene: SLC7A5 were set to 29884839 Phenotypes for gene: SLC7A5 were set to Large neutral amino acid transporter deficiency (MIM#600182) Review for gene: SLC7A5 was set to RED Added comment: Classified an inborn error of amino acid metabolism by IEMbase however more evidence is required to support the gene-disease association. Sources: Other |
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| Mendeliome v1.1876 | SELENBP1 |
Sangavi Sivagnanasundram gene: SELENBP1 was added gene: SELENBP1 was added to Mendeliome. Sources: ClinGen Mode of inheritance for gene: SELENBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SELENBP1 were set to 29255262 Phenotypes for gene: SELENBP1 were set to extraoral halitosis due to methanethiol oxidase deficiency MONDO:0029144 Review for gene: SELENBP1 was set to GREEN Added comment: 3 unrelated probands in one publication. All reported individuals had a “cabbage-like” breath odour due to the elevated levels of methanethiol and dimethylsulfide in their breath. Knockout mouse model recapitulating the human phenotype including the biochemical characteristics. Classified as Moderate by ClinGen Aminoacidopathy GCEP on 11/11/2022 https://search.clinicalgenome.org/CCID:006103 Sources: ClinGen |
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| Mendeliome v1.1837 | HYKK |
Zornitza Stark gene: HYKK was added gene: HYKK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HYKK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HYKK were set to 23242558 Phenotypes for gene: HYKK were set to inborn disorder of lysine and hydroxylysine metabolism MONDO:0017351 Review for gene: HYKK was set to RED Added comment: No known gene-disease association as classified by ClinGen Aminoacidopathy GCEP on 14/07/2023 - https://search.clinicalgenome.org/CCID:005104 HYKK has been reported as a disorders of lysine, hydroxylysine, and tryptophan metabolism by ICIMD however there are no reported pathogenic variants in this gene to support the gene-disease association. Sources: Literature |
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| Mendeliome v1.1836 | KMO |
Zornitza Stark gene: KMO was added gene: KMO was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KMO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KMO were set to 28187857; 24189070 Phenotypes for gene: KMO were set to pellagra MONDO:0019975 Review for gene: KMO was set to RED Added comment: Classified as no known disease relationship by ClinGen Aminoacidopathy GCEP on 12/05/2023 - https://search.clinicalgenome.org/CCID:005248 Only two knock out mouse models have ben reported that exhibited behavioural changes including memory impairment and anxiety like behaviour. Not reported as disease causing in any affected individuals at this stage and no evidence of any inborn errors of amino acid metabolism. Sources: Literature |
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| Mendeliome v1.1814 | FAM177A1 |
Chirag Patel gene: FAM177A1 was added gene: FAM177A1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM177A1 were set to PMID: 38767059, 25558065 Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder, MONDO_0100500 Review for gene: FAM177A1 was set to GREEN gene: FAM177A1 was marked as current diagnostic Added comment: PMID: 38767059 5 individuals from 3 unrelated families reported with with biallelic loss of function variants in FAM177A1. Clinical features included: global developmental delay, intellectual disability, seizures, behavioural abnormalities, hypotonia, gait disturbance, and macrocephaly. They showed that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. PMID: 25558065 A study of 143 multiplex consanguineous families identified a homozygous frameshift variant in FAM177A1 in 1 family with 4 affected siblings with intellectual disability, dolicocephaly, obesity, and macrocephaly. The variant segregated with all 4 affected siblings and parents were confirmed heterozygous carriers. Sources: Literature |
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| Mendeliome v1.1781 | UFSP2 |
Zornitza Stark edited their review of gene: UFSP2: Added comment: PMID: 37214758: Additional patient with spondyloepimetaphyseal dysplasia type Di Rocco: - het missense Cys302Ser - confirmed de novo in segregation analyses - absent in gnomAD - no functional studies on the missense. Four AD missense reported in the literature so far are located in the C-term catalytic domain - 1x hip dysplasia, Beukes type and 3x spondyloepimetaphyseal dysplasia type Di Rocco. The well reported AR missense (associated with neurodevelopmental anomalies and epilepsy) is located in the N-terminal domain possibly involved in substrate binding.; Changed publications: 33473208, 26428751, 28892125, 32755715, 37214758 |
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| Mendeliome v1.1768 | SLC52A1 | Bryony Thompson reviewed gene: SLC52A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37510312, 29122468, 21089064; Phenotypes: Maternal riboflavin deficiency MONDO:0014013, Disorders of riboflavin metabolism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1765 | GLUL | Zornitza Stark Phenotypes for gene: GLUL were changed from Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism to Developmental and epileptic encephalopathy 116, MIM# 620806; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1732 | PRMT9 |
Chirag Patel gene: PRMT9 was added gene: PRMT9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRMT9 were set to PMID: 38561334 Phenotypes for gene: PRMT9 were set to Neurodevelopmental disorder, MONDO:0100500 Review for gene: PRMT9 was set to RED Added comment: A homozygous variant (G189R) in PRMT9 is reported based on large WGS study in 136 consanguineous families - unclear if only found in 1 family and no clinical information on case(s). PMRTs (protein arginine methyltransferases) catalyse post translational modification via arginine methylation. Functional studies showed that the G189R variant abolishes PRMT9's methyltransferase activity - specifically at the R508 residue of SF3B2 RNA (exclusively methylated by PRMT9) - and leads to heavy PRMT9 ubiquitination, and abnormal splicing activity of SF3B2. Knock out mouse model showed PRMT9 loss in excitatory neurons leads to aberrant synapse development and impaired learning and memory. Sources: Literature |
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| Mendeliome v1.1685 | GALE | Zornitza Stark Phenotypes for gene: GALE were changed from Galactose epimerase deficiency MIM#230350; Disorders of galactose metabolism to Galactose epimerase deficiency MIM#230350; Thrombocytopenia 12, syndromic, MIM#620776 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1673 | GLUL | Zornitza Stark Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism to Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1660 | TRPV5 |
Sangavi Sivagnanasundram changed review comment from: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. Sources: Other; to: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. PMID: 14679186 TRPV5 knockout mice model was used to assess whether the abolishment of TRPV5 led to a disruption in Ca2+ handling. The effects of the disruption in Ca2+ handling resulted in bone abnormalities in the mice and is likely the cause of idiopathic hypercalciuria. Sources: Other |
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| Mendeliome v1.1639 | ZNF143 | Bryony Thompson reviewed gene: ZNF143: Rating: AMBER; Mode of pathogenicity: None; Publications: 27349184, 33845046, 9009278, 22268977, 27349184, 27349184; Phenotypes: methylmalonic aciduria and homocystinuria MONDO:0016826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1634 | TRPV5 |
Sangavi Sivagnanasundram gene: TRPV5 was added gene: TRPV5 was added to Mendeliome. Sources: Other Mode of inheritance for gene: TRPV5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRPV5 were set to PMID: 38528055 Phenotypes for gene: TRPV5 were set to TRPV5-related hypercalciuria (MONDO:0009550) Review for gene: TRPV5 was set to RED Added comment: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. Sources: Other |
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| Mendeliome v1.1630 | PRDX1 |
Bryony Thompson gene: PRDX1 was added gene: PRDX1 was added to Mendeliome. Sources: Literature digenic tags were added to gene: PRDX1. Mode of inheritance for gene: PRDX1 was set to Other Publications for gene: PRDX1 were set to 29302025; 35190856 Phenotypes for gene: PRDX1 were set to methylmalonic aciduria and homocystinuria type cblC MONDO:0010184 Mode of pathogenicity for gene: PRDX1 was set to Other Review for gene: PRDX1 was set to GREEN Added comment: Only variants affecting the canonical splice acceptor site of intron 5 (e.g. c.515-1G-T, c.515-2A-T) that cause skipping of exon 6 and the polyA termination signal of PRDX1 produce an MMACHC epimutation. The resulting read-through transcript extends through the adjacent MMACHC locus in the antisense orientation. These PRDX1 exon 6 acceptor splice site variants cause disease through digenic inheritance with a pathogenic MMACHC on the other allele. Sources: Literature |
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| Mendeliome v1.1587 | ZSCAN10 |
Rylee Peters gene: ZSCAN10 was added gene: ZSCAN10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZSCAN10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZSCAN10 were set to PMID: 38386308 Phenotypes for gene: ZSCAN10 were set to syndromic disease MONDO:0002254 Review for gene: ZSCAN10 was set to GREEN Added comment: Bi-allelic ZSCAN10 loss-of-function variants were identified in seven affected individuals from five unrelated families with syndromic neurodevelopmental disorder. Highly consistent phenotypic features include global developmental delay, behavioural abnormalities, and variable facial asymmetry with outer and inner ear malformations leading to profound SNHL. Facial asymmetry was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Sources: Literature |
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| Mendeliome v1.1580 | NIT1 |
Paul De Fazio gene: NIT1 was added gene: NIT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NIT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NIT1 were set to 38430071 Phenotypes for gene: NIT1 were set to Cerebrovascular disorder, NIT1-related (MONDO:0011057) Penetrance for gene: NIT1 were set to unknown gene: NIT1 was marked as current diagnostic Added comment: 5 unrelated families reported with recessively inherited cerebral small vessel disease had compound hetereozygous or homozygous variants in NIT1. 1 family (3 siblings) had p.(Ala68*) in trans with p.(Arg243Trp), the remaining 4 families (1 individual each) were all homozygous for p.(Arg243Trp). Patients presented in mid-adulthood with progressive movement disorders (e.g. dystonia, chorea, bradykinesia and tremor, gait disturbance, dysarthria) and had abnormal brain MRI findings (honeycomb appearance of the basal ganglia-thalamus complex, due to numerous strongly dilated PVS). 3 patients had non-lobar intracerebral hemorrhage. Slowly progressive cognitive decline was also a key feature. Metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Note p.(Arg243Trp) has 1 homozygote in gnomAD v4, but permitted due to later presentation in reported patients. Sources: Literature |
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| Mendeliome v1.1564 | KLF14 |
Hali Van Niel changed review comment from: PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other; to: Cannot find any evidence of association with mendelian disease PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other |
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| Mendeliome v1.1564 | KLF14 |
Hali Van Niel gene: KLF14 was added gene: KLF14 was added to Mendeliome. Sources: Other Mode of inheritance for gene: KLF14 was set to Unknown Publications for gene: KLF14 were set to 33389382; 35081256; 24486580 Phenotypes for gene: KLF14 were set to diabetes mellitus MONDO:0005015 Review for gene: KLF14 was set to RED Added comment: PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other |
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| Mendeliome v1.1558 | STAB1 | Zornitza Stark Phenotypes for gene: STAB1 were changed from Iron metabolism disease (MONDO:0002279), STAB1-related to Hyperferritinemia, MIM# 620729 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1543 | ONECUT1 |
Bryony Thompson gene: ONECUT1 was added gene: ONECUT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ONECUT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ONECUT1 were set to 37639628; 34663987; 10825208 Phenotypes for gene: ONECUT1 were set to Neonatal diabetes mellitus MONDO:0016391 Review for gene: ONECUT1 was set to GREEN Added comment: 3 unrelated neonatal diabetes cases with homozygous variants & supporting iPSC/mouse models PMID: 37639628 - UK biobank study of ONECUT1 variants in neonatal diabetes mellitus (NDM), MODY, and type 2 diabetes. Identified a case with syndromic NDM with a homozygous frameshift (p.Met289Argfs*8). Rare heterozygous variants were not enriched in individuals with suspected MODY (n=484). Heterozygous null variants were significantly associated with type 2 diabetes (p=0.006) as a potential susceptibility gene. PMID: 34663987 - 2 consanguineous families with homozygous variants (Glu231Ter or Glu231Asp) in cases with syndromic ND. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation. PMID: 10825208 - Hnf6 (old gene name) null mice have diabetes Sources: Literature |
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| Mendeliome v1.1529 | NDUFB9 |
Zornitza Stark edited their review of gene: NDUFB9: Added comment: PMID: 38129218: Thr144Met, listed as ACMG-P, hom in 1x pt with mito complex I deficiency and leukodystrophy, no functional studies, both parents are het. However, this variant has 2 homozygotes in gnomADv4 so unlikely pathogenic.; Changed publications: 22200994, 38129218 |
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| Mendeliome v1.1502 | SH2B3 |
Ain Roesley commented on gene: SH2B3: PMID:37206266 2x families - hom missense variant Val402Met: functional performed on patient's fibroblasts demonstrated increased basal pSTAT5, pSTAT3 and increased pJAK2 + pSTAT5 after stimulation with IL-3, GH, GM-CSF and EPO - hom fs Arg148Profs*40 functional performed in zebrafish demonstrated increased number of macrophages and thrombocytes PMID:23908464; 1 fam with 2 affecteds with dev delay + autoimmunity + (1x) ALL, hom for Asp231Gly fs*3 PMID:38152053; JMML cohort - 2x hom missense + 2x het PTCs |
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| Mendeliome v1.1486 | PCYT1A | Zornitza Stark Phenotypes for gene: PCYT1A were changed from Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Congenital lipodystrophy to Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Lipodystrophy, congenital generalized, type 5, MIM# 620680 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1485 | PCYT1A | Zornitza Stark edited their review of gene: PCYT1A: Changed phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940, Lipodystrophy, congenital generalized, type 5, MIM# 620680 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1449 | ERI1 | Zornitza Stark Phenotypes for gene: ERI1 were changed from Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related to Hoxha-Aliu syndrome, MIM# 620662; Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1448 | ERI1 | Zornitza Stark reviewed gene: ERI1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hoxha-Aliu syndrome, MIM# 620662, Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1401 | PLA2G16 |
Lauren Rogers changed review comment from: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature; to: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature |
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| Mendeliome v1.1401 | PLA2G16 |
Lauren Rogers gene: PLA2G16 was added gene: PLA2G16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLA2G16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PLA2G16 were set to PMID: 37919452 Phenotypes for gene: PLA2G16 were set to Lipodystrophy (MONDO:0006573) Review for gene: PLA2G16 was set to GREEN Added comment: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature |
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| Mendeliome v1.1401 | SEL1L |
Sarah Pantaleo gene: SEL1L was added gene: SEL1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEL1L were set to PMID: 37943610; PMID: 37943617 Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder, MONDO:0700092, SEL1L-related Penetrance for gene: SEL1L were set to Complete Added comment: Wang paper PMID: 37943610 SEL1L protein is involved in the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation. Report two biallelic missense variants in SEL1L in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia (termed ERAD-associated neurodevelopment disorder with onset in infancy (ENDI). The variants were hypomorphic and impaired ERAD function. Identified by WES. Parents heterozygous and asymptomatic. P.(Gly585Asp) in Patient 1, p.(Met528Arg) in Patients 2 and 3 (siblings). All variants cause substrate accumulation. The extent of substrate accumulation in knockin cells was modest compared to those in knockout cells, pointing to a hypomorphic nature. They also had a variant in HRD1. Weis paper PMID: 37943617 Third variant p.(Cys141Tyr), biallelic, causing premature death in five patients from a consanguineous family with early-onset neurodevelopmental disorders and agammaglobulinaemia due to severe SEL1L-HRD1 ERAD dysfunction. This variant appears to have a more severe outcome, exhibiting B cell depletion and agammaglobulinaemia, causing the most severe dysfunction among all of the variants described by this group so far. They postulate that functionality of SEL1L-HRD1 ERAD is inversely correlated with disease severity in humans. Their symptoms were dev delay, neurological disorder and agammaglobulinaemia in childhood. Along with severe axial hypotonia, short stature and microcephaly. “Not a complete loss-of-function variant”. Sources: Literature |
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| Mendeliome v1.1401 | FOXL1 |
Lilian Downie gene: FOXL1 was added gene: FOXL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOXL1 were set to PMID: 34633540 Phenotypes for gene: FOXL1 were set to Otosclerosis 11 #MIM620576 Review for gene: FOXL1 was set to RED Added comment: Single paper with variant in large AD family from Newfoundland with otosclerosis, hearing loss onset varied from late teens onwards. Segregation not completely convincing, 1 person with the deletion without otosclerosis. Conductive HL, sometimes mixed, not isolated SNHL. Second family with common haplotype and same 15bp deletion with otosclerosis. Functional studies. High population frequency and 3x homozygotes. Sources: Literature |
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| Mendeliome v1.1380 | DOT1L |
Zornitza Stark gene: DOT1L was added gene: DOT1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DOT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DOT1L were set to 37827158 Phenotypes for gene: DOT1L were set to Neurodevelopmental disorder, MONDO:0700092, DOT1L-related Mode of pathogenicity for gene: DOT1L was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: DOT1L was set to GREEN Added comment: Nine individuals reported with seven de novo missense variants. All had DD/ID and variable patterns of associated congenital anomalies. Variants demonstrated to be GoF and lead to increased H3K79 methylation levels in flies and human cells. Sources: Literature |
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| Mendeliome v1.1363 | MDM4 |
Bryony Thompson gene: MDM4 was added gene: MDM4 was added to Mendeliome. Sources: Other Mode of inheritance for gene: MDM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MDM4 were set to 32300648; 33104793 Phenotypes for gene: MDM4 were set to bone marrow failure syndrome MONDO:0000159, MDM4-related Review for gene: MDM4 was set to AMBER Added comment: A single family was reported to segregate a missense variant (p.Thr454Met) with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. A mouse model of p.Thr454Met showed increased p53 activity, decreased telomere length, and bone marrow failure. Sources: Other |
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| Mendeliome v1.1327 | AXIN1 |
Zornitza Stark edited their review of gene: AXIN1: Added comment: PMID: 37582359 - four families (7 individuals) with three homozygous truncating variants. - all variant shown to result in reduced protein, though 1/3 would be NMD predicted - Probands had macrocephaly (4/6), GDD (3/7), hip dysplasia (5/6), cardiac anomalies eg. VSD/ASD (3/7), cranial hyperostosis and vertebral endplate sclerosis; Changed rating: GREEN; Changed publications: 37582359; Changed phenotypes: Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v1.1327 | AXIN1 | Zornitza Stark Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related to Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1318 | ZFHX3 | Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1235 | CYBRD1 | Zornitza Stark Phenotypes for gene: CYBRD1 were changed from Iron overload to Iron metabolism disease, MONDO:0002279, CYBRD1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1234 | CYBRD1 | Zornitza Stark edited their review of gene: CYBRD1: Changed phenotypes: Iron metabolism disease, MONDO:0002279, CYBRD1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1188 | MCCC1 | Bryony Thompson reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36822454, 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1165 | FTCD |
Bryony Thompson changed review comment from: Well-established gene-disease association (see OMIM entry). Glutamate formiminotransferase deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism. Sources: NHS GMS; to: Glutamate formiminotransferase deficiency is classified as a benign form of folate metabolism disorder and an inborn error of amino acid metabolism without clinically significant phenotype (http://iembase.com/disorder/47). |
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| Mendeliome v1.1117 | APOL1 |
Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021 Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2. PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance. PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN rs73885319 (G1) OR 9.66, p=9.97E-25 rs60910145 (G1) OR 9.75, p=9.04E-24 rs71785313 (G2) OR 5.69, p=3.39E-06 2 APOL1 risk alleles OR 18.31, p=3.31E-58 PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease G1: p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes) p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes) G2: p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER |
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| Mendeliome v1.1117 | GOSR2 |
Achchuthan Shanmugasundram changed review comment from: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).; to: This gene should be added in 'Deafness_IsolatedAndComplex' panel with red rating. Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134). |
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| Mendeliome v1.1116 | DDRGK1 |
Ain Roesley gene: DDRGK1 was added gene: DDRGK1 was added to Mendeliome. Sources: Literature founder tags were added to gene: DDRGK1. Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336 Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type (MIM#602557) Review for gene: DDRGK1 was set to GREEN gene: DDRGK1 was marked as current diagnostic Added comment: RNA and protein studies performed for the splice variant. These two variants likely represents founder variants PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development. PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD. In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455). Sources: Literature |
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| Mendeliome v1.1074 | EZH1 |
Zornitza Stark gene: EZH1 was added gene: EZH1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EZH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: EZH1 were set to 37433783 Phenotypes for gene: EZH1 were set to Neurodevelopmental disorder (MONDO:0700092), EZH1-related Review for gene: EZH1 was set to GREEN Added comment: PMID: 37433783 Variants were identified 19 individuals from 14 unrelated families, all sharing a clinical phenotype of a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features. Functional studies have shown that some missense EZH1 variants lead to GOF with increased methyltransferase activity and recessive variants impair EZH1 expression causing loss of function effects. Sources: Literature |
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| Mendeliome v1.1064 | STAB1 |
Chern Lim gene: STAB1 was added gene: STAB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STAB1 were set to 37490907; 28052375 Phenotypes for gene: STAB1 were set to Iron metabolism disease (MONDO:0002279), STAB1-related Review for gene: STAB1 was set to GREEN gene: STAB1 was marked as current diagnostic Added comment: PMID: 37490907 - Biallelic variants identified in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies. - Homozygous/compound heterozygous variants: missense, frameshift, stopgain, inframe del of 3 AAs, one synonymous. - Samples from three of the patients from two families showed no immunoreactivity with anti-stabilin-1 compared to control liver where high signal was detected in the liver sinusoids (immunohistochemistry analysis). - Patients’ peripheral monocytes and monocyte-derived macrophages showed very little expression of stabilin-1 on CD14+ monocytes and macrophages compared to control subjects (flow cytometry analysis). - These families have also been published in PMID: 28052375. Sources: Literature |
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| Mendeliome v1.1054 | STX5 |
Ain Roesley gene: STX5 was added gene: STX5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related Review for gene: STX5 was set to AMBER gene: STX5 was marked as current diagnostic Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US). Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start) phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol. Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking Sources: Literature |
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| Mendeliome v1.1007 | KDM2A |
Chirag Patel gene: KDM2A was added gene: KDM2A was added to Mendeliome. Sources: Other Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder Review for gene: KDM2A was set to GREEN gene: KDM2A was marked as current diagnostic Added comment: ESHG 2023: 14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense) Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism. Functional studies: -patient blood showed aberrant genome wide methylation profile - potential episignature -HEK293T cells showed altered subcellular localisation of KDM2A -Drosophila models showed variants caused neurotoxicity Sources: Other |
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| Mendeliome v1.1001 | DCAF15 |
Chirag Patel gene: DCAF15 was added gene: DCAF15 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome Review for gene: DCAF15 was set to AMBER Added comment: ESHG 2023: 3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child) Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment. WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3). Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli. Sources: Other |
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| Mendeliome v1.997 | PMVK |
Zornitza Stark changed review comment from: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; to: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype. Amber for bi-allelic disease association. |
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| Mendeliome v1.997 | PMVK |
Zornitza Stark edited their review of gene: PMVK: Added comment: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; Changed publications: 26202976, 37364720, 36410683; Changed phenotypes: Porokeratosis 1, multiple types, MIM# 175800, Autoinflammatory syndrome, MONDO:0019751, PMVK-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.992 | ANO1 | Zornitza Stark edited their review of gene: ANO1: Added comment: PMID 37253099: screening analysis of Moyamoya disease (MMD) cohort revealed 8 individuals with variants in the ANO1 gene. Two families had the same rare variant p.Met658Val. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Amber rating due to somewhat conflicting segregation and functional data presented.; Changed publications: 37253099; Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease, MONDO:0016820, ANO1 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.976 | DMAP1 |
Chirag Patel gene: DMAP1 was added gene: DMAP1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DMAP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DMAP1 were set to Neurodevelopmental disorder Review for gene: DMAP1 was set to GREEN gene: DMAP1 was marked as current diagnostic Added comment: ESHG 2023: 9 patients/8 families with bilallelic variants in DMAP1 (3 missense, 7 LOF) All with DD, speech delay, hypotonia, and ID Some with epilepsy (4/6), FTT (4/5), and brain malformations (3/5) Drosophila showed abnormal behaviour pattern and bang sensitivity Specific methylation episignature also seen Sources: Other |
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| Mendeliome v1.957 | ERI1 |
Elena Savva gene: ERI1 was added gene: ERI1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERI1 were set to 37352860 Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related Review for gene: ERI1 was set to GREEN Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families - Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly - Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly - Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive - Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells - K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy with ERI1, staying bound to those RNA molecules" Sources: Literature |
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| Mendeliome v1.956 | RAB34 |
Sarah Pantaleo gene: RAB34 was added gene: RAB34 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAB34 were set to PMID: 37384395 Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies Penetrance for gene: RAB34 were set to Complete Review for gene: RAB34 was set to GREEN Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS. Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher). Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects. RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function. Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands. In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth. All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities. All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance. Sources: Literature |
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| Mendeliome v1.932 | MFN2 | Zornitza Stark Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM #609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM #617087; Hereditary motor and sensory neuropathy VIA, OMIM #601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A 609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087; Hereditary motor and sensory neuropathy VIA, MIM# 601152; Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.931 | MFN2 | Zornitza Stark edited their review of gene: MFN2: Changed phenotypes: Charcot-Marie-Tooth disease, axonal, type 2A2A 609260, Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087, Hereditary motor and sensory neuropathy VIA, MIM# 601152, Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.906 | NSUN6 |
Michelle Torres gene: NSUN6 was added gene: NSUN6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSUN6 were set to 37226891 Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related Review for gene: NSUN6 was set to AMBER Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants: - p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested. - p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers. - p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers. Sources: Literature |
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| Mendeliome v1.836 | SRSF1 |
Paul De Fazio gene: SRSF1 was added gene: SRSF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SRSF1 were set to 37071997 Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092 Review for gene: SRSF1 was set to GREEN gene: SRSF1 was marked as current diagnostic Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism. Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS. Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms. Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17). Sources: Literature |
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| Mendeliome v1.819 | INTS11 |
Achchuthan Shanmugasundram gene: INTS11 was added gene: INTS11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS11 were set to 37054711 Review for gene: INTS11 was set to GREEN Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association. PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Sources: Literature |
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| Mendeliome v1.743 | THAP11 |
Zornitza Stark gene: THAP11 was added gene: THAP11 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: THAP11 were set to 28449119 Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related Review for gene: THAP11 was set to RED Added comment: Single individual reported with homozygous missense variant, supportive functional data. Sources: Expert Review |
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| Mendeliome v1.711 | ATP5B |
Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data. Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism. Sources: Literature; to: PMID 36860166: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data. Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism. Sources: Literature |
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| Mendeliome v1.711 | ATP5B |
Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data. Sources: Literature; to: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data. Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism. Sources: Literature |
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| Mendeliome v1.703 | ZNF143 |
Zornitza Stark gene: ZNF143 was added gene: ZNF143 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF143 were set to 27349184 Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related Review for gene: ZNF143 was set to RED Added comment: Single individual reported with compound heterozygous variants. Sources: Literature |
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| Mendeliome v1.698 | MCF2L |
Michelle Torres gene: MCF2L was added gene: MCF2L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MCF2L was set to Unknown Publications for gene: MCF2L were set to 36760094 Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related Review for gene: MCF2L was set to RED Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7). Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery). Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery). Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested. Sources: Literature |
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| Mendeliome v1.665 | WNT11 |
Achchuthan Shanmugasundram gene: WNT11 was added gene: WNT11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WNT11 were set to 34875064 Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures Review for gene: WNT11 was set to GREEN Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene. Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures. A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures. A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met). This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells. This gene has not yet been reported with any phenotypes either in OMIM or in G2P. Sources: Literature |
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| Mendeliome v1.646 | TRU-TCA1-1 | Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.630 | TRU-TCA1-1 |
Paul De Fazio gene: TRU-TCA1-1 was added gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927 Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425 Review for gene: TRU-TCA1-1 was set to AMBER gene: TRU-TCA1-1 was marked as current diagnostic Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA. PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy. Sources: Literature |
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| Mendeliome v1.593 | UHRF1 |
Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022 - One patient with compound het missense and nonsense variants, both parents are carriers (hets). - The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical. - Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. - Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v1.587 | PHLDB1 |
Seb Lunke gene: PHLDB1 was added gene: PHLDB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PHLDB1 were set to 36543534 Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019 Review for gene: PHLDB1 was set to AMBER Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided. Sources: Literature |
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| Mendeliome v1.541 | TNNC2 |
Zornitza Stark gene: TNNC2 was added gene: TNNC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TNNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNNC2 were set to 33755597 Phenotypes for gene: TNNC2 were set to Congenital myopathy, MONDO:0019952, TNNC2-related Review for gene: TNNC2 was set to GREEN Added comment: Two families reported: Family 1: 4 individuals, three generations; missense variant p.(Asp34Tyr) Family 2: de novo variant, missense p.(Met79Ile) Physiological studies in myofibers isolated from patients’ biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC. Borderline Green: sufficient segregation in Fam 1 plus de novo status in Fam 2, plus functional data. Sources: Literature |
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| Mendeliome v1.507 | GABRA3 |
Sarah Pantaleo gene: GABRA3 was added gene: GABRA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GABRA3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GABRA3 were set to PMID: 29053855 Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features, Penetrance for gene: GABRA3 were set to Incomplete Review for gene: GABRA3 was set to GREEN Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor. Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. Sources: Literature |
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| Mendeliome v1.490 | TAMM41 | Zornitza Stark Phenotypes for gene: TAMM41 were changed from inborn mitochondrial metabolism disorder MONDO:0004069; hypotonia; developmental delay; myopathy; ptosis to Combined oxidative phosphorylation deficiency-56 (COXPD56), MIM#620139; hypotonia; developmental delay; myopathy; ptosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.472 | MTSS1 |
Zornitza Stark gene: MTSS1 was added gene: MTSS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTSS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTSS1 were set to 36067766 Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071) Review for gene: MTSS1 was set to GREEN Added comment: Five individuals with the same heterozygous de novo variant in MTSS2 (NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals presented with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. Sources: Literature |
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| Mendeliome v1.462 | ATP5F1 |
Zornitza Stark gene: ATP5F1 was added gene: ATP5F1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ATP5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP5F1 were set to 36239646 Phenotypes for gene: ATP5F1 were set to Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation-2 (HUMOP2), MIM#620085 Review for gene: ATP5F1 was set to RED Added comment: Identical twins reported with a de novo missense variant in this gene and hyper metabolism: normal thyroid function, hyperphagia, tachypnea, increased basal temperature, and increased sweating. Biochemical studies demonstrated increased mitochondrial oxygen consumption with inefficient production of ATP in the final steps of oxidative phosphorylation due to an uncoupling defect Sources: Expert list |
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| Mendeliome v1.452 | WDR5 |
Bryony Thompson gene: WDR5 was added gene: WDR5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157 Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related Mode of pathogenicity for gene: WDR5 was set to Other Review for gene: WDR5 was set to GREEN Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established. Sources: Literature |
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| Mendeliome v1.439 | METTL23 | Lucy Spencer reviewed gene: METTL23: Rating: AMBER; Mode of pathogenicity: None; Publications: 36099048; Phenotypes: glaucoma MONDO:0005041; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.388 | EXOC6B |
Bryony Thompson gene: EXOC6B was added gene: EXOC6B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC6B were set to 26669664; 30284759; 36150098 Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity MONDO:0019675 Review for gene: EXOC6B was set to GREEN Added comment: 6 affected individuals from 4 families, and supporting assays in patient cells PMID: 26669664 - 2 brothers with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones from a consanguineous family, with a homozygous nonsense variant [c.906T>A/p.(Tyr302*)] PMID: 30284759 - 2 sisters with dislocations of the hips and knees, long slender fingers with distal tapering, significant motor disability but normal (older sister) or low-normal intelligence (younger sister), with a homozygous in-frame deletion of exons 9-20 PMID: 36150098 - 2 unrelated probands from consanguineous families, one with a homozygous frameshift exon 20 deletion and one with a homozygous nonsense variant (c.401T>G p.Leu134Ter). Function assessment of patient fibroblast cell lines indicated abrogation of exocytosis leading to impaired primary ciliogenesis Sources: Literature |
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| Mendeliome v1.364 | SLC13A1 |
Lucy Spencer gene: SLC13A1 was added gene: SLC13A1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC13A1 were set to 36175384 Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related Review for gene: SLC13A1 was set to RED Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad. Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype. Sources: Literature |
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| Mendeliome v1.338 | AQP2 |
Zornitza Stark changed review comment from: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.; to: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants. Onset in infancy. Causes severe dehydration, can be life-threatening. Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin. Clinical trials. |
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| Mendeliome v1.338 | APRT |
Zornitza Stark changed review comment from: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.; to: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic. Treatable: allopurinol or febuxostat, low purine diet. |
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| Mendeliome v1.332 | PTPA |
Zornitza Stark gene: PTPA was added gene: PTPA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPA were set to 36073231 Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related Review for gene: PTPA was set to AMBER Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below. There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID. Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports. ------ Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants. These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation. Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies. Role of the gene: As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders. Variant studies: Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt. Drosophila / animal models: Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment. Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice. Sources: Literature |
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| Mendeliome v1.325 | PPP2R5C |
Teresa Zhao changed review comment from: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability - PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth - VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability; to: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability - PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth - VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability |
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| Mendeliome v1.320 | UFSP2 | Zornitza Stark Phenotypes for gene: UFSP2 were changed from Neurodevelopmental disorder; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974 to Developmental and epileptic encephalopathy 106, MIM# 620028; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.319 | UFSP2 | Zornitza Stark edited their review of gene: UFSP2: Changed phenotypes: Developmental and epileptic encephalopathy 106, MIM# 620028, Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.285 | TYMS |
Lucy Spencer gene: TYMS was added gene: TYMS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TYMS was set to Other Publications for gene: TYMS were set to 35931051 Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780 Review for gene: TYMS was set to RED Added comment: 8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant. The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance. The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children. Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. Sources: Literature |
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| Mendeliome v1.285 | HNRNPH1 |
Hazel Phillimore changed review comment from: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2). In gnomAD, there are very few LOF variants. (LOF shows pLI = 1). The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.; to: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2. In gnomAD, there are very few LOF variants. (LOF shows pLI = 1). The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma. |
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| Mendeliome v1.285 | MET | Zornitza Stark Phenotypes for gene: MET were changed from Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 to Arthrogryposis, distal, type 11 (MIM#620019), AD; Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.284 | MET | Zornitza Stark Publications for gene: MET were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.283 | MET |
Zornitza Stark changed review comment from: PMID 30777867: Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; to: PMID 30777867: Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination. AMBER for this association |
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| Mendeliome v1.283 | MET |
Zornitza Stark edited their review of gene: MET: Added comment: PMID 30777867: Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; Changed publications: 30777867 |
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| Mendeliome v1.259 | NPNT |
Chirag Patel gene: NPNT was added gene: NPNT was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792 Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM # Review for gene: NPNT was set to GREEN Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models. Sources: Literature |
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| Mendeliome v1.151 | KITLG | Zornitza Stark Phenotypes for gene: KITLG were changed from Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697 to Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697; deafness; heterochromia iridis; hypopigmentation of the skin; hyperpigmentation of the skin; Waardenburg syndrome,MONDO:0018094, KITLG-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.96 | NEK8 | Zornitza Stark edited their review of gene: NEK8: Added comment: ESHG 2022: 12 families with paediatric renal cystic disease (enlarged kidneys, kidney cysts, ESKF <20yrs) -3 recurrent HTZ variants in NEK8 kinase domain (Arg45Trp, Ile150Met, Lys157Gln) -suspected dominant negative effect -patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8 (Note carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF); Changed phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174, Familial renal cystic disease MONDO:0019741, NEK8-related, dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.7 | PROSER1 |
Zornitza Stark gene: PROSER1 was added gene: PROSER1 was added to Mendeliome. Sources: Expert Review founder tags were added to gene: PROSER1. Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PROSER1 were set to 35229282 Phenotypes for gene: PROSER1 were set to Syndromic disease MONDO:0002254, PROSER1-related Review for gene: PROSER1 was set to RED Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families, likely founder effect. Sources: Expert Review |
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| Mendeliome v0.14722 | GALT | Zornitza Stark Phenotypes for gene: GALT were changed from to Galactosaemia MIM#230400; Disorders of galactose metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14719 | GAMT | Zornitza Stark Phenotypes for gene: GAMT were changed from to Cerebral creatine deficiency syndrome 2 MIM#612736; Disorders of creatinine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14677 | GIF | Zornitza Stark Phenotypes for gene: GIF were changed from to Intrinsic factor deficiency MIM#261000; Disorders of cobalamin absorption, transport and metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14674 | PRKAG3 | Elena Savva Phenotypes for gene: PRKAG3 were changed from increased glycogen content in skeletal muscle; [Skeletal muscle glycogen content and metabolism QTL] MIM#619030 to increased glycogen content in skeletal muscle | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14671 | PRKAG3 | Elena Savva Phenotypes for gene: PRKAG3 were changed from to increased glycogen content in skeletal muscle; [Skeletal muscle glycogen content and metabolism QTL] MIM#619030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14663 | DMGDH | Elena Savva Phenotypes for gene: DMGDH were changed from to Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14634 | GK | Zornitza Stark Phenotypes for gene: GK were changed from to Glycerol kinase deficiency MIM#307030; Disorders of glycerol metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14622 | GLUL | Zornitza Stark Phenotypes for gene: GLUL were changed from to Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14619 | GLYCTK | Zornitza Stark Phenotypes for gene: GLYCTK were changed from to D-glyceric aciduria MIM#220120; Disorders of serine, glycine or glycerate metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14603 | GNMT | Zornitza Stark Phenotypes for gene: GNMT were changed from to Glycine N-methyltransferase deficiency MIM#606664; Disorders of the metabolism of sulphur amino acids | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14530 | MMADHC | Zornitza Stark Phenotypes for gene: MMADHC were changed from to 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14527 | MMACHC | Zornitza Stark Phenotypes for gene: MMACHC were changed from to Methylmalonic aciduria and homocystinuria, cblC type MIM#277400; Disorders of cobalamin absorption, transport and metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14524 | MMAB | Zornitza Stark Phenotypes for gene: MMAB were changed from to Methylmalonic aciduria, vitamin B12-responsive, cblB type, MIM# 251110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14522 | MMAB | Zornitza Stark reviewed gene: MMAB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, vitamin B12-responsive, cblB type, MIM# 251110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14522 | MMAA | Zornitza Stark Phenotypes for gene: MMAA were changed from to Methylmalonic aciduria, vitamin B12-responsive, cblA type, MIM# 251100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14520 | MMAA | Zornitza Stark reviewed gene: MMAA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, vitamin B12-responsive, cblA type, MIM# 251100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14491 | METTL23 | Zornitza Stark Marked gene: METTL23 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14491 | METTL23 | Zornitza Stark Gene: mettl23 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14491 | METTL23 | Zornitza Stark Phenotypes for gene: METTL23 were changed from to Intellectual developmental disorder, autosomal recessive 44, MIM# 615942 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14490 | METTL23 | Zornitza Stark Publications for gene: METTL23 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14489 | METTL23 | Zornitza Stark Mode of inheritance for gene: METTL23 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14488 | METTL23 | Zornitza Stark reviewed gene: METTL23: Rating: GREEN; Mode of pathogenicity: None; Publications: 24501276, 24626631; Phenotypes: Intellectual developmental disorder, autosomal recessive 44, MIM# 615942; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14488 | MET | Zornitza Stark Marked gene: MET as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14488 | MET | Zornitza Stark Gene: met has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14488 | MET | Zornitza Stark Phenotypes for gene: MET were changed from to Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14487 | MET | Zornitza Stark Mode of inheritance for gene: MET was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14486 | MET | Zornitza Stark edited their review of gene: MET: Changed phenotypes: Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074, Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14486 | MET | Zornitza Stark reviewed gene: MET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Papillary renal cell carcinoma MONDO:0017884; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14441 | MCEE | Zornitza Stark Phenotypes for gene: MCEE were changed from to Methylmalonyl-CoA epimerase deficiency MIM#251120; Organic acidurias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14438 | MCCC2 | Zornitza Stark Phenotypes for gene: MCCC2 were changed from to 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Organic acidurias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14435 | MCCC2 | Zornitza Stark reviewed gene: MCCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14435 | MCCC1 | Zornitza Stark Phenotypes for gene: MCCC1 were changed from to 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Organic acidurias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14432 | MCCC1 | Zornitza Stark reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14404 | PAH | Zornitza Stark Phenotypes for gene: PAH were changed from to Phenylketonuria MIM#261600; Disorders of phenylalanine or tyrosine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14398 | PEPD | Zornitza Stark Phenotypes for gene: PEPD were changed from to Prolidase deficiency MIM#170100; disorders of peptide metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14341 | UGT1A1 | Zornitza Stark Phenotypes for gene: UGT1A1 were changed from to Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport); Crigler-Najjar syndrome, type I 218800; Crigler-Najjar syndrome, type II 606785 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14305 | MTHFR | Zornitza Stark Phenotypes for gene: MTHFR were changed from to Homocystinuria due to MTHFR deficiency MIM#236250; Disorders of folate metabolism and transport | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14288 | MUT | Zornitza Stark Phenotypes for gene: MUT were changed from to Methylmalonic aciduria, mut(0) type, MIM# 251000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14285 | MUT | Zornitza Stark reviewed gene: MUT: Rating: GREEN; Mode of pathogenicity: None; Publications: 1977311, 11528502, 12948746; Phenotypes: Methylmalonic aciduria, mut(0) type, MIM# 251000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14115 | SLC19A3 | Zornitza Stark Phenotypes for gene: SLC19A3 were changed from to Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), MIM# 607483 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14112 | SLC19A3 | Zornitza Stark reviewed gene: SLC19A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15871139, 20065143, 23482991, 24878502, 23589815, 24166474, 26975589, 27896110; Phenotypes: Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), MIM# 607483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14075 | ASS1 | Elena Savva Phenotypes for gene: ASS1 were changed from to Citrullinemia MIM#215700; Urea cycle disorders and inherited hyperammonaemias; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14046 | ASPA | Elena Savva Phenotypes for gene: ASPA were changed from to Canavan disease MIM#271900; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13935 | LMBRD1 | Alison Yeung Phenotypes for gene: LMBRD1 were changed from to Methylmalonic aciduria and homocystinuria, cblF type MIM# 277380 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13919 | CYP2C19 |
Ain Roesley changed review comment from: Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386) (PMID:27981572) Voriconazole, moderate strength. Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events." Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing."; to: Pharmacogenomics gene Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386) (PMID:27981572) Voriconazole, moderate strength. Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events." Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing." |
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| Mendeliome v0.13856 | CYP2B6 | Ain Roesley Phenotypes for gene: CYP2B6 were changed from to Efavirenz, poor metabolism of MIM#614546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13854 | CYP2B6 | Ain Roesley reviewed gene: CYP2B6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Efavirenz, poor metabolism of MIM#614546; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13843 | DARS2 | Zornitza Stark changed review comment from: Slowly progressive disorder with variable age of onset, multiple families reported.; to: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13805 | DYRK1B | Zornitza Stark Phenotypes for gene: DYRK1B were changed from to Abdominal obesity-metabolic syndrome 3 - MIM#615812 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13774 | HTRA2 | Zornitza Stark Phenotypes for gene: HTRA2 were changed from to 3-methylglutaconic aciduria, type VIII, MIM# 617248 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13771 | HTRA2 | Zornitza Stark reviewed gene: HTRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27208207, 27696117; Phenotypes: 3-methylglutaconic aciduria, type VIII, MIM# 617248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13683 | DUSP6 |
Krithika Murali changed review comment from: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted. |
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| Mendeliome v0.13683 | DUSP6 |
Krithika Murali changed review comment from: 1 study cited by OMIM (Miraoui et al 2013) - heterozygous variants in 5 unrelated individuals with congenital hypogonadotrophic hypogonadism (CHH). 4/5 variants highly prevalent in healthy population and/or in conjunction with variants in other genes either known to be associated with CHH or possibly associated. No additional studies published since this paper. PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted. |
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| Mendeliome v0.13674 | DYRK1B | Krithika Murali reviewed gene: DYRK1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 34193236, 34786696, 24827035, 28743892; Phenotypes: Abdominal obesity-metabolic syndrome 3 - MIM#615812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13607 | HGD | Zornitza Stark Phenotypes for gene: HGD were changed from to Alkaptonuria MIM#203500; Disorders of phenylalanine or tyrosine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13565 | HBA1 | Zornitza Stark Phenotypes for gene: HBA1 were changed from to Erythrocytosis 7, MIM# 617981; Heinz body anemias, alpha-, MIM# 140700; Methemoglobinemia, alpha type , MIM#617973; Thalassemias, alpha-, MIM# 604131; Hemoglobin H disease, nondeletional, MIM# 613978 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13563 | HBA1 | Zornitza Stark reviewed gene: HBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Erythrocytosis 7, MIM# 617981, Heinz body anemias, alpha-, MIM# 140700, Methemoglobinemia, alpha type , MIM#617973, Thalassemias, alpha-, MIM# 604131, Hemoglobin H disease, nondeletional, MIM# 613978; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13507 | BCKDK | Zornitza Stark Phenotypes for gene: BCKDK were changed from to Branched-chain ketoacid dehydrogenase kinase deficiency MIM#614923; disorder of branched-chain amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13429 | DIO1 | Zornitza Stark Phenotypes for gene: DIO1 were changed from to Thyroid hormone metabolism, abnormal, 2, MIM# 619855 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13426 | DIO1 | Zornitza Stark reviewed gene: DIO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Thyroid hormone metabolism, abnormal, 2, MIM# 619855; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13390 | PHYH |
Zornitza Stark edited their review of gene: PHYH: Added comment: Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. Well established gene-disease association.; Changed publications: 9326939, 9326940 |
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| Mendeliome v0.13121 | FBP1 | Bryony Thompson changed review comment from: Well-established gene-disease association. Fructose-1,6-bisphosphatase (FBP1) deficiency is metabolic disorder characterised by episodic acute crises of lactic acidosis and ketotic hypoglycaemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Both SNVs and CNVs have been reported.; to: Well-established gene-disease association. Fructose-1,6-bisphosphatase (FBP1) deficiency is a metabolic disorder characterised by episodic acute crises of lactic acidosis and ketotic hypoglycaemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Both SNVs and CNVs have been reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13121 | CLPB | Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13120 | CLPB | Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13058 | PPP1R15B | Zornitza Stark Phenotypes for gene: PPP1R15B were changed from to Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13054 | PPP1R15B | Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 26159176, 26307080, 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12955 | PSPH | Zornitza Stark Phenotypes for gene: PSPH were changed from to Phosphoserine phosphatase deficiency MIM#614023; Disorders of serine, glycine or glycerate metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12943 | PTH1R | Zornitza Stark Phenotypes for gene: PTH1R were changed from to Failure of tooth eruption, primary MIM#125350; Eiken syndrome MIM#600002; Metaphyseal chondrodysplasia, Murk Jansen type MIM#156400; Chondrodysplasia, Blomstrand type MIM#215045 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12940 | PTH1R | Zornitza Stark reviewed gene: PTH1R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Failure of tooth eruption, primary MIM#125350, Eiken syndrome MIM#600002, Metaphyseal chondrodysplasia, Murk Jansen type MIM#156400, Chondrodysplasia, Blomstrand type MIM#215045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12934 | CLPB | Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12933 | CLPB | Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12827 | SLC25A19 | Zornitza Stark Phenotypes for gene: SLC25A19 were changed from to Microcephaly, Amish type, MIM#607196; Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type), MIM#613710 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12824 | SLC25A19 | Zornitza Stark reviewed gene: SLC25A19: Rating: GREEN; Mode of pathogenicity: None; Publications: 31506564, 31295743, 12185364, 19798730; Phenotypes: Microcephaly, Amish type, MIM#607196, Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type), MIM#613710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12806 | TPMT | Zornitza Stark Phenotypes for gene: TPMT were changed from to {Thiopurines, poor metabolism of, 1} 610460 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12804 | TPMT | Zornitza Stark reviewed gene: TPMT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Thiopurines, poor metabolism of, 1} 610460; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12756 | TPK1 | Zornitza Stark Phenotypes for gene: TPK1 were changed from to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type), MIM# 614458 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12753 | TPK1 | Zornitza Stark reviewed gene: TPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22152682, 33626592, 33231275, 33086386; Phenotypes: Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type), MIM# 614458; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12691 | TMEM106B |
Zornitza Stark changed review comment from: Cerebellar signs including ataxia prominent.; to: Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum. At least 5 unrelated individuals reported. |
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| Mendeliome v0.12673 | SLC25A42 | Zornitza Stark Phenotypes for gene: SLC25A42 were changed from to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12670 | SLC25A42 | Zornitza Stark reviewed gene: SLC25A42: Rating: GREEN; Mode of pathogenicity: None; Publications: 26541337, 29327420, 29923093, 34258143; Phenotypes: Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12583 | PAM16 | Zornitza Stark Phenotypes for gene: PAM16 were changed from to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12561 | PAM16 | Krithika Murali reviewed gene: PAM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12550 | ANKH | Elena Savva Phenotypes for gene: ANKH were changed from to Chondrocalcinosis 2 MIM#118600; Craniometaphyseal dysplasia MIM#123000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12546 | ANKH | Elena Savva reviewed gene: ANKH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32366894; Phenotypes: Chondrocalcinosis 2 MIM#118600, Craniometaphyseal dysplasia MIM#123000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12517 | AMT | Elena Savva Phenotypes for gene: AMT were changed from to Glycine encephalopathy MIM#605899; disorder of glycine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12508 | ALDH18A1 | Elena Savva Phenotypes for gene: ALDH18A1 were changed from Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism to Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12507 | ALDH6A1 | Elena Savva Phenotypes for gene: ALDH6A1 were changed from to Methylmalonate semialdehyde dehydrogenase deficiency MIM#614105; disorder of valine and pyrimidine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12505 | ALDH18A1 | Elena Savva Phenotypes for gene: ALDH18A1 were changed from to Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12475 | FTCD | Zornitza Stark Phenotypes for gene: FTCD were changed from Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism to Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12472 | FTCD | Zornitza Stark Phenotypes for gene: FTCD were changed from to Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12378 | TAMM41 |
Bryony Thompson gene: TAMM41 was added gene: TAMM41 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAMM41 were set to 35321494; 29253589 Phenotypes for gene: TAMM41 were set to inborn mitochondrial metabolism disorder MONDO:0004069; hypotonia; developmental delay; myopathy; ptosis Review for gene: TAMM41 was set to GREEN Added comment: Three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis with biallelic variants. Tissue-specific observations on OXPHOS were identified, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. The missense variants identified were defective in yeast models. In an in vitro cell model knockdown of TAMM41 resulted in decreased mitochondrial CDP diacylglycerol synthase activity, decreased cardiolipin levels and a decrease in oxygen consumption. Sources: Literature |
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| Mendeliome v0.12356 | TIMM50 | Zornitza Stark Phenotypes for gene: TIMM50 were changed from to 3-methylglutaconic aciduria, type IX, MIM# 617698 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12353 | TIMM50 | Zornitza Stark reviewed gene: TIMM50: Rating: GREEN; Mode of pathogenicity: None; Publications: 27573165, 32369862, 30190335, 31058414; Phenotypes: 3-methylglutaconic aciduria, type IX, MIM# 617698; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12304 | AHCY | Elena Savva Phenotypes for gene: AHCY were changed from to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM#613752 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12115 | SERAC1 | Zornitza Stark Phenotypes for gene: SERAC1 were changed from to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MIM# 614739 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12066 | SERAC1 | Samantha Ayres reviewed gene: SERAC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205472, 32684373, 24741715; Phenotypes: 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MIM# 614739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12028 | MAT1A | Zornitza Stark Phenotypes for gene: MAT1A were changed from to Hypermethioninemia, persistent, autosomal dominant, due to methionine adenosyltransferase I/III deficiency MIM#250850; Methionine adenosyltransferase deficiency, autosomal recessive MIM#250850; Disorders of the metabolism of sulphur amino acids | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11975 | TEAD1 |
Zornitza Stark changed review comment from: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family. Functional data supports gene-disease association.; to: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family. A de novo nonsense variant has also been reported in a case with Aicardi syndrome with infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. |
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| Mendeliome v0.11932 | TANGO2 | Zornitza Stark Phenotypes for gene: TANGO2 were changed from to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11929 | TANGO2 | Zornitza Stark reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26805782, 30245509; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11848 | STS | Zornitza Stark Phenotypes for gene: STS were changed from to Ichthyosis, X-linked 308100; Sterol metabolism disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11834 | NKX3-2 | Zornitza Stark Phenotypes for gene: NKX3-2 were changed from to Spondylo-megaepiphyseal-metaphyseal dysplasia - MIM#613330 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11792 | NKX3-2 | Krithika Murali reviewed gene: NKX3-2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20004766, 29704686; Phenotypes: Spondylo-megaepiphyseal-metaphyseal dysplasia - MIM#613330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11711 | ACADSB | Elena Savva Phenotypes for gene: ACADSB were changed from to 2-methylbutyrylglycinuria MIM#610006 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11708 | ACADSB | Elena Savva reviewed gene: ACADSB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25778941, 17945527; Phenotypes: 2-methylbutyrylglycinuria MIM#610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UCP3 |
Belinda Chong changed review comment from: Inheritance: Autosomal dominant, autosomal recessive and multifactorial PMID: 21544083 Identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. Indicated that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Also suggested that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants (V56M & Q252X). All variants are present in GnomAD there are 56 - V56M, 325 - A111V, 9 - V192I and 2 - A252X; to: Inheritance: Autosomal dominant, autosomal recessive and multifactorial PMID: 21544083 Identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. Indicated that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Also suggested that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants (V56M & Q252X). Single pathogenic variant in ClinVar All variants are present in GnomAD there are 56 - V56M, 325 - A111V, 9 - V192I and 2 - A252X |
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| Mendeliome v0.11540 | NDUFAF4 |
Krithika Murali edited their review of gene: NDUFAF4: Added comment: 3 unrelated families reported with patient-specific functional evidence provided for each. PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID.; Changed publications: 32949790, 28853723, 18179882 |
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| Mendeliome v0.11221 | NANS | Zornitza Stark Phenotypes for gene: NANS were changed from to Spondyloepimetaphyseal dysplasia, Camera-Genevieve type - MIM#610442 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11192 | NANS | Krithika Murali reviewed gene: NANS: Rating: GREEN; Mode of pathogenicity: None; Publications: 8152878, 15726110, 8723082, 27213289, 7551156; Phenotypes: Spondyloepimetaphyseal dysplasia, Camera-Genevieve type - MIM#610442; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11169 | KYNU | Zornitza Stark Phenotypes for gene: KYNU were changed from to Hydroxykynureninuria MIM#236800; Vertebral, cardiac, renal, and limb defects syndrome 2 MIM#617661; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11107 | AL117258.1 |
Melanie Marty changed review comment from: Gene also known as CIROP Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature; to: Gene also known as CIROP and LMLN2 Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature |
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| Mendeliome v0.11097 | AL117258.1 |
Melanie Marty gene: AL117258.1 was added gene: AL117258.1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AL117258.1 were set to 34903892 Phenotypes for gene: AL117258.1 were set to Heterotaxy, congenital heart defects Review for gene: AL117258.1 was set to GREEN Added comment: Gene also known as CIROP Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature |
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| Mendeliome v0.11071 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants. Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6. Eventual previous genetic testing was not discussed. Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies. Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype. 3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2): - c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families], - c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents], - c.2T>C/p.(Met1?) [1 hmz individual born to related parents], - c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual. CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes. CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP. As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants]. Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc. CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect. In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine). Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively). NMD is thought to underly the deleterious effect of the frameshift one (not studied). The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein. Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714). There is no associated phenotype in OMIM, Gene2Phenotype or SysID. Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset). Sources: Literature |
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| Mendeliome v0.11053 | SUCLG1 | Zornitza Stark Phenotypes for gene: SUCLG1 were changed from to Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11050 | RUNX2 | Zornitza Stark Phenotypes for gene: RUNX2 were changed from to Cleidocranial dysplasia MIM#119600; Cleidocranial dysplasia, forme fruste, dental anomalies only MIM#119600; Cleidocranial dysplasia, forme fruste, with brachydactyly MIM#119600; Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly MIM#156510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | SUCLG1 | Ain Roesley reviewed gene: SUCLG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230783, 28358460; Phenotypes: Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | RUNX2 | Ain Roesley reviewed gene: RUNX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301686; Phenotypes: Cleidocranial dysplasia MIM#119600, Cleidocranial dysplasia, forme fruste, dental anomalies only MIM#119600, Cleidocranial dysplasia, forme fruste, with brachydactyly MIM#119600, Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly MIM#156510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11010 | DLC1 |
Bryony Thompson gene: DLC1 was added gene: DLC1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DLC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DLC1 were set to 29773874 Phenotypes for gene: DLC1 were set to Nephrotic syndrome MONDO:0005377 Review for gene: DLC1 was set to GREEN Added comment: Biallelic variants in 4 families, and knockdown of DLC1 in cultured podocytes reduces migration rate and treatment with dexamethasone abolishes RhoA activation. Sources: Expert list |
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| Mendeliome v0.10917 | ABCB4 | Zornitza Stark Phenotypes for gene: ABCB4 were changed from Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism to Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism; Gallbladder disease 1 (MIM#600803) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10907 | ARR3 |
Bryony Thompson gene: ARR3 was added gene: ARR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARR3 was set to Other Publications for gene: ARR3 were set to 27829781; 35001458 Phenotypes for gene: ARR3 were set to Myopia 26, X-linked, female-limited MIM#301010 Review for gene: ARR3 was set to GREEN Added comment: At least 6 multi-generational families with female-limited early-onset high myopia. Only female carriers are affected and hemizygous males are unaffected. Authors hypothesise the mode of inheritance might be explained by metabolic interference due to X-inactivation. Sources: Literature |
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| Mendeliome v0.10835 | ARSK |
Paul De Fazio gene: ARSK was added gene: ARSK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARSK were set to 34916232; 32856704 Phenotypes for gene: ARSK were set to Mucopolysaccharidosis Review for gene: ARSK was set to GREEN gene: ARSK was marked as current diagnostic Added comment: 4 individuals from 2 unrelated consanguineous families (Turkish and Indian) reported with a homozygous missense and an NMD-predicted nonsense variant. Affected individuals had features of mucopolysaccharidosis such as short stature, coarse facial features and dysostosis multiplex. Urinary GAG excretion was normal by conventional methods, but LC-MS/MS in 2 individuals revealed an increase in specific dermatan sulfate-derived disaccharides. Functional studies showed reduced protein levels and reduced enzyme activity for the nonsense and missense variant respectively. A mouse model also shows a mucopolysaccharidosis phenotype, albeit milder. Rated green (2 families, functional evidence, mouse model). Sources: Literature |
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| Mendeliome v0.10776 | CYP2C8 | Zornitza Stark Phenotypes for gene: CYP2C8 were changed from to {Drug metabolism, altered, CYP2C8-related} 618018 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10774 | CYP2C8 | Zornitza Stark reviewed gene: CYP2C8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Drug metabolism, altered, CYP2C8-related} 618018; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10746 | PAPSS2 | Zornitza Stark Phenotypes for gene: PAPSS2 were changed from to Brachyolmia 4 with mild epiphyseal and metaphyseal changes MIM#612847 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10743 | PAPSS2 | Zornitza Stark reviewed gene: PAPSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22791835, 25594860, 31461705, 23633440, 9771708, 19474428; Phenotypes: Brachyolmia 4 with mild epiphyseal and metaphyseal changes MIM#612847; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10573 | INPP5K |
Ain Roesley changed review comment from: At least 20 probands reported thus far. Noted that Val23Met is an Italian founder mutation and Ile50thr is a Paskitani/Bangladeshi founder; to: At least 20 probands reported thus far. Noted that Val23Met is an Italian founder mutation and Ile50thr is a Pakistani/Bangladeshi founder |
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| Mendeliome v0.10573 | INPP5K |
Ain Roesley changed review comment from: At least 20 probands reported thus far. Noted that Val23Met is an Italian founder mutation; to: At least 20 probands reported thus far. Noted that Val23Met is an Italian founder mutation and Ile50thr is a Paskitani/Bangladeshi founder |
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| Mendeliome v0.10518 | PRDM9 |
Zornitza Stark gene: PRDM9 was added gene: PRDM9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRDM9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRDM9 were set to 34257419 Phenotypes for gene: PRDM9 were set to Inherited primary ovarian failure MONDO:0019852 Review for gene: PRDM9 was set to GREEN Added comment: The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. PRDM9 is a meiosis-specific histone H3 methyltransferase and a major determinant of meiotic recombination hotspots in mammals. 3 pathogenic heterozygous variants in PRDM9 identified in 4 patients with POI. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity. Prdm9+/- mice were subfertile, and showed increased percentage of germ cells at abnormal pachytene stage with decreased number of PRDM9-dependent DSBs and insufficient recombination. Sources: Literature |
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| Mendeliome v0.10510 | NAA20 |
Zornitza Stark gene: NAA20 was added gene: NAA20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAA20 were set to 34230638 Phenotypes for gene: NAA20 were set to Intellectual disability; Microcephaly; Neurodevelopmental disorder MONDO:0700092 Review for gene: NAA20 was set to GREEN Added comment: 2 consanguineous families with 5 affected individuals with developmental delay, intellectual disability, and microcephaly (-2-4SD). Exome and genome sequencing identified 2 different homozygous variants in NAA20 gene (p.Met54Val and p.Ala80Val), and segregated with affected individuals. N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Sources: Literature |
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| Mendeliome v0.10496 | DNAJC19 | Zornitza Stark Phenotypes for gene: DNAJC19 were changed from to 3-methylglutaconic aciduria, type V MIM#610198 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10477 | DNAJC19 | Belinda Chong reviewed gene: DNAJC19: Rating: GREEN; Mode of pathogenicity: None; Publications: 16055927, 17244376, 22797137; Phenotypes: 3-methylglutaconic aciduria, type V MIM#610198; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10461 | GPX4 | Zornitza Stark Phenotypes for gene: GPX4 were changed from to Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10448 | GPX4 | Ain Roesley reviewed gene: GPX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24706940, 32827718; Phenotypes: Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10392 | AUH | Zornitza Stark Phenotypes for gene: AUH were changed from to 3-methylglutaconic aciduria, type I, MIM# 250950 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10389 | AUH | Zornitza Stark reviewed gene: AUH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12434311, 16354225, 20855850, 21840233; Phenotypes: 3-methylglutaconic aciduria, type I, MIM# 250950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10377 | ASL | Zornitza Stark Phenotypes for gene: ASL were changed from to Argininosuccinic aciduria MIM#207900; Urea cycle disorders and inherited hyperammonaemias; disorder of amino acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10375 | ARG1 | Zornitza Stark Phenotypes for gene: ARG1 were changed from to Argininaemia MIM#207800; Urea cycle disorders and inherited hyperammonaemias; disorder of arginine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10366 | ALDH4A1 | Zornitza Stark Phenotypes for gene: ALDH4A1 were changed from to Hyperprolinemia, type II MIM#239510; disorders of ornithine or proline metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10308 | ACAT1 | Zornitza Stark Phenotypes for gene: ACAT1 were changed from to Alpha-methylacetoacetic aciduria, MIM#203750; Beta-ketothiolase deficiency MONDO:0008760 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10306 | ACAT1 | Zornitza Stark reviewed gene: ACAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alpha-methylacetoacetic aciduria, MIM#203750, Beta-ketothiolase deficiency MONDO:0008760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10224 | GALE | Zornitza Stark Phenotypes for gene: GALE were changed from to Galactose epimerase deficiency MIM#230350; Disorders of galactose metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10215 | GALK1 | Zornitza Stark Phenotypes for gene: GALK1 were changed from to Galactokinase deficiency with cataracts MIM#230200; Disorders of galactose metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10194 | CHRNA3 |
Zornitza Stark changed review comment from: Five individuals from three unrelated families.; to: Five individuals from three unrelated families. Onset is in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension. |
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| Mendeliome v0.10018 | OGDH |
Zornitza Stark gene: OGDH was added gene: OGDH was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OGDH were set to 32383294 Phenotypes for gene: OGDH were set to Developmental delay; ataxia; seizure; raised lactate Review for gene: OGDH was set to AMBER Added comment: Two siblings reported with homozygous missense variant in this gene and global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Note previous report of an individual with developmental delay, hypotonia, and movement disorders and metabolic decompensation and biochemical evidence of OGDH deficiency but genetic testing not done. Sources: Literature |
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| Mendeliome v0.10017 | FAAH2 |
Ain Roesley changed review comment from: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature; to: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomAD Sources: Literature |
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| Mendeliome v0.10017 | FAAH2 |
Ain Roesley gene: FAAH2 was added gene: FAAH2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAAH2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FAAH2 were set to PMID: 34645488 Penetrance for gene: FAAH2 were set to unknown Review for gene: FAAH2 was set to RED gene: FAAH2 was marked as current diagnostic Added comment: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature |
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| Mendeliome v0.9996 | MMP9 | Zornitza Stark Phenotypes for gene: MMP9 were changed from to Metaphyseal anadysplasia 2, MIM# 613073 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9993 | MMP9 | Zornitza Stark reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19615667, 28342220, 34407464; Phenotypes: Metaphyseal anadysplasia 2, MIM# 613073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9979 | DHCR24 | Zornitza Stark Phenotypes for gene: DHCR24 were changed from to Desmosterolosis MIM#602398; Disorders of the metabolism of sterols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9955 | AMACR | Zornitza Stark Phenotypes for gene: AMACR were changed from to Bile acid synthesis defect, congenital, 4, MIM# 214950; Alpha-methylacyl-CoA racemase deficiency, MIM# 614307 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9952 | AMACR | Zornitza Stark reviewed gene: AMACR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31951345, 24735479, 12512044, 10655068, 34267495, 33047465; Phenotypes: Bile acid synthesis defect, congenital, 4, MIM# 214950, Alpha-methylacyl-CoA racemase deficiency, MIM# 614307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9950 | DMC1 |
Bryony Thompson gene: DMC1 was added gene: DMC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DMC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DMC1 were set to 34794894; 29331980; 9660954; 9660953; 18166824 Phenotypes for gene: DMC1 were set to Primary ovarian insufficiency; non-obstructive azoospermia Review for gene: DMC1 was set to GREEN Added comment: PMID: 34515795 - a homozygous frameshift (p. Glu10Asnfs*31) cosegregated with non-obstructive azoospermia in 1 brother and diminished ovarian reserve (not primary ovarian insufficiency) in 2 sisters in a non-consanguineous family. Further homozygous knockout mice study demonstrated total failure of follicle development and spermatogenesis in male mice. PMID: 29331980 - a homozygous missense (p.Asp36Asn) cosegregated with non-obstructive azoospermia and POI phenotypes in a single family. PMID: 18166824 - a POI case identified with a homozygous missense (p.Met200Val, 185 homozygotes in gnomAD v2.1), which is too common for a recessive Mendelian disease PMID: 9660954, 9660953 - both male and female knockout mice are sterile Sources: Literature |
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| Mendeliome v0.9943 | DDR2 | Zornitza Stark Phenotypes for gene: DDR2 were changed from to Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665; Warburg-Cinotti syndrome, MIM# 618175 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9940 | DDR2 | Zornitza Stark reviewed gene: DDR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19110212, 20223752, 30449416; Phenotypes: Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665, Warburg-Cinotti syndrome, MIM# 618175; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9940 | PRKG2 | Zornitza Stark Phenotypes for gene: PRKG2 were changed from Acromesomelic dysplasia to Acromesomelic dysplasia 4, MIM# 619636; Spondylometaphyseal dysplasia, Pagnamenta type, MIM# 619638 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9939 | PRKG2 | Zornitza Stark edited their review of gene: PRKG2: Changed phenotypes: Acromesomelic dysplasia 4, MIM# 619636, Spondylometaphyseal dysplasia, Pagnamenta type, MIM# 619638 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9926 | MOCS2 | Zornitza Stark Phenotypes for gene: MOCS2 were changed from to Molybdenum cofactor deficiency B MIM#252160; Disorders of molybdenum cofactor metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9835 | MATN3 | Zornitza Stark Phenotypes for gene: MATN3 were changed from to Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728); Epiphyseal dysplasia, multiple, 5 (MIM#607078) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9820 | MMP13 | Zornitza Stark Phenotypes for gene: MMP13 were changed from to Metaphyseal anadysplasia 1 (MIM#602111); Metaphyseal dysplasia, Spahr type (MIM#250400); ?Spondyloepimetaphyseal dysplasia, Missouri type (MIM#602111) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9785 | MATN3 | Daniel Flanagan reviewed gene: MATN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31724101, 32025536, 11968079, 14729835; Phenotypes: Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728), Epiphyseal dysplasia, multiple, 5 (MIM#607078); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | MMP13 | Daniel Flanagan reviewed gene: MMP13: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19615667, 24781753, 24648384; Phenotypes: Metaphyseal anadysplasia 1 (MIM#602111), Metaphyseal dysplasia, Spahr type (MIM#250400), ?Spondyloepimetaphyseal dysplasia, Missouri type (MIM#602111); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9774 | SPATA5L1 | Zornitza Stark changed review comment from: Note some of the affected individuals had isolated deafness, hence two OMIM phenotypes have been associated with this gene. All were of Ashkenazi Jewish origin, and had the p.Ile466Met founder variant, either hmz or compound het with another variant.; to: Note some of the affected individuals had isolated deafness, hence two OMIM phenotypes have been associated with this gene. All were of Ashkenazi Jewish origin, and had the p.Ile466Met founder variant, compound het with another variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9774 | SPATA5L1 | Zornitza Stark edited their review of gene: SPATA5L1: Added comment: Note some of the affected individuals had isolated deafness, hence two OMIM phenotypes have been associated with this gene. All were of Ashkenazi Jewish origin, and had the p.Ile466Met founder variant, either hmz or compound het with another variant.; Changed publications: 34626583; Changed phenotypes: Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616, Deafness, autosomal recessive 119, MIM# 619615 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9643 | SIK3 | Zornitza Stark Phenotypes for gene: SIK3 were changed from ?Spondyloepimetaphyseal dysplasia, Krakow type - #618162 to Spondyloepimetaphyseal dysplasia, Krakow type - #618162 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9631 | ASXL1 |
Zornitza Stark changed review comment from: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound ID, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints -- many of these features would be identifiable antenatally.; to: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound ID, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints. Multiple individuals reported. |
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| Mendeliome v0.9628 | SIK3 |
Krithika Murali gene: SIK3 was added gene: SIK3 was added to Mendeliome. Sources: Expert list,Literature Mode of inheritance for gene: SIK3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SIK3 were set to 30232230; 22318228 Phenotypes for gene: SIK3 were set to ?Spondyloepimetaphyseal dysplasia, Krakow type - #618162 Review for gene: SIK3 was set to AMBER Added comment: Biallelic SIK3 variants reported in 2 siblings from a consanguineous family with an uncharacterised skeletal dysplasia. Radiographic features included widened/flared metaphyses with irregular ossifications, motheaten long bones, fragmentation of the proximal metacarpals, rounded vertebral bodies, and a distinctive transverse gap seen in the tibias. In addition to the skeletal phenotype, the siblings manifested significant developmental delay with brain MRI abnormalities, a severe unclassified immunodeficiency, and normal parathyroid hormone concentration with mild hypercalcemia. One sibling had a more severe phenotype, particularly immunodeficiency, and died of Epstein-Barr virus induced small muscle cancer at 10 years of age. Mouse models support impaired chondrocyte development with skeletal dysplasia phenotye. Sources: Expert list, Literature |
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| Mendeliome v0.9616 | CSF2RB | Zornitza Stark Phenotypes for gene: CSF2RB were changed from to Surfactant metabolism dysfunction, pulmonary, 5, MIM#614370 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9613 | CSF2RB | Zornitza Stark reviewed gene: CSF2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: 21205713, 27514590, 7568173, 30846703; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 5, MIM#614370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9613 | CSF2RA | Zornitza Stark Phenotypes for gene: CSF2RA were changed from to Surfactant metabolism dysfunction, pulmonary, 4, MIM# 300770 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9610 | CSF2RA | Zornitza Stark reviewed gene: CSF2RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 20622029, 25425184, 18955570; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 4, MIM# 300770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9537 | BGN |
Krithika Murali gene: BGN was added gene: BGN was added to Mendeliome. Sources: Expert list,Literature Mode of inheritance for gene: BGN was set to Other Publications for gene: BGN were set to 27236923; 27632686 Phenotypes for gene: BGN were set to Meester-Loeys syndrome - #300989; Spondyloepimetaphyseal dysplasia, X-linked - #300106 Review for gene: BGN was set to GREEN Added comment: Well-established gene-disease associated with X-linked spondyloepimetaphyseal dysplasia (SEMD) and Meester-Loeys syndrome (connective tissue disorder with phenotypic features including aortic dissection, aortic aneurysym, dysmorphism, joint hypermobility and mild skeletal dysplasia - with juvenile-onset reported in males) SEMD - X-linked recessive inheritance Meester-Loeys syndrome - hemizygous males, monoallelic mutations may cause disease in females (may be less severe, later onset than males) Sources: Expert list, Literature |
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| Mendeliome v0.9502 | ETHE1 | Zornitza Stark commented on gene: ETHE1: Severe metabolic disorder characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Brain MRI shows necrotic lesions in deep gray matter structures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9437 | SFTPC | Zornitza Stark Phenotypes for gene: SFTPC were changed from to Surfactant metabolism dysfunction, pulmonary, 2, MIM# 610913 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9434 | SFTPC | Zornitza Stark reviewed gene: SFTPC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11207353, 11991887, 11893657, 15557112, 19443464; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 2, MIM# 610913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9434 | SFTPB | Zornitza Stark Phenotypes for gene: SFTPB were changed from to Surfactant metabolism dysfunction, pulmonary, 1, MIM# 265120 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9431 | SFTPB | Zornitza Stark reviewed gene: SFTPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8163685, 8021783, 10378403, 10571948; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 1, MIM# 265120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9392 | KCTD13 |
Daniel Flanagan gene: KCTD13 was added gene: KCTD13 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: KCTD13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KCTD13 were set to PMID: 33409479 Review for gene: KCTD13 was set to RED Added comment: Mouse model and in vitro evidence suggesting the deletion of KCTD13 has a similar metabolic affect as adenylosuccinate lyase deficiency, which has seizures and autistic features. Sources: Expert list |
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| Mendeliome v0.9383 | KCNQ1OT1 |
Zornitza Stark gene: KCNQ1OT1 was added gene: KCNQ1OT1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: KCNQ1OT1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) Publications for gene: KCNQ1OT1 were set to 22205991; 15372379; 23511928; 30794780; 29377879; 10220444; 32447323; 33177595; 29047350 Phenotypes for gene: KCNQ1OT1 were set to Beckwith-Wiedemann syndrome OMIM:130650; Russell-Silver Syndrome Review for gene: KCNQ1OT1 was set to AMBER Added comment: Limited evidence that isolated intragenic variation in KCNQ1OT1 is definitively associated with a phenotype. KCNQ1OT1 encodes the regulatory antisense non-coding RNA KCNQ1OT1 (KCNQ1 overlapping) and is located within the KCNQ1OT1:TSS DMR (imprinting control region 2; IC2) at 11p15.5. IC2 is located within KCNQ1 intron 10. KCNQ1OT1 is maternally imprinted and paternally expressed. On the paternal chromosome, KCNQ1OT1 is transcribed and represses in cis the flanking imprinted genes, including the growth inhibitor CDKN1C, which is normally transcribed from the maternal allele. In 50% of the BWS patients, loss of methylation (LOM) of IC2 leads to biallelic expression of KCNQ1OT1 and biallelic silencing of CDKN1C (PMID 30635621). Expression is increased in BWS due to IC2 epimutations or paternal UPD. Single nucleotide variants within KCNQ1OT1 have not been definitively associated with human disease. A heterozygous maternally inherited non-coding variant was identified in an individual with isolated omphalocele. This variant was shown to alter the methylation pattern of the imprinted allele (PMID 29047350). Eggerman et al (PMID 32447323) described a 132 base pair deletion within KCNQ1OT1 associated with growth retardation in the case of paternal but not maternal transmission. This intragenic deletion did not affect IC2 methylation. Microdeletions of IC2 involving KCNQ1OT1 on the paternal allele have been identified in a small number of patients with Russell-Silver syndrome. Similarly, microdeletions of IC2 involving KCNQ1OT1 on the maternal allele have been identified in a small number of patients with BWS. These deletions also variably involve KCNQ1 or CDKN1C. LoF in CDKN1C is a known cause of BWS. There is some evidence to suggest that disruption of KCNQ1 prevents maternal methylation at IC2 (PMID 30778172). Sources: Expert Review |
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| Mendeliome v0.9382 | H19 |
Zornitza Stark gene: H19 was added gene: H19 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: H19 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) Publications for gene: H19 were set to 20007505; 15743916; 23118352; 21863054; 21571108; 18245780; 24916376; 25943194 Phenotypes for gene: H19 were set to Phenotypes resulting from gene over expression: Silver-Russell Syndrome (proven effects of dosage alteration rather than gene muation); Affected tissue: all; Phenotype resulting from under expression: Beckwith-Wiedemann Syndrome Review for gene: H19 was set to RED Added comment: Methylation changes rather than sequence variation are associated with BWS/RSS. Sources: Expert Review |
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| Mendeliome v0.9378 | ZNF445 |
Zornitza Stark gene: ZNF445 was added gene: ZNF445 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF445 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF445 were set to 34039421; 30602440; 30846001 Phenotypes for gene: ZNF445 were set to Temple syndrome; Multi locus imprinting disturbance (MLID) Review for gene: ZNF445 was set to RED Added comment: Single report (Kagami 2021) of a child with Temple syndrome and MLID found to have a novel homozygous truncating variant in ZNF445. ZNF445 has been shown to play a critical role in the maintenance of postfertilisation methylation imprints (Takahashi 2019). Mechanism and parent of origin effects remain uncertain. Sources: Literature |
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| Mendeliome v0.9294 | SARS |
Bryony Thompson gene: SARS was added gene: SARS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SARS were set to 28236339; 34570399 Phenotypes for gene: SARS were set to Intellectual disability Review for gene: SARS was set to AMBER Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays. PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function. PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells. Sources: Literature |
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| Mendeliome v0.9256 | MPL | Zornitza Stark Phenotypes for gene: MPL were changed from Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR to Myelofibrosis with myeloid metaplasia, somatic, MIM#254450; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9230 | LRRK1 |
Zornitza Stark gene: LRRK1 was added gene: LRRK1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750 Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198) Review for gene: LRRK1 was set to GREEN Added comment: At least 4 unrelated families reported. Sources: Expert Review |
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| Mendeliome v0.9160 | CYB5A | Zornitza Stark Phenotypes for gene: CYB5A were changed from to Methemoglobinaemia and ambiguous genitalia, MIM# 250790 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9157 | CYB5A | Zornitza Stark reviewed gene: CYB5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22170710, 32051920; Phenotypes: Methemoglobinemia and ambiguous genitalia 250790; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9051 | CYB5R3 | Zornitza Stark Phenotypes for gene: CYB5R3 were changed from to Methaemoglobinaemia, type I and II, MIM# 250800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9048 | CYB5R3 | Zornitza Stark reviewed gene: CYB5R3: Rating: GREEN; Mode of pathogenicity: None; Publications: 2107882, 1707593, 12393396; Phenotypes: Methaemoglobinaemia, type I and II, MIM# 250800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8956 | RMRP |
Zornitza Stark changed review comment from: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function. *Founder variant g.70A>G (Amish and Finnish populations) CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency.; to: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function. *Founder variant g.70A>G (Amish and Finnish populations) CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency. Anauxetic dysplasia 1, MIM# 607095 is a more severe phenotype, whereas Metaphyseal dysplasia without hypotrichosis, MIM# 250460 is milder. |
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| Mendeliome v0.8956 | RMRP | Zornitza Stark edited their review of gene: RMRP: Changed phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, Anauxetic dysplasia 1, MIM# 607095, Metaphyseal dysplasia without hypotrichosis, MIM# 250460 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8953 | RMRP | Zornitza Stark reviewed gene: RMRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16244706, 21396580, 22420014; Phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities, CID, impaired lymphocyte proliferation, low Ig levels, antibodies variably decreased, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8853 | PLAG1 |
Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green. Silver-Russell syndrome-4 (SRS4) is characterised by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed. So far 4 families have been reported with some functional studies of the role of the gene in the growth pathway. Abi Habib et al. (2018) reported 1 family (child, sister and mother) patient with Silver-Russell syndrome (with normal methylation on chromosomes 7, 11, and 14, and exclusion of maternal UPD and chromosomal rearrangements). Using WES they identified a heterozygous 1-bp deletion in the PLAG1 gene. The variant segregated with disease, and was not present in polymorphism databases or ExAC. They also reported another patient with a different heterozygous 1-bp deletion in the PLAG1 gene. This was not found in her unaffected twin brother, older brother, or parents. Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 promoter P3, independently and via the HMGA2-PLAG1-IGF2 pathway. Disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus. Inoue et al. (2020) reported 1 family with 2 affected people with Silver-Russell syndrome with a nonsense variant in the PLAG1 gene, which segregated with disease. Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215 |
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| Mendeliome v0.8703 | VAV1 |
Zornitza Stark gene: VAV1 was added gene: VAV1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: VAV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VAV1 were set to 20638113; 23058036 Phenotypes for gene: VAV1 were set to Common variable immnodeficiency Review for gene: VAV1 was set to RED Added comment: Reduced VAV1 expression has been reported in multiple T-CVID cases, however only one large deletion (exon 2-27) has been reported in a single case in a publication from 2012. The CNV was detected using real-time qPCR, but was not confirmed by an orthogonal method. Sources: Expert Review |
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| Mendeliome v0.8657 | ACAN |
Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations. Well established gene-disease association, multiple families reported. Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813 |
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| Mendeliome v0.8522 | SYNCRIP |
Zornitza Stark gene: SYNCRIP was added gene: SYNCRIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937 Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology Review for gene: SYNCRIP was set to GREEN Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases. Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals. The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence. Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance. Overall the variants reported to date include [NM_006372.5]: 1 - c.858_859del p.(Gly287Leufs*5) 2 - c.854dupA p.(Asn285Lysfs*8) 3 - c.734T>C p.(Leu245Pro) 4 - chr6:85605276-85683190 deletion (GRCh38) 5 - c.629T>C p.(Phe210Ser) 6 - c.1573_1574delinsTT p.(Gln525Leu) 7 - c.1247_1250del p.(Arg416Lysfs*145) 8 - c.1518_1519insC p.(Ala507Argfs*14) [P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1] SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation. Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD. The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2. There are no additional studies performed. Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%] Animal models are not discussed. There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes. Sources: Literature |
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| Mendeliome v0.8467 | ABCD4 | Zornitza Stark reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33729671; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type, MIM# 614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8467 | ABCD4 | Zornitza Stark Phenotypes for gene: ABCD4 were changed from to Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8335 | LINGO4 |
Laura Raiti gene: LINGO4 was added gene: LINGO4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LINGO4 were set to PMID: 33098801 Phenotypes for gene: LINGO4 were set to Developmental Delay, Intellectual disability, speech disorder Review for gene: LINGO4 was set to GREEN Added comment: 3 unrelated individuals 1 x individual compound heterozygous for 2x missense variants: c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln comp het. Phenotype: infancy-onset generalized dystonia; DD/hypo, ID, speech disorder (isolated plus non-MD symptoms) NDD 1 x individual homozygous for missense variant: c.679C>A p.Leu227Met Phenotype: DD/hypo, ID, speech disorder 1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: DD/hypo, ID, speech disorder Sources: Literature |
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| Mendeliome v0.8335 | ARFGEF3 |
Laura Raiti gene: ARFGEF3 was added gene: ARFGEF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARFGEF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARFGEF3 were set to PMID: 33098801 Phenotypes for gene: ARFGEF3 were set to Dystonia Review for gene: ARFGEF3 was set to GREEN Added comment: 3 x unrelated individuals 1 x de novo missense variant: c.6212T>C p.Met2071Thr, phenotype: infancy-onset generalized dystonia (isolated) 1x stop-gain variant c.1773T>G p.Tyr591* (inherited from mosaic mother), phenotype: infancy-onset generalized dystonia (isolated) 1 x de novo missense variant (Gene Matcher) c.250A>C p.Met84Leu childhood-onset generalized dystonia (isolated) Sources: Literature |
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| Mendeliome v0.8229 | ATP2C2 |
Eleanor Williams gene: ATP2C2 was added gene: ATP2C2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP2C2 were set to 33864365; 28440294 Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463 Review for gene: ATP2C2 was set to RED Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment. PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W). Sources: Literature |
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| Mendeliome v0.8130 | C21orf2 |
Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. 7 families also reported with isolated retinal dystrophy.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. 7 families also reported with isolated retinal dystrophy. New HGNC approved name is CFAP410. |
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| Mendeliome v0.8130 | C21orf2 | Zornitza Stark Phenotypes for gene: C21orf2 were changed from to Spondylometaphyseal dysplasia, axial, MIM# 602271; Retinal dystrophy with macular staphyloma, MIM# 617547 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8127 | C21orf2 | Zornitza Stark reviewed gene: C21orf2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26974433, 27548899, 28422394, 26294103, 23105016, 27548899; Phenotypes: Spondylometaphyseal dysplasia, axial, MIM# 602271, Retinal dystrophy with macular staphyloma, MIM# 617547; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8100 | CLPB | Zornitza Stark Phenotypes for gene: CLPB were changed from to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8097 | CLPB | Zornitza Stark reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25597510, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8094 | ABCB4 | Zornitza Stark Phenotypes for gene: ABCB4 were changed from to Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7703 | UFSP2 | Zornitza Stark Phenotypes for gene: UFSP2 were changed from to Neurodevelopmental disorder; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7700 | UFSP2 |
Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Additional cases identified through the 100,000 Genomes project. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported. |
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| Mendeliome v0.7670 | UFSP2 |
Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: single 3-generation family reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported. |
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| Mendeliome v0.7670 | UFSP2 | Zornitza Stark reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208, 26428751, 28892125; Phenotypes: Neurodevelopmental disorder, Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7561 | SLC25A46 |
Zornitza Stark changed review comment from: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. At least 10 unrelated families reported, supportive functional data.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. New disease entity added by OMIM in 2021 to reflect this more severe end of the spectrum. At least 10 unrelated families reported, supportive functional data. |
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| Mendeliome v0.7537 | ZNFX1 |
Zornitza Stark gene: ZNFX1 was added gene: ZNFX1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNFX1 were set to 33872655; 33876776 Phenotypes for gene: ZNFX1 were set to Multisystem inflammation; susceptibility to viral infections Review for gene: ZNFX1 was set to GREEN Added comment: 15 individuals from 8 families reported with multi-system inflammation and susceptibility to viral infections. In addition, four indviduals from two unrelated kindreds reported with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis. Sources: Literature |
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| Mendeliome v0.7502 | YWHAG | Zornitza Stark Added comment: Comment when marking as ready: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7470 | NEPRO |
Chern Lim gene: NEPRO was added gene: NEPRO was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEPRO were set to 26633546; 29620724; 31250547 Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853 Review for gene: NEPRO was set to AMBER Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant. PMID 31250547: 1 family with homozygous novel missense All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies. Sources: Literature |
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| Mendeliome v0.7464 | JAG2 |
Belinda Chong gene: JAG2 was added gene: JAG2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: JAG2 were set to PMID: 33861953 Phenotypes for gene: JAG2 were set to muscular dystrophy Review for gene: JAG2 was set to GREEN Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Sources: Literature |
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| Mendeliome v0.7394 | CHST11 |
Zornitza Stark gene: CHST11 was added gene: CHST11 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHST11 were set to 26436107; 29514872 Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167 Review for gene: CHST11 was set to AMBER Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum. Two unrelated families reported, note one had a homozygous deletion. One family had 10 affected individuals. Sources: Expert Review |
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| Mendeliome v0.7378 | PCYT1A | Zornitza Stark Phenotypes for gene: PCYT1A were changed from to Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Congenital lipodystrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7375 | PCYT1A | Zornitza Stark reviewed gene: PCYT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24387990, 24387991, 24889630; Phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940, Congenital lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7360 | HNRNPDL |
Bryony Thompson gene: HNRNPDL was added gene: HNRNPDL was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: HNRNPDL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HNRNPDL were set to 24647604; 31267206; 31995753; 32407983; 32904822; 32367994 Phenotypes for gene: HNRNPDL were set to Muscular dystrophy, limb-girdle, autosomal dominant 3 MIM#609115 Review for gene: HNRNPDL was set to GREEN gene: HNRNPDL was marked as current diagnostic Added comment: At least 5 families reported with either D378H/N, and supporting functional assays demonstrating that these variants affect protein function. No other pathogenic variants have been reported. A VUS has been reported (along with another SETX variant) in an individual with a multi-system disorder, including a metabolic myopathy. Sources: Expert list |
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| Mendeliome v0.7358 | JMJD1C |
Zornitza Stark gene: JMJD1C was added gene: JMJD1C was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JMJD1C were set to 26181491; 32996679 Phenotypes for gene: JMJD1C were set to Intellectual disability Review for gene: JMJD1C was set to GREEN Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity. Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679). Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype. Sources: Expert Review |
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| Mendeliome v0.7161 | PSAP | Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson disease, AD; Combined SAP deficiency 611721; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900 to Parkinson disease, AD; Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722; MONDO:0012720; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; MONDO:0009590; Gaucher disease, atypical, MIM# 610539; MONDO:0012517 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7160 | PSAP | Zornitza Stark edited their review of gene: PSAP: Changed phenotypes: Combined SAP deficiency, MIM# 611721, Encephalopathy due to prosaposin deficiency, MONDO:0012719, Krabbe disease, atypical, MIM# 611722, MONDO:0012720, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, MONDO:0009590, Gaucher disease, atypical, MIM# 610539, MONDO:0012517 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7121 | CLDN11 |
Melanie Marty gene: CLDN11 was added gene: CLDN11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLDN11 were set to 33313762 Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy Review for gene: CLDN11 was set to GREEN Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Sources: Literature |
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| Mendeliome v0.7084 | FBN2 |
Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy. Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.6990 | TRMT10A | Zornitza Stark Phenotypes for gene: TRMT10A were changed from to Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033; MONDO:0000208 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6987 | TRMT10A | Zornitza Stark reviewed gene: TRMT10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24204302, 25053765, 33448213, 33067246, 26535115, 26526202, 26297882; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033, MONDO:0000208; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6963 | MSMO1 | Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793; Disorders of the metabolism of sterols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6901 | SPINT2 | Zornitza Stark changed review comment from: More than 15 unrelated families reported.; to: Well established gene-disease association. PMID 30445423 reviews 34 patients from 26 families: 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation. Choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhoea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhoea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6854 | FN1 | Zornitza Stark Phenotypes for gene: FN1 were changed from to Glomerulopathy with fibronectin deposits 2 (MIM#601894); Spondylometaphyseal dysplasia, corner fracture type (MIM#184255) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6850 | FN1 | Ain Roesley reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100092; Phenotypes: Glomerulopathy with fibronectin deposits 2 (MIM#601894), Spondylometaphyseal dysplasia, corner fracture type (MIM#184255); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6769 | ALDH1L2 |
Naomi Baker gene: ALDH1L2 was added gene: ALDH1L2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALDH1L2 were set to PMID: 31341639; 33168096 Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks Review for gene: ALDH1L2 was set to RED Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease. Sources: Literature |
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| Mendeliome v0.6582 | SYCP2L |
Arina Puzriakova gene: SYCP2L was added gene: SYCP2L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SYCP2L were set to 32303603 Phenotypes for gene: SYCP2L were set to Premature ovarian insufficiency Review for gene: SYCP2L was set to AMBER Added comment: - PMID: 32303603 (2021) - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L. In vitro assays revealed that mutant SYCP2L proteins induced mislocalisation and reduced expression. Sycp2l knockout mice exhibit accelerated reproductive ageing. Sources: Literature |
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| Mendeliome v0.6509 | PSAP | Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson disease, AD to Parkinson disease, AD; Combined SAP deficiency 611721; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6508 | PSAP | Zornitza Stark reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32201884; Phenotypes: Combined SAP deficiency 611721, Gaucher disease, atypical, MIM# 610539, Krabbe disease, atypical, MIM# 611722, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6471 | KIF22 | Zornitza Stark reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: 25256152; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2, MIM# 603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6471 | KIF22 | Zornitza Stark Phenotypes for gene: KIF22 were changed from to Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson changed review comment from: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature; to: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system. Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson gene: CLTCL1 was added gene: CLTCL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784 Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain Review for gene: CLTCL1 was set to AMBER Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.6462 | KIF22 | Elena Savva reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22152677, 22152678; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6307 | CETP | Bryony Thompson Phenotypes for gene: CETP were changed from to Hyperalphalipoproteinemia MIM#143470; Disorders of high density lipoprotein metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6304 | CETP | Bryony Thompson Added comment: Comment on list classification: Benign metabolic condition | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6303 | CETP | Bryony Thompson reviewed gene: CETP: Rating: ; Mode of pathogenicity: None; Publications: 12070157, 2586614, 27604308, 2215607, 2390095; Phenotypes: Hyperalphalipoproteinemia MIM#143470, Disorders of high density lipoprotein metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6301 | DMGDH | Bryony Thompson reviewed gene: DMGDH: Rating: ; Mode of pathogenicity: None; Publications: 11231903, 18937046, 28881522, 27604308; Phenotypes: Dimethylglycine dehydrogenase deficiency MIM#605850, Disorders and variants of other enzymes that oxidise xenobiotics; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6301 | CD320 | Bryony Thompson Phenotypes for gene: CD320 were changed from to Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646; Disorders of cobalamin absorption, transport and metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6298 | CD320 | Bryony Thompson reviewed gene: CD320: Rating: ; Mode of pathogenicity: None; Publications: 29663633, 27604308, 30303736; Phenotypes: Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646, Disorders of cobalamin absorption, transport and metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6296 | PNLIP | Bryony Thompson Added comment: Comment on list classification: Appears to be a clinically benign metabolic condition | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6295 | PNLIP |
Bryony Thompson gene: PNLIP was added gene: PNLIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PNLIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308 Phenotypes for gene: PNLIP were set to Pancreatic lipase deficiency MIM#614338; disorders of lipid and lipoprotein metabolism Review for gene: PNLIP was set to GREEN Added comment: 4 cases from 2 unrelated families, with supporting biochemical assays in patient cells and cellular-based assays. The cases have decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. Sources: Literature |
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| Mendeliome v0.6294 | TDO2 |
Zornitza Stark gene: TDO2 was added gene: TDO2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TDO2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TDO2 were set to 28285122; 27604308 Phenotypes for gene: TDO2 were set to Hypertryptophanemia MIM#600627; Disorders of histidine, tryptophan or lysine metabolism Review for gene: TDO2 was set to RED Added comment: Single case reported, biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences Sources: Expert list |
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| Mendeliome v0.6285 | SARDH | Zornitza Stark Phenotypes for gene: SARDH were changed from to Sarcosinemia MIM#268900; Disorders of serine, glycine or glycerate metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6281 | SARDH | Zornitza Stark reviewed gene: SARDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 22825317, 27604308; Phenotypes: Sarcosinemia MIM#268900, Disorders of serine, glycine or glycerate metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6277 | KHK | Zornitza Stark Phenotypes for gene: KHK were changed from to Fructosuria MIM#229800; Disorders of fructose metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6273 | KHK | Zornitza Stark reviewed gene: KHK: Rating: AMBER; Mode of pathogenicity: None; Publications: 7833921, 27604308, 29870677; Phenotypes: Fructosuria MIM#229800, Disorders of fructose metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6273 | HAL | Zornitza Stark Phenotypes for gene: HAL were changed from to Histidinemia MIM#235800; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6269 | HAL | Zornitza Stark reviewed gene: HAL: Rating: AMBER; Mode of pathogenicity: None; Publications: 27604308, 15806399, 20156889; Phenotypes: Histidinemia MIM#235800, Disorders of histidine, tryptophan or lysine metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6266 | DCXR |
Zornitza Stark gene: DCXR was added gene: DCXR was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DCXR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DCXR were set to 22042873 Phenotypes for gene: DCXR were set to Pentosuria MIM#260800; Disorders of pentose metabolism Review for gene: DCXR was set to AMBER Added comment: At least 9 Ashkenazi Jewish probands reported. The condition is clinically benign. Sources: Expert list |
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| Mendeliome v0.6261 | ACSF3 | Zornitza Stark Phenotypes for gene: ACSF3 were changed from to Combined malonic and methylmalonic aciduria MIM#614265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6257 | ACSF3 | Zornitza Stark reviewed gene: ACSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: 21841779, 30740739; Phenotypes: Combined malonic and methylmalonic aciduria MIM#614265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6213 | BMP7 | Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6211 | BMP7 |
Zornitza Stark changed review comment from: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT. Sources: Literature; to: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT. Sources: Literature PMID 33434492: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS. |
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| Mendeliome v0.6211 | BMP7 | Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract, Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6211 | BMP7 | Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6210 | BMP7 | Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | EGFR | Eleanor Williams changed review comment from: PMID: 33326033 - Akhavanfard et al 2020 - identified a heterozygous germline variant in EGFR (c.3238 G>A, p.Asp1080Asn) in a 21 year old female with metastatic bilateral Adrenocortical carcinoma (ACC). Then they analyzed germline exome data from 21 children, 32 adolescents and young adults (15-39y), and 60 adult participants with ACC. 3.5% of all 113 ACC cases had at least a highly prioritized VUS germline EGFR variant, compared to only 0.3% in a non-TCGA (The Cancer Genome Atlas) ExAC control group (P < 0.0001). No segregation data.; to: PMID: 33326033 - Akhavanfard et al 2020 - identified a heterozygous germline variant in EGFR (c.3238 G>A, p.Asp1080Asn) in a 21 year old female with metastatic bilateral Adrenocortical carcinoma (ACC). Then they analyzed germline exome data from 21 children, 32 adolescents and young adults (15-39y), and 60 adult participants with ACC. 3.5% of all 113 ACC cases had at least a highly prioritized VUS germline EGFR variant, compared to only 0.3% in a non-TCGA (The Cancer Genome Atlas) ExAC control group (P < 0.0001). In the adolescents and young adults group 6.2% had ECGR variants. No segregation data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6187 | PIGF |
Paul De Fazio changed review comment from: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness - only one of the two had seizures (GTCS), the other was 14mo and noted to have tonic posturing. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated by flow cytometry and a rescue assay. Alkaline phosphatase in both individuals was normal. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature |
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| Mendeliome v0.6172 | BCAT2 |
Bryony Thompson gene: BCAT2 was added gene: BCAT2 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: BCAT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BCAT2 were set to 14755340; 25653144 Phenotypes for gene: BCAT2 were set to Hypervalinemia or hyperleucine-isoleucinemia MIM#618850; disorder of branched-chain amino acid metabolism Review for gene: BCAT2 was set to AMBER Added comment: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease. Sources: NHS GMS |
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| Mendeliome v0.6167 | METAP1 | Zornitza Stark Marked gene: METAP1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6167 | METAP1 | Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6167 | METAP1 | Zornitza Stark Classified gene: METAP1 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6167 | METAP1 | Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6166 | METAP1 |
Paul De Fazio gene: METAP1 was added gene: METAP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METAP1 were set to PMID: 32764695 Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay Review for gene: METAP1 was set to RED gene: METAP1 was marked as current diagnostic Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family. Sources: Literature |
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| Mendeliome v0.6164 | MYADML2 |
Paul De Fazio gene: MYADML2 was added gene: MYADML2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYADML2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYADML2 were set to 32778762 Phenotypes for gene: MYADML2 were set to Cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles Review for gene: MYADML2 was set to RED gene: MYADML2 was marked as current diagnostic Added comment: 5 sibs from a consanguineous family identified to have biallelic deletion encompassing part of the PYCR1 gene and the coding region of the MYADML2 gene. According to the authors: "All five affected sibs had the most common features of ARCL (autosomal recessive cutis laxa) but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found." Phenotype may still be explained by the PYCR1 deletion alone. Sources: Literature |
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| Mendeliome v0.6141 | NDUFC2 |
Zornitza Stark gene: NDUFC2 was added gene: NDUFC2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NDUFC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFC2 were set to 32969598 Phenotypes for gene: NDUFC2 were set to Mitochondrial complex I deficiency, nuclear type 36, MIM# 619170 Review for gene: NDUFC2 was set to AMBER Added comment: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome. Two unrelated families reported, some functional data. Sources: Expert list |
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| Mendeliome v0.6123 | OPA3 | Zornitza Stark Phenotypes for gene: OPA3 were changed from to 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR; Optic atrophy 3 with cataract (MIM#165300), AD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6119 | OPA3 | Zornitza Stark reviewed gene: OPA3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25159689, 31119193, 31928268; Phenotypes: 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR, Optic atrophy 3 with cataract (MIM#165300), AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6119 | FOXF1 |
Zornitza Stark changed review comment from: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.; to: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs. Over 50 families reported. |
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| Mendeliome v0.6035 | SCAMP5 | Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed publications: 31439720, 33390987 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5743 | FBLN1 | Zornitza Stark reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: 24084572; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5743 | FBLN1 | Zornitza Stark Phenotypes for gene: FBLN1 were changed from to Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5736 | FBLN1 | Elena Savva reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 11836357; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5736 | SUCLA2 | Zornitza Stark Phenotypes for gene: SUCLA2 were changed from to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), MIM# 612073, MONDO:0012791 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5733 | SUCLA2 | Zornitza Stark edited their review of gene: SUCLA2: Changed phenotypes: Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), MIM# 612073, MONDO:0012791 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5733 | SUCLA2 | Zornitza Stark reviewed gene: SUCLA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15877282, 17287286, 17301081, 23759946, 33231368, 33230181, 28243576, 27913098, 27651038; Phenotypes: Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), MIM# 612073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5696 | B3GALT6 | Zornitza Stark Phenotypes for gene: B3GALT6 were changed from to Al-Gazali syndrome, MIM# 609465; Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349, MONDO:0014139; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM# 271640, MONDO:0010075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5693 | B3GALT6 | Zornitza Stark reviewed gene: B3GALT6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25149931, 29443383, 23664117, 29931299, 23664117, 23664118, 31614862; Phenotypes: Al-Gazali syndrome, MIM# 609465, Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349, MONDO:0014139, Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM# 271640, MONDO:0010075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5567 | VPS4A |
Kristin Rigbye changed review comment from: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A |
Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A | Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5558 | VPS4A |
Kristin Rigbye gene: VPS4A was added gene: VPS4A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to PMID: 33186543; 33186545 Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder Review for gene: VPS4A was set to GREEN Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature |
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| Mendeliome v0.5519 | TONSL | Zornitza Stark Phenotypes for gene: TONSL were changed from to Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510; spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5507 | TONSL | Eleanor Williams reviewed gene: TONSL: Rating: GREEN; Mode of pathogenicity: None; Publications: 30773277, 30773278, 32959051; Phenotypes: Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510, spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5381 | LRIF1 |
Bryony Thompson changed review comment from: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus. Sources: Literature; to: A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus. Sources: Literature |
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| Mendeliome v0.5380 | LRIF1 |
Bryony Thompson gene: LRIF1 was added gene: LRIF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRIF1 were set to 32467133 Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy Review for gene: LRIF1 was set to AMBER Added comment: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus. Sources: Literature |
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| Mendeliome v0.5357 | ADAR | Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010; Dyschromatosis symmetrica hereditaria, MIM# 127400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5355 | ADAR | Zornitza Stark reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM# 615010, Dyschromatosis symmetrica hereditaria, MIM# 127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5353 | FOXJ1 | Zornitza Stark Phenotypes for gene: FOXJ1 were changed from hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry to Ciliary dyskinesia, primary, 43, MIM#618699; hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5352 | FOXJ1 | Zornitza Stark edited their review of gene: FOXJ1: Changed phenotypes: Ciliary dyskinesia, primary, 43, MIM#618699, hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5317 | UBA1 | Zornitza Stark edited their review of gene: UBA1: Added comment: Association with VEXAS: 25 men reported with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation, and an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopaenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.; Changed publications: 18179898, 32181232, 31932168, 29034082, 27699224, 26028276, 23518311, 33108101; Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830, Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5315 | ZFHX4 |
Bryony Thompson changed review comment from: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Literature; to: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). PMID: 24038936 - a single case with developmental delay, macrocephaly, ventriculomegaly, hypermetropia, recurrent infections, dysmorphism and a de novo deletion of the last 7 exons of the gene. Sources: Literature |
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| Mendeliome v0.5272 | PRKG2 |
Arina Puzriakova gene: PRKG2 was added gene: PRKG2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRKG2 were set to 33106379 Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia Review for gene: PRKG2 was set to GREEN Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper). Sources: Literature |
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| Mendeliome v0.5222 | MPP5 |
Konstantinos Varvagiannis gene: MPP5 was added gene: MPP5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MPP5 were set to 33073849 Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality Penetrance for gene: MPP5 were set to unknown Review for gene: MPP5 was set to GREEN Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants. Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features. All were investigated by exome sequencing (previous investigations not mentioned). One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24). The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK p55 subfamily), determining cell polarity at tight junctions. Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided] The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness. Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision. Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice. Sources: Literature |
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| Mendeliome v0.5182 | HBB | Zornitza Stark Phenotypes for gene: HBB were changed from to Delta-beta thalassemia 141749; Erythrocytosis 6 617980; Heinz body anemia 140700; Hereditary persistence of fetal hemoglobin 141749; Methemoglobinemia, beta type 617971; Sickle cell anemia 603903; Thalassemia-beta, dominant inclusion-body 603902; Thalassemia, beta 613985 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5174 | HBB | Elena Savva reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31788855, 20301599, 29700171; Phenotypes: {Malaria, resistance to} 611162, Delta-beta thalassemia 141749, Erythrocytosis 6 617980, Heinz body anemia 140700, Hereditary persistence of fetal hemoglobin 141749, Methemoglobinemia, beta type 617971, Sickle cell anemia 603903, Thalassemia-beta, dominant inclusion-body 603902, Thalassemia, beta 613985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5093 | BMP7 |
Zornitza Stark gene: BMP7 was added gene: BMP7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP7 were set to 32266521; 24429398 Phenotypes for gene: BMP7 were set to Non-syndromic metopic craniosynostosis Mode of pathogenicity for gene: BMP7 was set to Other Review for gene: BMP7 was set to RED Added comment: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT. Sources: Literature |
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| Mendeliome v0.4998 | CSNK1G1 |
Zornitza Stark gene: CSNK1G1 was added gene: CSNK1G1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CSNK1G1 were set to 33009664 Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures Review for gene: CSNK1G1 was set to GREEN Added comment: Borderline Green/Amber rating. Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883). Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress). CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited). One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn]. Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD. There were no variant studies performed. The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies). Sources: Literature |
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| Mendeliome v0.4872 | SHMT2 |
Zornitza Stark gene: SHMT2 was added gene: SHMT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly Review for gene: SHMT2 was set to GREEN Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs. Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones. SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes. While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect. The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity). Sources: Literature |
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| Mendeliome v0.4860 | VPS16 |
Zornitza Stark gene: VPS16 was added gene: VPS16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS16 were set to 32808683 Phenotypes for gene: VPS16 were set to Dystonia Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals. Sources: Literature |
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| Mendeliome v0.4602 | SECISBP2 | Zornitza Stark Phenotypes for gene: SECISBP2 were changed from to Thyroid hormone metabolism, abnormal, MIM# 609698 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4599 | SECISBP2 | Zornitza Stark reviewed gene: SECISBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16228000, 19602558, 21084748, 22247018; Phenotypes: Thyroid hormone metabolism, abnormal, MIM# 609698; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4520 | SLC12A2 |
Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic : DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift). Biallelic : DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects). --- Monoallelic SLC12A2 mutations : ► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below). ► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6). Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested). SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1). The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients. Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690). Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder. In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis. ► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx. ► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range. ----- Biallelic SLC12A2 mutations: ► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G]. ► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model. ► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.4501 | MTX2 |
Zornitza Stark gene: MTX2 was added gene: MTX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTX2 were set to 32917887 Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification Review for gene: MTX2 was set to GREEN Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature |
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| Mendeliome v0.4500 | RREB1 |
Zornitza Stark gene: RREB1 was added gene: RREB1 was added to Mendeliome. Sources: Literature SV/CNV tags were added to gene: RREB1. Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RREB1 were set to 32938917 Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder Review for gene: RREB1 was set to RED Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes. In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association. Sources: Literature |
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| Mendeliome v0.4496 | FNIP1 |
Arina Puzriakova gene: FNIP1 was added gene: FNIP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FNIP1 were set to 32181500; 32905580 Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia Review for gene: FNIP1 was set to GREEN Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed. - PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway. Sources: Literature |
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| Mendeliome v0.4463 | NAXE | Zornitza Stark changed review comment from: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.; to: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4392 | SLC25A46 |
Zornitza Stark changed review comment from: Age of onset is variable, but childhood onset described. Ataxia is a feature.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. At least 10 unrelated families reported, supportive functional data. |
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| Mendeliome v0.4015 | ABCA3 | Zornitza Stark Phenotypes for gene: ABCA3 were changed from to Surfactant metabolism dysfunction, pulmonary, 3, MIM# 610921 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4012 | ABCA3 | Zornitza Stark reviewed gene: ABCA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15044640; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 3, MIM# 610921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4002 | AASS | Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. Hyperlysinemia is generally considered to be a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3938 | PDE2A |
Zornitza Stark gene: PDE2A was added gene: PDE2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDE2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE2A were set to 32467598; 32196122; 29392776 Phenotypes for gene: PDE2A were set to Paroxysmal dyskinesia Review for gene: PDE2A was set to GREEN Added comment: Four unrelated families reported with childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy. One of the reports characterises the disorder as 'Rett-like'. Sources: Literature |
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| Mendeliome v0.3732 | FAM50A |
Zornitza Stark gene: FAM50A was added gene: FAM50A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM50A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Review for gene: FAM50A was set to GREEN Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Sources: Literature |
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| Mendeliome v0.3731 | ADK | Zornitza Stark Phenotypes for gene: ADK were changed from to Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3728 | ADK | Zornitza Stark reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963049, 17120046; Phenotypes: Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3678 | AIFM1 | Zornitza Stark Phenotypes for gene: AIFM1 were changed from to Combined oxidative phosphorylation deficiency 6, 300816; Cowchock syndrome, 310490; Deafness, X-linked 5, 300614; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3675 | AIFM1 | Elena Savva reviewed gene: AIFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28842795; Phenotypes: Combined oxidative phosphorylation deficiency 6, 300816, Cowchock syndrome, 310490, Deafness, X-linked 5, 300614, Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3675 | PIGQ |
Zornitza Stark edited their review of gene: PIGQ: Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548). Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362). Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality. PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis. More than 10 variants have been reported to date (missense / pLoF).; Changed phenotypes: Epileptic encephalopathy, early infantile, 77, MIM# 618548 |
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| Mendeliome v0.3657 | CALCRL |
Hazel Phillimore gene: CALCRL was added gene: CALCRL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CALCRL were set to PMID: 30115739 Phenotypes for gene: CALCRL were set to ?Lymphatic malformation 8 (MIM# 618773); hydrops fetalis Review for gene: CALCRL was set to RED Added comment: Homozygous in-frame deletion (Val205del) in the CALCRL gene (Val205del) in a 22 week-old fetus with hydrops details due to lymphatic malformation. Consanguineous parents. Heterozygosity of the variant was also suggested to be associated with spontaneous miscarriage and subfertility. Consanguineous family with 8 total miscarriages from 3 carrier women, and 2 of these were confirmed to be due to hydrops fetalis. Note: possible association of a variant in ASAH1 gene that is associated with Farber lipogranulomatosis which can sometimes present with antenatal hydrops fetalis. (Homozygosity in one of the fetuses, fetus and heterozygosity in some of the family members). In vitro biochemical assays indicated that the variant causes misfolding of the protein and reduced association with its chaperone, RAMP2, and reduced translocation to the plasma membrane. (PMID: 30115739; Mackie, DI. et al., 2018). Sources: Literature |
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| Mendeliome v0.3626 | AMBRA1 |
Bryony Thompson gene: AMBRA1 was added gene: AMBRA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AMBRA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AMBRA1 were set to 17589504; 32333458 Phenotypes for gene: AMBRA1 were set to Neural tube defects Review for gene: AMBRA1 was set to GREEN Added comment: 5 rare missense variants were identified in 6 cases from a neural tube defect cohort, and 4 (p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) of them were functionally validated to affect autophagy regulation in vitro or zebrafish embryo development in vivo. There is also null mouse model with neural tube defects. Sources: Literature |
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| Mendeliome v0.3590 | GNPNAT1 |
Arina Puzriakova changed review comment from: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1. Sources: Literature |
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| Mendeliome v0.3590 | GNPNAT1 |
Arina Puzriakova gene: GNPNAT1 was added gene: GNPNAT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNPNAT1 were set to 32591345 Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia Review for gene: GNPNAT1 was set to RED Added comment: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Sources: Literature |
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| Mendeliome v0.3507 | PLCB3 |
Zornitza Stark gene: PLCB3 was added gene: PLCB3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PLCB3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLCB3 were set to 29122926 Phenotypes for gene: PLCB3 were set to Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961 Review for gene: PLCB3 was set to RED Added comment: Single consanguineous family reported. Sources: Expert list |
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| Mendeliome v0.3502 | MPL | Zornitza Stark Phenotypes for gene: MPL were changed from to Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3496 | MPL | Chern Lim reviewed gene: MPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28955303, 26423830; Phenotypes: Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503, Thrombocythemia 2, MIM#601977, AD, SMu, Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3325 | TBC1D2B |
Zornitza Stark gene: TBC1D2B was added gene: TBC1D2B was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D2B were set to 32623794 Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality Review for gene: TBC1D2B was set to GREEN Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants. Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations. All were born to non-consanguineous couples and additional investigations were performed in some. Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses. In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts. TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation. Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24. Sources: Expert Review |
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| Mendeliome v0.3308 | SGMS2 |
Bryony Thompson gene: SGMS2 was added gene: SGMS2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SGMS2 were set to 30779713; 32028018 Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550 Review for gene: SGMS2 was set to GREEN Added comment: 12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments. 2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. Sources: Expert list |
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| Mendeliome v0.2795 | COL10A1 | Zornitza Stark Phenotypes for gene: COL10A1 were changed from to Metaphyseal chondrodysplasia, Schmid type, MIM#156500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2792 | COL10A1 | Zornitza Stark reviewed gene: COL10A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15880705, 31633898; Phenotypes: Metaphyseal chondrodysplasia, Schmid type, MIM#156500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2625 | ALPK1 | Zornitza Stark edited their review of gene: ALPK1: Added comment: Six unrelated families reported with same recurrent missense variant c.710C>T, (p.Thr237Met) and ROSAH syndrome phenotype. Pancytopaenia and recurrent infections present in some.; Changed rating: GREEN; Changed publications: 31053777, 30967659, 31939038; Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, ROSAH syndrome, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2577 | RHOA | Zornitza Stark Phenotypes for gene: RHOA were changed from normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia to normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia; dental anomalies; body asymmetry; limb length discrepancy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2575 | RHOA | Zornitza Stark reviewed gene: RHOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31821646; Phenotypes: hypopigmented areas of the skin, dental anomalies, body asymmetry, limb length discrepancy, MRI abnormalities; Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2574 | IQCE |
Zornitza Stark gene: IQCE was added gene: IQCE was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IQCE were set to 31549751; 28488682 Phenotypes for gene: IQCE were set to Postaxial polydactyly Review for gene: IQCE was set to GREEN Added comment: Four families reported with bi-allelic variants in this gene. The c.895_904del (p.Val301Serfs*8) was found in three of the families without sharing a common haplotype, suggesting a recurrent mechanism. RNA expression analysis on patients’ fibroblasts showed that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrated a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. Sources: Literature |
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| Mendeliome v0.2298 | MTCL1 |
Bryony Thompson gene: MTCL1 was added gene: MTCL1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MTCL1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MTCL1 were set to 30548255; 28283581 Phenotypes for gene: MTCL1 were set to slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia Review for gene: MTCL1 was set to AMBER Added comment: Single case with a homozygous loss of function variant in a Polish study of early-onset cerebellar ataxia, and a single family with a single heterozygous missense (p.Val1435Met) identified in two family members with adult-onset spinocerebellar ataxia. Mtcl1 gene disruption in mice results in abnormal motor coordination with Purkinje cell degeneration Sources: Expert list |
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| Mendeliome v0.2266 | MAP3K7 | Zornitza Stark Phenotypes for gene: MAP3K7 were changed from to Cardiospondylocarpofacial syndrome 157800 AD; Frontometaphyseal dysplasia 2 617137 AD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1999 | HAVCR2 |
Zornitza Stark gene: HAVCR2 was added gene: HAVCR2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: HAVCR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HAVCR2 were set to 30374066; 30792187 Phenotypes for gene: HAVCR2 were set to T-cell lymphoma, subcutaneous panniculitis-like, MIM# 618398 Review for gene: HAVCR2 was set to GREEN Added comment: Over 20 unrelated individuals reported, note germline confirmation in only a few. Some variants are recurrent: c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met). Sources: Expert list |
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| Mendeliome v0.1801 | MRM2 |
Zornitza Stark gene: MRM2 was added gene: MRM2 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: MRM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRM2 were set to 28973171 Phenotypes for gene: MRM2 were set to MELAS-like Review for gene: MRM2 was set to AMBER Added comment: Single individual reported plus functional data. MRM2 encodes an enzyme responsible for 2'-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. Sources: NHS GMS |
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| Mendeliome v0.1784 | HCFC1 | Zornitza Stark Phenotypes for gene: HCFC1 were changed from to Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ) 309541 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1772 | HCFC1 | Elena Savva reviewed gene: HCFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23000143; Phenotypes: Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ) 309541; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1727 | NADK2 |
Zornitza Stark gene: NADK2 was added gene: NADK2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NADK2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NADK2 were set to 24847004; 29388319; 27940755 Phenotypes for gene: NADK2 were set to 2,4-dienoyl-CoA reductase deficiency, MIM# 616034 Review for gene: NADK2 was set to GREEN gene: NADK2 was marked as current diagnostic Added comment: Mitochondrial dysfunction resulting in severe neurologic and metabolic dysfunction beginning in early infancy reported in two individuals with confirmed variants in this gene. Another individual with homozygous hypomorphic start loss variant g.36241900 A>G p. Met1Val and milder phenotype reported (PMID:29388319). Sources: Expert list |
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| Mendeliome v0.1683 | RSPRY1 | Zornitza Stark Phenotypes for gene: RSPRY1 were changed from to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1679 | RSPRY1 | Zornitza Stark reviewed gene: RSPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365341; Phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1656 | MAPRE2 | Zornitza Stark Phenotypes for gene: MAPRE2 were changed from to Symmetric circumferential skin creases, congenital, 2, MIM# 616734 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1653 | MAPRE2 | Zornitza Stark reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975; Phenotypes: Symmetric circumferential skin creases, congenital, 2, MIM# 616734; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1635 | MAP3K7 | Michelle Torres reviewed gene: MAP3K7: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27426734, 27426733; Phenotypes: Cardiospondylocarpofacial syndrome 157800 AD, Frontometaphyseal dysplasia 2 617137 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1603 | AIRE | Zornitza Stark Phenotypes for gene: AIRE were changed from to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, MIM#240300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1590 | AIRE | Teresa Zhao reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1479 | FMO3 | Zornitza Stark changed review comment from: Comment when marking as ready: Inborn error of metabolism accompanied by fish-like body odor resulting from deficiency of dimethylglycine dehydrogenase; to: Comment when marking as ready: Inborn error of metabolism accompanied by fish-like body odour resulting from deficiency of dimethylglycine dehydrogenase | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1479 | FMO3 | Zornitza Stark Added comment: Comment when marking as ready: Inborn error of metabolism accompanied by fish-like body odor resulting from deficiency of dimethylglycine dehydrogenase | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1479 | FMO3 | Zornitza Stark Phenotypes for gene: FMO3 were changed from to Trimethylaminuria, MIM#602079 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | FMO3 | Elena Savva reviewed gene: FMO3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28649550, 31240165; Phenotypes: Trimethylaminuria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1471 | COX4I2 | Zornitza Stark edited their review of gene: COX4I2: Added comment: Glu138Lys present in 3 homozygotes in gnomad, wich is out of keeping for this rare metabolic disorder. Note no other variants reported in this gene since original report in 2009. All variants submitted to ClinVar are VOUS/LB/B.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1425 | PTPN11 | Zornitza Stark Phenotypes for gene: PTPN11 were changed from to LEOPARD syndrome 1 (MIM#151100); Noonan syndrome 1 (MIM#163950); Metachondromatosis (MIM#156250) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1415 | PTPN11 | Crystle Lee reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 24935154, 11704759, 21533187; Phenotypes: LEOPARD syndrome 1 (MIM#151100), Noonan syndrome 1 (MIM#163950), Metachondromatosis (MIM#156250); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1338 | TOR1AIP1 |
Bryony Thompson gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937 Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072 Review for gene: TOR1AIP1 was set to GREEN Added comment: At least 5 families/cases reported with muscular dystrophy and sometimes cardiomyopathy. Sources: Expert list |
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| Mendeliome v0.1111 | FLNA | Zornitza Stark Phenotypes for gene: FLNA were changed from to ?FG syndrome 2, XL; Cardiac valvular dysplasia, X-linked; Congenital short bowel syndrome; Frontometaphyseal dysplasia 1; Heterotopia, periventricular, 1; Intestinal pseudoobstruction, neuronal Melnick-Needles syndrome; Otopalatodigital syndrome, type I; Otopalatodigital syndrome, type II; Terminal osseous dysplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1075 | ARSA | Zornitza Stark Phenotypes for gene: ARSA were changed from to Metachromatic leukodystrophy, MIM#250100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1069 | FLNA | Elena Savva reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30089473; Phenotypes: ?FG syndrome 2, XL, Cardiac valvular dysplasia, X-linked, Congenital short bowel syndrome, Frontometaphyseal dysplasia 1, Heterotopia, periventricular, 1, Intestinal pseudoobstruction, neuronal Melnick-Needles syndrome, Otopalatodigital syndrome, type I, Otopalatodigital syndrome, type II, Terminal osseous dysplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1054 | ARSA | Elena Savva reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Metachromatic leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.899 | FGF16 |
Zornitza Stark gene: FGF16 was added gene: FGF16 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FGF16 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: FGF16 were set to Metacarpal 4-5 fusion, MIM# 309630 Review for gene: FGF16 was set to GREEN gene: FGF16 was marked as current diagnostic Added comment: Sources: Expert list |
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| Mendeliome v0.870 | RPL13 |
Zornitza Stark gene: RPL13 was added gene: RPL13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPL13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPL13 were set to 31630789 Phenotypes for gene: RPL13 were set to Spondyloepimetaphyseal Dysplasia with Severe Short Stature Review for gene: RPL13 was set to GREEN Added comment: Four unrelated individuals reported with de novo variants. Sources: Literature |
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| Mendeliome v0.869 | FOXJ1 | Zornitza Stark Phenotypes for gene: FOXJ1 were changed from to hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.866 | FOXJ1 | Zornitza Stark reviewed gene: FOXJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630787; Phenotypes: hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.833 | ACAN |
Zornitza Stark gene: ACAN was added gene: ACAN was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ACAN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: ACAN were set to Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800; Spondyloepimetaphyseal dysplasia, aggrecan type 612813 Review for gene: ACAN was set to GREEN Added comment: Sources: Expert list |
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| Mendeliome v0.637 | METTL5 | Zornitza Stark Marked gene: METTL5 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.637 | METTL5 | Zornitza Stark Gene: mettl5 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.637 | METTL5 | Zornitza Stark Classified gene: METTL5 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.637 | METTL5 | Zornitza Stark Gene: mettl5 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.636 | METTL5 |
Zornitza Stark gene: METTL5 was added gene: METTL5 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL5 were set to 29302074; 31564433 Phenotypes for gene: METTL5 were set to Intellectual developmental disorder, autosomal recessive 72, MIM# 618665 Review for gene: METTL5 was set to GREEN Added comment: Three unrelated families and animal model. Sources: Expert list |
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| Mendeliome v0.624 | TRPM3 |
Zornitza Stark gene: TRPM3 was added gene: TRPM3 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRPM3 were set to 31278393 Phenotypes for gene: TRPM3 were set to Intellectual disability; epilepsy Review for gene: TRPM3 was set to GREEN Added comment: 8 unrelated individuals with de novo variants in this gene. Recurrent variant p.(Val837Met) identified in 7/8. Sources: Literature |
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| Mendeliome v0.549 | CAD |
Zornitza Stark gene: CAD was added gene: CAD was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAD were set to 28007989; 25678555 Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50, MIM# 616457 Review for gene: CAD was set to GREEN Added comment: Five individuals from four unrelated families reported, seizures are a prominent part of the phenotype of this progressive neurometabolic condition. Sources: Expert list |
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| Mendeliome v0.471 | KITLG | Zornitza Stark Phenotypes for gene: KITLG were changed from to Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.469 | KITLG | Zornitza Stark reviewed gene: KITLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 26522471; Phenotypes: Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.311 | PPP2CA |
Zornitza Stark gene: PPP2CA was added gene: PPP2CA was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PPP2CA were set to 30595372 Phenotypes for gene: PPP2CA were set to Neurodevelopmental disorder and language delay with or without structural brain abnormalities; OMIM #618354 Review for gene: PPP2CA was set to GREEN Added comment: 15 unrelated patients with a neurodevelopmental disorder with de novo heterozygous PPP2CA mutations, and 1 with partial deletion of PPP2CA. Functional studies showed complete PP2A dysfunction in 4 individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Sources: Literature |
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| Mendeliome v0.0 | METTL23 |
Zornitza Stark gene: METTL23 was added gene: METTL23 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: METTL23 was set to Unknown |
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| Mendeliome v0.0 | MET |
Zornitza Stark gene: MET was added gene: MET was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MET was set to Unknown |
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