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| Intellectual disability syndromic and non-syndromic v0.5064 | CBS | Zornitza Stark Marked gene: CBS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5064 | CBS | Zornitza Stark Gene: cbs has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5064 | CBS | Zornitza Stark Phenotypes for gene: CBS were changed from to Homocystinuria (MIM# 236200) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5063 | CBS | Zornitza Stark Mode of inheritance for gene: CBS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5062 | CBS | Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Homocystinuria (MIM# 236200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5060 | CBS |
Lloyd Pereira changed review comment from: Listed in OMIM with a strong disease association (MIM #236200 homocysteinuria). Multiple experimental and clinical studies demonstrate link between CBS and homocysteinuria (see below): Multiple LOF variants classified as pathogenic or likely pathogenic in ClinVar and reported in the literature in multiple homozygote and compound heterozygote individuals affected with homocystinuria, e.g. c.19dup p.(Gln7fs) (PMID: 25218699; 12124992) and c.919G>A p.(Gly307Ser) (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). Multiple CBS variants reported in CBS deficiency (PMID: 12124992). ClinGen classify as definitive for Homocysteinuria. Clingen states- Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (PMID 1301198, 10408774, 7762555, 12815602, 16307898, 25455305, 26667307, 29508359). Gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (PMID 13654400, 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (PMID 9590298, 25331909), as well as the biochemical and clinical features of mouse models (PMID 18987302) and enzyme replacement studies in mice (PMID 29398487). Recent review reports on role of CBS in down syndrome (PMID: 31955501). However, caveat that multiple genes are associated with down syndrome. Not a strong body of research available linking CBS variants and down syndrome.; to: Listed in OMIM with a strong disease association (MIM #236200 homocysteinuria). Multiple experimental and clinical studies demonstrate link between CBS and homocysteinuria (see below): Multiple LOF variants classified as pathogenic or likely pathogenic in ClinVar and reported in the literature in multiple homozygote and compound heterozygote individuals affected with homocystinuria, e.g. c.19dup p.(Gln7fs) (PMID: 25218699; 12124992) and c.919G>A p.(Gly307Ser) (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). Multiple CBS variants reported in CBS deficiency (PMID: 12124992). ClinGen classify as definitive for Homocysteinuria. Clingen states- Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (PMID 1301198, 10408774, 7762555, 12815602, 16307898, 25455305, 26667307, 29508359). Gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (PMID 13654400, 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (PMID 9590298, 25331909), as well as the biochemical and clinical features of mouse models (PMID 18987302) and enzyme replacement studies in mice (PMID 29398487). Recent review reports on role of CBS in down syndrome (PMID: 31955501). However, caveat that multiple genes are associated with down syndrome. Not a strong body of research available linking CBS variants and down syndrome. |
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| Intellectual disability syndromic and non-syndromic v0.5060 | CBS | Lloyd Pereira reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Homocysteinuria B6-responsive and nonresponsive types, Thrombosis hyperhomocysteinemic.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4953 | CBS | Zornitza Stark Tag treatable tag was added to gene: CBS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.3978 | IMPDH2 |
Laura Raiti gene: IMPDH2 was added gene: IMPDH2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IMPDH2 were set to PMID: 33098801 Added comment: 6 unrelated individuals 1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein. IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition. 1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified: 3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg) 1 x deletion: c.478_480delTCC (p.Ser160del) The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair. The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1. The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.0 | CBS |
Zornitza Stark gene: CBS was added gene: CBS was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: CBS was set to Unknown |
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