Intellectual disability syndromic and non-syndromic
Gene: CBS

CBS (cystathionine-beta-synthase)
EnsemblGeneIds (GRCh38): ENSG00000160200
EnsemblGeneIds (GRCh37): ENSG00000160200
OMIM: 613381, Gene2Phenotype
CBS is in 15 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Intellectual disability is a feature.

Treatable disorder.
Created: 1 Dec 2022, 5:17 a.m. | Last Modified: 1 Dec 2022, 5:17 a.m.

Panel Version: 0.5062

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Homocystinuria (MIM# 236200)

Created: 1 Dec 2022, 5:17 a.m.
Last Modified: 1 Dec 2022, 5:17 a.m.
Panel version: 0.5062

Lloyd Pereira (Peter MacCallum Cancer Centre)

Green List (high evidence)

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.
Created: 1 Dec 2022, 4:12 a.m. | Last Modified: 1 Dec 2022, 4:15 a.m.

Panel Version: 0.5060

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Homocysteinuria B6-responsive and nonresponsive types; Thrombosis hyperhomocysteinemic.

Created: 1 Dec 2022, 4:12 a.m.
Last Modified: 1 Dec 2022, 4:15 a.m.
Panel version: 0.5060

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Genetic Health Queensland

Phenotypes

Homocystinuria (MIM# 236200)

Tags

treatable

OMIM

613381

Clinvar variants

Variants in CBS

Penetrance

None

Panels with this gene