ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
11391481 The CBS gene on chromosome 21 is overexpressed in patients with trisomy 21. This paper (Pogribna et al., 2001; PMID: 11391481) evaluated the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. They found that plasma levels of cystathionine and cysteine were significantly increased in children with DS, consistent with an increase in CBS activity. The increased activity of CBS in Down syndrome significantly alters homocysteine metabolism so that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established 'folate trap,' creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.