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Desmoglein-2 (DSG2) encodes a desmosomal cadherin critical for cardiomyocyte adhesion and integrity. While DSG2 is well established in arrhythmogenic right ventricular cardiomyopathy, emerging evidence implicates DSG2 variants in dilated cardiomyopathy (DCM). Functional and genetic studies support a role for heterozygous DSG2 mutations in autosomal dominant DCM pathology.
A familial DCM study of 73 index cases identified two DSG2 missense variants, of which c.166G>A (p.Val56Met) co-segregated with disease in a multigenerational pedigree and was absent in 360 control alleles (segregation in ≥4 affected relatives) ([PMID:18678517]). Subsequent screening of 538 unrelated DCM patients found 13 carriers of p.Val56Met versus 3 in 617 controls, indicating a significant enrichment in DCM (p < 0.01) ([PMID:18678517]).
Inheritance is autosomal dominant with high penetrance in p.Val56Met carriers. The variant spectrum in DCM remains narrow, predominantly heterozygous missense changes disrupting desmosomal adhesion. No deep-intronic or large structural variants have been reported in DCM to date.
Functional assessment of p.Val56Met in myocardial tissue revealed pale intercalated disc staining and significantly shortened desmosomes compared to non-carriers, indicating compromised cell–cell adhesion ([PMID:18678517]). These findings parallel in vitro data showing altered desmosomal ultrastructure in mutant DSG2 hearts.
No studies to date dispute the association of DSG2-p.Val56Met with DCM; alternative phenotypes (e.g., ARVC) for this variant have not been reported. However, broader variant screening in DCM cohorts and mechanistic modeling in cardiomyocytes would strengthen the evidence base.
In summary, heterozygous DSG2-p.Val56Met causes autosomal dominant DCM through disrupted desmosomal adhesion. DSG2 genetic testing, including p.Val56Met screening, has clinical utility for early diagnosis and family counseling in DCM.
Gene–Disease AssociationModerate13 unrelated DCM probands with DSG2 p.Val56Met and segregation in ≥4 affected relatives; variant absent in 360 controls ([PMID:18678517]). Genetic EvidenceModerateHeterozygous c.166G>A (p.Val56Met) observed in 13/538 DCM patients vs 3/617 controls; co-segregation in a family pedigree ([PMID:18678517]). Functional EvidenceLimitedMyocardial immunohistochemistry and ultrastructural analysis show shortened desmosomes and intercalated disc abnormalities in p.Val56Met carriers ([PMID:18678517]). |