DSC2 – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by fibrofatty replacement of right ventricular myocardium, ventricular arrhythmias, and risk of sudden cardiac death. Desmocollin-2 (DSC2) encodes a cadherin in cardiac desmosomes and is recognized as a definitive ARVC gene due to numerous independent reports and functional studies establishing its causal role (Gene Symbol; Disease Name).

Heterozygous missense DSC2 variant c.304G>A (p.Glu102Lys) was first reported in a 43-year-old man with paroxysmal atrial fibrillation who met modified Task Force Criteria after genetic testing, yet remained free of ventricular arrhythmias over 2 years, illustrating incomplete penetrance and variable expressivity (1 proband) ([PMID:23147450]).

In a Chinese family, whole-exome sequencing identified a novel DSC2 missense mutation c.1090G>A (p.Val364Met) that co-segregated with ARVC in 4 affected relatives, establishing autosomal dominant inheritance and familial linkage (4 carriers co-segregating) ([PMID:28256248]).

A Danish cohort of 65 unrelated ARVC patients screened for desmosomal genes uncovered 4 distinct DSC2 variants—including c.4G>A (p.Glu2Lys) and c.2471C>T (p.Ser824Leu)—in index cases, contributing to a broad spectrum of disease-associated alleles (4 probands) ([PMID:20864495]).

An Italian study identified a homozygous founder DSC2 c.536A>G (p.Asp179Gly) variant in 4 patients presenting with severe biventricular cardiomyopathy, whereas heterozygous carriers were asymptomatic, underscoring dosage effects and recessive phenotypes (4 homozygotes) ([PMID:26310507]).

Functional assays demonstrate that DSC2 splice-site mutation c.631-2A>G leads to cryptic splicing, transcript reduction, and impaired desmosome formation in zebrafish, causing myocardial dysfunction, while missense mutations R203C and T275M impair proteolytic activation and plakoglobin binding in vitro, consistent with ARVC pathogenesis (functional concordance) ([PMID:17186466]; [PMID:21062920]).

Integration of genetic and experimental data supports a definitive DSC2–ARVC association: autosomal dominant inheritance with variable penetrance, a diverse variant spectrum (missense, splice, frameshift), documented segregation in families, and concordant in vitro/in vivo disruption of desmosomal integrity. Key take-home: pathogenic DSC2 variants warrant inclusion as a major diagnostic criterion and guide cascade screening for ARVC.

References

• Cardiology • 2012 • Arrhythmogenic right ventricular cardiomyopathy: the challenge of genetic interpretation in clinically suspected cases. PMID:23147450
• Journal of medical genetics • 2010 • Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. PMID:20864495
• The American journal of cardiology • 2017 • Whole-Exome Sequencing Identifies a Novel Mutation of Desmocollin 2 in a Chinese Family With Arrhythmogenic Right Ventricular Cardiomyopathy. PMID:28256248
• American journal of human genetics • 2006 • Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. PMID:17186466
• Cardiovascular research • 2011 • Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations. PMID:21062920
• The American journal of cardiology • 2015 • Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy. PMID:26310507

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