DSG2 – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, life-threatening ventricular arrhythmias, and sudden cardiac death. The desmosomal cadherin DSG2 is the sole desmoglein isoform expressed in cardiomyocytes and is critical for intercellular adhesion at the intercalated disk. Pathogenic variants in DSG2 underlie autosomal dominant ARVC with variable penetrance and expressivity.

Initial screening of 80 unrelated ARVC probands identified heterozygous DSG2 mutations in 8 individuals (10%) (PMID:16505173) (PMID:16505173). All mutation carriers fulfilled Task Force criteria, with histological analysis revealing fibrofatty replacement and ultrastructural desmosomal remodeling in endomyocardial biopsies.

Subsequent case reports documented de novo heterozygous missense variants such as c.146G>A (p.Arg49His) in sporadic ARVC (PMID:19151369) and a homozygous founder variant c.1592T>G (p.Phe531Cys) with 100% penetrance in East Asian families (PMID:35941102). Segregation of DSG2 pathogenic alleles was observed in 16 additional affected relatives across multiple pedigrees (PMID:35941102).

The variant spectrum includes missense mutations disrupting the extracellular cadherin domains, truncating and splice-site mutations leading to loss of function, and rare deep-intronic changes affecting splicing. Recurrent and founder alleles (e.g., p.Phe531Cys) contribute to population-specific risk, while de novo events inform genetic counseling regarding recurrence risk.

Functional studies support a dominant-negative or haploinsufficient mechanism. Transgenic mice expressing the orthologous DSG2-N271S mutation develop progressive myocyte necrosis, inflammation, and calcification, followed by fibro-fatty replacement mirroring human ARVC (PMID:19635863) (PMID:19635863). In vitro assays demonstrate impaired prodomain cleavage, reduced homophilic binding, and abnormal desmosomal incorporation for propeptide-cleavage site and missense variants.

Collectively, the genetic, segregation, and experimental data fulfill ClinGen criteria for a definitive gene-disease relationship. DSG2 variant analysis is essential in ARVC diagnostic workflows, risk stratification, and cascade screening. Key take-home: Pathogenic DSG2 variants cause autosomal dominant ARVC with high clinical utility in guiding molecular diagnosis, family counseling, and management.

References

• Circulation • 2006 • Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. PMID:16505173
• Europace • 2009 • Sporadic arrhythmogenic right ventricular cardiomyopathy/dysplasia due to a de novo mutation. PMID:19151369
• The Journal of Experimental Medicine • 2009 • Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy. PMID:19635863
• International Journal of Cardiology • 2022 • Arrhythmogenic right ventricular cardiomyopathy in a Japanese patient with a homozygous founder variant of DSG2 in the East Asian population. PMID:35941102

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