CDH2 – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by fibrofatty replacement of the right ventricular myocardium, predisposing to ventricular arrhythmias and sudden cardiac death. Although pathogenic variants in desmosomal genes account for up to 60% of cases, a substantial genotype-negative fraction suggests involvement of non-desmosomal substrates. Recent evidence implicates cadherin 2 (CDH2), encoding N-cadherin, in ARVC pathogenesis, expanding the genetic spectrum for diagnostic testing.

Whole exome sequencing in two affected cousins from a three-generation family with autosomal dominant ARVC identified a novel missense variant c.686A>C (p.Gln229Pro) that cosegregated with disease status and yielded significant parametric linkage (LOD score not reported) in multiple affected relatives ([PMID:28280076]). This variant affects a highly conserved residue in the extracellular cadherin domain and was absent from public population databases (>200 000 chromosomes). Subsequent high-resolution melting analysis in 73 additional genotype-negative ARVC probands revealed an independent c.1219G>A (p.Asp407Asn) missense change in one case, further supporting CDH2 as a bona fide ARVC gene ([PMID:28280076]).

Both reported variants are heterozygous missense substitutions occurring in critical extracellular cadherin repeats, consistent with a dominant mode of inheritance and a variant spectrum restricted to missense alterations disrupting cell–cell adhesion interfaces. No loss-of-function or splice variants have yet been described in ARVC cohorts, and no founder alleles have been identified to date.

CDH2 encodes N-cadherin, a calcium-dependent adhesion molecule essential for intercellular junction integrity in cardiac myocytes. Disruption of N-cadherin homophilic binding is known to impair mechanical coupling and may predispose to myocardial remodeling and arrhythmogenesis, constituting a biologically plausible mechanism for disease.

No conflicting reports have been published to date regarding CDH2 and ARVC. However, larger cohorts and functional validation of disease-associated variants remain necessary to fully establish pathogenic mechanisms.

Key Take-Home: Heterozygous missense variants in CDH2 cause autosomal dominant ARVC, supporting inclusion of CDH2 in cardiomyopathy gene panels for improved diagnostic yield and risk stratification.

References

• Circulation. Cardiovascular genetics • 2017 • Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy PMID:28280076

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