Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been associated with mutations in genes encoding cellular adhesion proteins. However, only about 40% of patients have mutations in known genes. We hypothesized that mutations in the genes encoding β-catenin (CTNNB1), α-T-catenin (CTNNA3), and PERP (PERP)-all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC. We screened 65 unrelated patients (55 fulfilling 1994 Task Force criteria and ten borderline cases) for mutations in CTNNB1, CTNNA3, and PERP by direct sequencing and LightScanner melting curve analysis. Our comprehensive mutation scanning did not identify any disease-causing mutations. Thirty-five sequence variants were found, including one rare nonsynonymous variant of unknown significance (CTNNA3 A689V). Fourteen of the variants were novel. In conclusion, in our cohort of a limited size, no mutations were identified in the three studied candidate genes despite their involvement in formation and maintenance of the intercalated disk. We recommend focus on other components of cardiomyocyte adhesion in future research into the pathogenesis of ARVC.