Genetics of cardiomyopathies: arrhythmogenic right ventricular cardiomyopathy

Abstract Arrhythmogenic cardiomyopathy (AC) is characterized by progressive non-ischaemic cardiomyocyte death and fibro-fatty repair, triggering ventricular arrhythmias and sudden death. A familial background consistent with an autosomal dominant trait of inheritance is described in nearly half of AC patients, even if recessive variants have also been reported, either associated or not with palmoplantar keratosis and woolly hair. Advances in DNA sequencing have led to the identification of more than 350 pathogenic mutations in 15 disease-causing genes associated with AC. Nearly half of patients with AC harbour mutations in genes encoding desmosomal proteins (plakoglobin, JUP; desmoplakin, DSP; plakophillin-2, PKP2; desmoglein-2, DSG2; and desmocollin-2, DSC2) and less than 1% carry mutations in non-desmosomal genes (transforming growth factor beta-3, TGFB3; desmin, DES; alpha-T catenin, CTNNA3; phospholamban, PLN; lamin A/C, LMNA; titin, and TTN; ryanodine receptor-2, RYR2). The inheritance pattern of AC is more complex than previously appreciated, with frequent requirement of more than one mutation for fully penetrant disease. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, explaining in part the phenotypic variability. In the era of next-generation sequencing, parallel analysis of thousands of genes is feasible and many rare variants can be detected (nearly 1000 nucleotide variants of unknown significance have been linked to AC), so the challenge is to distinguish causative mutations from the genetic noise since genetic testing may be a precious tool in distinguishing AC patients at risk of disease onset and of sudden death.