Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease

Aims Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. Methods and results We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. Conclusion Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The tow prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.