Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?

Purpose of review Recent developments in the elucidation of genes underlying arrhythmogenic right ventricular cardiomyopathy and possible pathogenic mechanisms will be highlighted.

Recent findings The cardiac desmosome is a multiprotein structure involved in cell-cell interactions. Mutations in genes encoding desmosomal proteins such as PKP2, DSP, JUP, DSC2 and DSG2 underlie arrhythmogenic right ventricular cardiomyopathy, which can therefore be considered a desmosome cardiomyopathy. Mutations in the plakophilin-2 genes are most prevalent. Current pathophysiological insights suggest a final common pathway in which plakoglobin release from the desmosome independent of the primarily affected desmosomal protein, results in desmosome impairment, intercalated disc remodeling and Wnt/beta-cantenin pathway signaling defects. The recognition of left ventricular involvement associated with mutations in desmosomal protein genes and low penetrance suggests that formal criteria should not be followed too closely in selecting patients for DNA analysis, because finding a mutation may have important implications for clinical practice.

Summary Recent developments have demonstrated that arrhythmogenic right ventricular cardiomyopathy can be considered a desmosome cardiomyopathy. Left ventricular involvement is not uncommon in this type of cardiomyopathy. Such findings are important for diagnostics and family screening and form a starting-point for the elucidation of other (non)-genetic factors influencing disease progression and outcome.