Penetrance of Mutations in Plakophilin-2 Among Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

ObjectivesThe purpose of our study was to characterize the penetrance of PKP2mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2mutation carriers.BackgroundArrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterized by fatty-fibrous myocardial replacement of the right ventricle, ventricular arrhythmias, and right ventricular dysfunction. Mutations in PKP2, the gene encoding plakophilin-2, are found in 11% to 43% of ARVD/C probands.MethodsThe study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology.ResultsIn addition to the probands, PKP2mutations were present in 52% of relatives screened. Forty-nine percent of PKP2mutation carriers met TFC. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria besides family history. Pedigrees showed wide intra-familial variability, ranging from severe disease with early death to individuals who were completely asymptomatic late in life. Male PKP2mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05).ConclusionsPKP2mutations in a group of North American families with ARVD/C have both reduced penetrance and variable expressivity. Gender may have an influence on penetrance of PKP2mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.