Background-Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results-DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28Ϯ11 years) than in those without (36Ϯ16 years) (PϽ0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (PϽ0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (PϽ0.05). Key Words: arrhythmia Ⅲ cardiomyopathy Ⅲ genetics Ⅲ sudden death Ⅲ tachyarrhythmias A rrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular (RV) dysfunction and ventricular arrhythmias, which may lead to sudden cardiac death. [1][2][3][4][5][6][7][8] Studies have shown that ARVD/C is present in up to 20% of individuals that experience sudden cardiac death and is even more common among athletes who die suddenly. 9 -12 Although fatty or fibrofatty replacement of the myocardium of the RV is the pathological hallmark of the disease, biopsy of the right ventricle is of limited value in establishing a clinical diagnosis. 11,13 Clinically, the diagnosis of ARVD/C is established by a set of criteria proposed by a task force based on subjective grading of clinical findings associated with the condition. 4,14 Molecular diagnosis by identification of genetic mutations may also be an important screening tool for predicting risk of ARVD/C in asymptomatic family members of an affected individual. Conclusions-Our Editorial p 1634 Clinical Perspective p 1649Several genes and genetic loci have been described in association with ARVD/C. Mutations in the gene encoding desmoplakin (DSP) have been described in both dominant .).The online-only Data Supplement, which contains Table I and Table II 24 reported mutations in PKP2, encoding the desmosomal protei...