Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: Wide spectrum of disease in mutation carriers within a family

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease, with male preponderance, characterized by progressive fibrofatty replacement of the right ventricle and ventricular arrhythmias. Mutations in plakophilin-2 (PKP2), a desmosomal protein, have been reported to underlie familial ARVC. We report a novel ARVC PKP2 mutation and present the clinical findings in three female mutation carriers. METHODS: We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives. Clinical testing and diagnosis of ARVC was based on International Task Force criteria. RESULTS: The proband was diagnosed with ARVC due to right ventricular enlargement and regional hypokinesis, along with repolarization abnormalities and frequent ventricular ectopy. A novel 28 bp insertion in exon 11 of the PKP2 gene was found which causes a frameshift in the coding region. This results in a change in the amino acid sequence of the protein with a premature stop codon at position 740. Of the four relatives, only the mother and younger sister were identified as mutation carriers. The mother was phenotypically normal, while the younger sister has repolarization abnormalities and frequent ventricular ectopy. CONCLUSIONS: We report a novel PKP2 mutation that causes familial ARVC. All mutation carriers in this kindred group were women, and the family showed incomplete penetrance and variable expression of ARVC. Premature truncation of the plakophilin-2 protein appears to be the predominant mechanism whereby PKP2 mutations elicit the ARVC phenotype.