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

• Published in: Journal of the American College of Cardiology Vol. 48; no. 7; pp. 1416 - 1424
• Main Authors: Dalal, Darshan, James, Cynthia, Devanagondi, Rajiv, Tichnell, Crystal, Tucker, April, Prakasa, Kalpana, Spevak, Philip J., Bluemke, David A., Abraham, Theodore, Russell, Stuart D., Calkins, Hugh, Judge, Daniel P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 03.10.2006; Elsevier Science; Elsevier Limited
• Subjects: Adolescent; Adult; Age Factors; Aged; Arrhythmogenic Right Ventricular Dysplasia - genetics; Biological and medical sciences; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiomyopathies - genetics; DNA Mutational Analysis; Electrocardiography; Female; Heart; Heart attacks; Humans; Male; Medical sciences; Middle Aged; Mutation; Pedigree; Penetrance; Phenotype; Plakophilins - genetics; Severity of Illness Index; Sex Factors; United States > US; California; TFC; RV; ARVD/C; DNA; ECG; ICD; SAECG; VT; Arrhythmia; Arrhythmogenic right ventricular dysplasia; Family study; Heart disease; Gene penetrance; Family environment; Cardiovascular disease; Circulatory system; Mutation; Cardiology; Phlebology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.06.045

Penetrance of Mutations in Plakophilin-2 Among Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Darshan Dalal, Cynthia James, Rajiv Devanagondi, Crystal Tichnell, April Tucker, Kalpana Prakasa, Philip J. Spevak, David A. Bluemke, Theodore Abraham, Stuart D. Russell, Hugh Calkins, Daniel P. Judge Mutations in PKP2, encoding the desmosomal protein plakophilin-2, are present in up to 43% of individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). We sought to characterize the clinical features of PKP2 mutation carriers in 9 ARVD/C families. Forty-nine percent of mutation carriers met task force criteria (TFC) for the diagnosis of ARVD/C. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria. Male PKP2 mutation carriers were more likely to have right ventricular structural and conduction abnormalities (p < 0.05). This finding illustrates the potential role of genetic testing and importance of clinical screening for relatives of ARVD/C patients. The 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. Arrhythmogenic 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. The 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. In 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). PKP2mutations 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.