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CLINICAL RESEARCH: HEART RHYTHM DISORDER

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

Darshan Dalal, MD, MPH^_*, Cynthia James, ScM, PhD^_*, Rajiv Devanagondi, BA^_*, Crystal Tichnell, MGC^_*, April Tucker, MGC^_*, Kalpana Prakasa, MD^_*, Philip J. Spevak, MD, FACC, David A. Bluemke, MD, PhD^_*,, Theodore Abraham, MD, FACC^_*, Stuart D. Russell, MD, FACC^_*, Hugh Calkins, MD, FACC^_* and Daniel P. Judge, MD^_*,_*

^_* Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Manuscript received March 20, 2006; revised manuscript received May 9, 2006, accepted June 6, 2006.

^_* Reprint requests and correspondence: Dr. Daniel Judge, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1049, Baltimore, Maryland 21205. (Email: djudge{at}jhmi.edu).

OBJECTIVES: The purpose of our study was to characterize the penetrance of PKP2 mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2 mutation carriers.

BACKGROUND: 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.

METHODS: The study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2 mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology.

RESULTS: In addition to the probands, PKP2 mutations were present in 52% of relatives screened. Forty-nine percent of PKP2 mutation 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 PKP2 mutation 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).

CONCLUSIONS: PKP2 mutations 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 PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.

Abbreviations and Acronyms   ARVD/C = arrhythmogenic right ventricular dysplasia/cardiomyopathy   DNA = deoxyribonucleic acid   ECG = electrocardiogram   ICD = implantable cardioverter-defibrillator   RV = right ventricle/ventricular   SAECG = signal-averaged electrocardiogram   TFC = task force criteria (for diagnosis of ARVD/C)   VT = ventricular tachycardia

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