Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy

• Published in: Journal of the American College of Cardiology Vol. 55; no. 6; pp. 587 - 597
• Main Authors: Xu, Tianhong, Yang, Zhao, Vatta, Matteo, Rampazzo, Alessandra, Beffagna, Giorgia, Pillichou, Kalliopi, Scherer, Steven E., Saffitz, Jeffrey, Kravitz, Joshua, Zareba, Wojciech, Danieli, Gian Antonio, Lorenzon, Alessandra, Nava, Andrea, Bauce, Barbara, Thiene, Gaetano, Basso, Cristina, Calkins, Hugh, Gear, Kathy, Marcus, Frank, Towbin, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 09.02.2010; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; arrhythmias; Arrhythmogenic Right Ventricular Dysplasia - genetics; Biological and medical sciences; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiomyocytes; cardiomyopathies; Cardiomyopathy; Cardiovascular; Cell adhesion & migration; Child; Deoxyribonucleic acid; Desmosomes; DNA; Family medical history; Female; Genes; genetic mutations; Genetic testing; Heart; Heart failure; Heterozygote; Humans; intercalated disks; Internal Medicine; Male; Medical sciences; Middle Aged; Mutation; NMR; Nuclear magnetic resonance; Pedigree; Proteins; Studies; Task forces; United States > US; California; ARVC; DSP; genetic mutations; RV; MRI; LV; arrhythmias; PKP; DSC; DNA; DSG; intercalated disks; desmosomes; cardiomyopathies; PCR; desmoplakin; magnetic resonance imaging; right ventricle/ventricular; deoxyribonucleic acid; left ventricle/ventricular; polymerase chain reaction; desmoglein; arrhythmogenic right ventricular cardiomyopathy; desmocollin; plakophilin; Arrhythmia; Arrhythmogenic right ventricular dysplasia; Heart disease; Cardiovascular disease; Circulatory system; Cardiology; Heterozygosity
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2009.11.020

The aim of this study was to define the genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy, characterized by right ventricular fibrofatty replacement and arrhythmias, causes sudden death. Autosomal dominant inheritance, reduced penetrance, and 7 desmosome-encoding causative genes are known. The basis of low penetrance is poorly understood. Arrhythmogenic right ventricular cardiomyopathy probands and family members were enrolled, blood was obtained, lymphoblastoid cell lines were immortalized, deoxyribonucleic acid was extracted, polymerase chain reaction (PCR) amplification of desmosome-encoding genes was performed, PCR products were sequenced, and diseased tissue samples were studied for intercellular junction protein distribution with confocal immunofluorescence microscopy and antibodies against key proteins. We identified 21 variants in plakophilin-2(PKP2) in 38 of 198 probands (19%), including missense, nonsense, splice site, and deletion/insertion mutations. Pedigrees showed wide intra-familial variability (severe early-onset disease to asymptomatic individuals). In 9 of 38 probands, PKP2variants were identified that were encoded in trans(compound heterozygosity). The 38 probands hosting PKP2variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16 of 38 subjects with PKP2variants (42%), including desmoplakin(DSP) (n = 6), desmoglein-2(DSG2) (n = 5), plakophilin-4(PKP4) (n = 1), and desmocollin-2(DSC2) (n = 1). Heterozygous mutations in non-PKP 2desmosomal genes occurred in 14 of 198 subjects (7%), including DSP(n = 4), DSG2(n = 5), DSC2(n = 3), and junctional plakoglobin(JUP) (n = 2). All variants occurred in conserved regions; none was identified in 700 ethnic-matched control subjects. Immunohistochemical analysis demonstrated abnormalities of protein architecture. These data suggest that the genetic basis of ARVC includes reduced penetrance with compound and digenic heterozygosity. Disturbed junctional cytoarchitecture in subjects with desmosomal mutations confirms that ARVC is a disease of the desmosome and cell junction.