CLINICAL RESEARCH: HEART RHYTHM DISORDER
Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy
Tianhong Xu, PhD*,
Zhao Yang, MD, PhD , ,
Matteo Vatta, PhD,
Alessandra Rampazzo, MD, PhD ,
Giorgia Beffagna, PhD,,
Kalliopi Pillichou, PhD,
Steven E. Scherer, PhD*,
Jeffrey Saffitz, MD, PhD#,
Joshua Kravitz, BS,
Wojciech Zareba, MD**,
Gian Antonio Danieli, PhD,
Alessandra Lorenzon, PhD,
Andrea Nava, MD||,
Barbara Bauce, MD, PhD||,
Gaetano Thiene, MD¶,
Cristina Basso, MD, PhD¶,
Hugh Calkins, MD,
Kathy Gear, RN,
Frank Marcus, MD and
Jeffrey A. Towbin, MD,*
* Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
Department of Medicine (Cardiovascular Sciences), Baylor College of Medicine, Houston, Texas
Department of Pediatrics (Section of Cardiology), Baylor College of Medicine, Houston, Texas
Department of Biology, University of Padua Medical School, Padua, Italy
|| Department of Cardiothoracic-Vascular Sciences, University of Padua Medical School, Padua, Italy
¶ Department of Medico-Diagnostic Sciences, University of Padua Medical School, Padua, Italy
# Department of Pathology, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts
** Department of Medicine, University of Rochester Medical Center, Rochester, New York
Department of Cardiology, Johns Hopkins School of Medicine and ARVD Program, Baltimore, Maryland
Department of Medicine, University of Arizona, Tucson, Arizona
Heart Institute and Department of Pediatrics (Pediatric Cardiology), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Manuscript received November 22, 2008;
revised manuscript received October 13, 2009,
accepted November 10, 2009.
* Reprint requests and correspondence: Dr. Jeffrey A. Towbin, The Heart Institute, Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, 333 Burnet Avenue, Cincinnati, Ohio 45229 (Email: jeffrey.towbin{at}cchmc.org).
Objectives: The aim of this study was to define the genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC).
Background: 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.
Methods: 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.
Results: 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, PKP2 variants were identified that were encoded in trans (compound heterozygosity). The 38 probands hosting PKP2 variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16 of 38 subjects with PKP2 variants (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 2 desmosomal 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.
Conclusions: 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.
Key Words: arrhythmias • cardiomyopathies • desmosomes • intercalated disks • genetic mutations
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Abbreviations and Acronyms
| | ARVC = arrhythmogenic right ventricular cardiomyopathy | | DNA = deoxyribonucleic acid | | DSC = desmocollin | | DSG = desmoglein | | DSP = desmoplakin | | LV = left ventricle/ventricular | | MRI = magnetic resonance imaging | | PCR = polymerase chain reaction | | PKP = plakophilin | | RV = right ventricle/ventricular |
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