Clinical Research
Heart Rhythm Disorder
Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy

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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, 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.

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

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

Cited by (0)

The Multidisciplinary Study of Right Ventricular Dysplasia (ARVD Registry) is supported by grants U01-65652, HL65691, and HL65549from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland. The Johns Hopkins ARVD Program is supported by the Campanella Family, the Wilmerding Endowment, and the Bogle Foundation. Drs. Rampazzo, Danieli, Thiene, and Basso were supported by Telethongrant GGP07220, Rome; ARVC/D projectQLG1-CT-2000-01091, Fifth Framework Programme European Commission; Ministry of Health, MIUR; and Fondazione Cassa di Risparmio, Padova e Rovigo. Dr. Towbin was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Healthgrant 1 R01 HL087000(PCSR), the Texas Children's Foundation Chair in Pediatric Molecular Cardiology Research, The Vivian L. Smith Foundation, The Abby Glaser Foundation, the Children's Cardiomyopathy Foundation, the Baylor College of Medicine Faculty Collaboration Grant, TexGen, and the John Patrick Albright Foundation. Drs. Xu and Yang contributed equally to this work.