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, 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.
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.
Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc.
All rights reserved.