Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.
OBJECTIVE
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Tianhong
T
Xu
Zhao
Z
Yang
Matteo
M
Vatta
Alessandra
A
Rampazzo
Giorgia
G
Beffagna
Kalliopi
K
Pilichou
Kalliopi
K
Pillichou
Steven E
SE
Scherer
Jeffrey
J
Saffitz
Joshua
J
Kravitz
Wojciech
W
Zareba
Gian Antonio
GA
Danieli
Alessandra
A
Lorenzon
Andrea
A
Nava
Barbara
B
Bauce
Gaetano
G
Thiene
Cristina
C
Basso
Hugh
H
Calkins
Kathy
K
Gear
Frank
F
Marcus
Jeffrey A
JA
Towbin
D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D002648:Child; D003896:Desmosomes; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree