Journal
CARDIOLOGY
Volume 138, Issue 1, Pages 41-54Publisher
KARGER
DOI: 10.1159/000462962
Keywords
Cardiomyopathy; Whole genome sequence; Arrhythmogenic cardiomyopathy; Genetics
Categories
Funding
- Science and Technology Program of Guangdong Province [2014B070705005]
- Science and Technology Program of Guangzhou City [2014Y-00196]
- Natural Science Foundation of Guangdong Province [2014A030310470, 2014A030313001]
- Science and Technology Development of Special Funding of Guangdong Province [2016A020216022]
- Livelihood Science and Technology Topics of Major Projects of Industrial-University Collaborative Innovation [201604020096]
- Science and Technology Planning Project of Guangdong Province [2013B022000074]
- National Natural Science Foundation of China [NSFC-81400259, NSFC-81470505]
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Background: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). Methods and Results: Probands II: 1 and II: 2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and ar-rhythmias were identified. When filtered using the 1000 Genomes Project (2014 version), NHLBI ESP6500, and ExAC databases, 12 missense SNP and 2 InDel in exonic regions remained, the allele frequencies of which were <0.01 or unknown. The potentially pathogenic mutations that occurred in the genes DSG2, PKP4, PRKAG2, FOXD4, CTTN, and DMD, which were identified by SIFT or PolyPhen-2 software as damaging, were validated using Sanger sequencing. Probands II: 1 and II: 2 shared an extremely rare homozygous mutation in the DSG2 (p.F531C) gene, which was also demonstrated using intersection analysis of WGS data from probands II: 1 and II: 2. Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs, and interrupted, atrophic, and disarranged myocardial fibers, and hyperplastic interstitial fibers, collagen fibers, and adipocytes were infiltrated and invaded. Conclusions: A homozygous mutation of DSG2 p. F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as a result of widened and impaired intercalated discs, interrupted myocardial fibers, and abnormally hyperplastic interstitial fibers, collagen fibers, and adipocytes. (C) 2017 S. Karger AG, Basel
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