Author + information
- Yubi Lin1
This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using the whole genome sequencing (WGS).
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 (SNPs) and 13,918 insertions/deletions (InDels) occurring at the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified. When filtered using the 1000 Genome Project (2014 version), NHLBI ESP6500 and ExAC databases, 12 missense SNPs and 2 InDels in exonic regions remained whose allele frequencies were <0.01 or unknown. The potentially pathogenic mutations that occurred in 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 the probands II:1 and II:2.
Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs; interrupted, atrophic and disarranged myocardial fibers; and hyperplastic interstitial fibers, collagen fibers and adipocytes were infiltrated and invaded.
A homozygous mutation of DSG2 p.F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as the result of widened and impaired intercalated discs; interrupted myocardial fibers; and abnormally hyperplastic interstitial fibers, collagen fibers and adipocytes.