Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles

Abstract

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 arrhythmias 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.

Distal myopathy induced arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant

“…In 2009, a Dutch multicenter cohort reported that DSG2 and DSC2 gene are most frequently identified to be compound in patients with ARVC [16]. Meanwhile, some studies have reported recessive inheritance pattern of DSG2 in ARVC pedigree [17][18][19]. These results suggested that single heterozygous variant in DSG2 might not be sufficient to penetrate ARVC phenotype, which could explain asymptomatic relatives of proband carrying DSG2-p.Leu237Ter variant.…”

Case report of familial sudden cardiac death caused by a DSG2 p.F531C mutation as genetic background when carrying with heterozygous KCNE5 p.D92E/E93X mutation

“…According to previous studies, the DSG2 p.N271S mutation in young transgenic mice (similar to the N266S mutation in humans) was associated with SCD induced by spontaneous VT, biventricular dilation and aneurysms, myocardial necrosis and heart failure [ 16 ]. According to previous report about a Chinese Han family with ARVC/D from our cardiac center, [ 17 ] we have identified a homozygous mutation of DSG2 p.F531C by the whole genome sequencing. The carriers of the homozygous genotype were shown to be affected with biventricular dilation and non-compaction, aneurysms in the left ventricle and spontaneous multifocal VTs.…”

“…A myocardial biopsy showed interrupted, atrophic and disarranged myocardial fibers; interstitial fibers, hyperplastic, infiltrated and collagen-invaded fibers and adipocytes; and widened and destroyed intercalated discs. Some carriers with heterozygous mutation of DSG2 p.F531C showed incomplete penetrance [ 17 ]. Similar phenotype of ARVC/D induced by homozygous mutation of DSG2 p.F531C was also found in another Chinese Han family and DSG2-F531C knock-in mice with decreased expression of CX43.…”

Young and early‐onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations

“…InDels were considered damaging, and nonsynonymous SNPs predicted by SIFT ( http://sift.jcvi.org/www/ ) (Kumar et al., 2009 ) and PolyPhen‐2 (Polymorphism Phenotyping v2, http://genetics.bwh.harvard.edu/pph2/ ) (Adzhubei et al., 2010 ). The mutations were screened in approximately 200 genes (shown in our previous study (Lin et al., 2017 )), associated with hereditary arrhythmias and cardiomyopathies. The filtering criteria for mutation inclusion were as follows: same mutations in the WES data; missense, nonsense, and InDel mutations; and SNPs with a minor allele frequency not more than 0.01, according to the NCBI SNP database (Smigielski et al., 2000 ; Via et al., 2010 ).…”