A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype. (1st January 2019)

• Record Type: Journal Article
• Authors: Chen, Liang; Rao, Man; Chen, Xiao; Chen, Kai; Ren, Jie; Zhang, Ningning; Zhao, Qian; Yu, Wenhua; Yuan, Bin; Song, Jiangping
• Is Part Of: International journal of cardiology. Volume 274(2019)
• Page Start: 263
• Page End: 270
• Publication Date: 2019-01-01
• Subjects: Arrhythmogenic right ventricular cardiomyopathy -- Desmoglein-2 -- Founder mutation -- Haplotype; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2018.06.105
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: Background: Variants in the desmoglein-2 ( DSG2 ) gene account for a significant proportion of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The aim of this study was to evaluate the genetic epidemiology of DSG2 and the impact of a frequent homozygous DSG2 variant in East Asia. Methods: Genetic screening of 14 ARVC related genes was performed in 118 unrelated index patients using next-generation sequencing. Following that, family screening, clinical evaluation and haplotype analysis were performed among eight probands who carry the same homozygous DSG2 variant. We also examined the histopathology and protein expression using immunofluorescence staining on the myocardial tissue of two probands undergoing heart transplant. Results: Eighteen (15.2%) patients bear rare putatively deleterious variants in DSG2, among which 8 patients shared the homozygous DSG2 p.Phe531Cys variant. Family screening demonstrated that only homozygous variant carriers exhibited definite ARVC phenotype with 100% penetrance, while heterozygous variant carriers were either unaffected or only presented mild ARVC related symptoms in 25% relatives. Left ventricular involvement and bi-ventricular failure were common among homozygous p. Phe531Cys variant patients even at early age. Haplotype analysis demonstrated p. Phe531Cys was a founder variant in East Asia population with an allele frequency of 0.12%. Conclusions: We identified, for the first time, a homozygous founder variant of DSG2 in East Asia, which was at surprisingly high frequency of 8.47% among Chinese ARVC patients with a full penetrance. This result suggested an urgent demand of genetic counseling for the probands and their relatives with heterozygous variant. Highlights: This study demonstrates the first founder mutation (p.F531C) of DSG2 among ARVC patients in East Asia; This homozygous founder mutation has a full penetrance, while heterozygotes are not affected or presented mild symptoms. This founder mutation is highly frequent (8.47%) in Chinese ARVC cohort, which could explain about 10 percent patients.