A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype
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 biventricular 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.
Arrhythmogenic right ventricular cardiomyopathy Desmoglein-2 Founder mutation Haplotype
Liang Chen Man Rao Xiao Chen Kai Chen Jie Ren Ningning Zhang Qian Zhao Wenhua Yu Bin Yuan Jiangping Song
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC),Beijing 100037, PR China
国际会议
北京
英文
15-26
2019-03-30（万方平台首次上网日期，不代表论文的发表时间）