Liang Chen1, Man Rao1, Xiao Chen1, Kai Chen1, Jie Ren1, Ningning Zhang1, Qian Zhao1, Wenhua Yu1, Bin Yuan1, Jiangping Song2. 1. 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. 2. 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. Electronic address: fwsongjiangping@126.com.
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.
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 DSG2p.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.
Authors: Cynthia A James; Jan D H Jongbloed; Ray E Hershberger; Ana Morales; Daniel P Judge; Petros Syrris; Kalliopi Pilichou; Argelia Medeiros Domingo; Brittney Murray; Julia Cadrin-Tourigny; Ronald Lekanne Deprez; Rudy Celeghin; Alexandros Protonotarios; Babken Asatryan; Emily Brown; Elizabeth Jordan; Jennifer McGlaughon; Courtney Thaxton; C Lisa Kurtz; J Peter van Tintelen Journal: Circ Genom Precis Med Date: 2021-04-08