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.
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.
Int J Cardiol. 2019 Jan 1;274:263-270. doi: 10.1016/j.ijcard.2018.06.105. Epub 2018 Jun 28.
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.
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.
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%.
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.
桥粒芯糖蛋白 2（DSG2）基因的变异可导致相当一部分心律失常性右室心肌病（ARVC）患者发病。本研究旨在评估 DSG2 的遗传流行病学，以及东亚人群中常见的纯合 DSG2 变异的影响。
采用下一代测序技术对 118 例无血缘关系的 ARVC 相关基因进行了基因筛查。随后，对携带相同纯合 DSG2 变异的 8 个先证者进行了家系筛查、临床评估和单体型分析。我们还对两名进行心脏移植的先证者的心肌组织进行了免疫荧光染色，以观察其组织病理学和蛋白表达情况。
18 例（15.2%）患者携带 DSG2 罕见的潜在致病性变异，其中 8 例患者携带纯合 DSG2 p.Phe531Cys 变异。家系筛查显示，只有纯合变异携带者表现出明确的 ARVC 表型，其外显率为 100%，而杂合变异携带者在 25%的亲属中无明显 ARVC 相关症状，或仅表现出轻度 ARVC 相关症状。携带纯合 p. Phe531Cys 变异的患者左心室受累和双心室衰竭较为常见，即使在早期也是如此。单体型分析表明，p. Phe531Cys 是东亚人群中的一个起源性变异，其等位基因频率为 0.12%。
我们首次在东亚人群中发现了 DSG2 的纯合起源性变异，在中国 ARVC 患者中其频率高达 8.47%，且完全外显。这一结果提示对携带杂合变异的先证者及其亲属进行遗传咨询的迫切需求。
