全外显子组测序在一个原因不明的猝死中国家系中鉴定出RYR2基因的一个致病突变。

Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death.

作者信息

Lin Yubi, He Siqi, Liao Zili, Feng Ruiling, Liu Ruilin, Peng Yongzheng, Yu Nan, Qi Hang, Chen Jia, Huang Zifeng, Lei Heping, Liu Yang, Rao Fang, Deng Chunyu, Xue Yumei, Zhang Guolin, Zhang Bin, Yao Hua, Wu Shulin

机构信息

Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Medical School of South China University of Technology, Guangzhou, PR China.

出版信息

J Electrocardiol. 2018 Mar-Apr;51(2):309-315. doi: 10.1016/j.jelectrocard.2017.10.002. Epub 2017 Oct 10.

DOI:10.1016/j.jelectrocard.2017.10.002

PMID:29132927

Abstract

OBJECTIVE

This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope.

MATERIALS AND METHODS

Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms.

RESULTS

We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia.

CONCLUSIONS

A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD.

摘要

目的

本研究旨在鉴定一个患有不明原因猝死（USD）或偶发晕厥的中国家系中的致病突变。

材料与方法

对两名相关患者分别进行全外显子组测序和目标捕获测序。利用千人基因组计划和单核苷酸多态性数据库（PubMed）筛选遗传数据，并使用SIFT和Polyphen-2算法评估鉴定出的突变的预测致病性。

结果

我们在三名患有USD、晕厥以及跑步机运动试验诱发的恶性室性心动过速的家系成员中，鉴定出RYR2基因存在一个杂合突变，即c.490C>T（p.P164S），该突变在所有物种中高度保守；同时在一名家系成员中检测到SCN5A基因存在另一个杂合新生突变，即c.5576G>A（p.R1859H）。这两个变异均通过桑格测序法进行了验证。重要的是，RYR2 p.P164S与心源性猝死风险相关，比如在儿茶酚胺能多形性室性心动过速中。