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

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

doi:10.1016/j.jelectrocard.2017.10.002

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

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

Authors

Yubi Lin¹, Siqi He², Zili Liao¹, Ruiling Feng², Ruilin Liu³, Yongzheng Peng⁴, Nan Yu⁴, Hang Qi⁴, Jia Chen⁵, Zifeng Huang², Heping Lei¹, Yang Liu¹, Fang Rao¹, Chunyu Deng¹, Yumei Xue¹, Guolin Zhang¹, Bin Zhang¹, Hua Yao⁶, Shulin Wu⁷

Affiliations

¹ 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.
² 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; Jinan University, Guangzhou, PR China.
³ Shunde Hospital of Southern Medical University, Shunde, PR China.
⁴ Department of Clinical Laboratory, Zhujiang Hospital of Southern Medical University, Guangzhou, PR China.
⁵ Second Department of Cardiology, Guangdong No.2 Provincial People's Hospital, Guangzhou, PR China.
⁶ 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. Electronic address: [email protected].
⁷ 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. Electronic address: [email protected].

PMID: 29132927
DOI: 10.1016/j.jelectrocard.2017.10.002

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.

Keywords: Genetics; Sudden death; Ventricular tachycardia.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Algorithms
Asian People
Child
Death, Sudden, Cardiac*
Exercise Test
Exome Sequencing*
Female
Humans
Male
Middle Aged
Mutation / genetics*
Pedigree
Ryanodine Receptor Calcium Release Channel / genetics*
Syncope / genetics

Substances

RyR2 protein, human
Ryanodine Receptor Calcium Release Channel