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. 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: yaohua2078@163.com. 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: doctorwushulin@163.com.
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.
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.