Digenic heterozygous mutations of KCNH2 and SCN5A induced young and early-onset long QT syndrome and sinoatrial node dysfunction

Annals of noninvasive electrocardiology: the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc

article

Zhe Yang MD¹  Yuting Ma PhD¹  Jiana Huang MD⁴  Jianzhong Xian MD¹  Yin Huang MD¹  Linbo Wu MD⁵  WenLiang Zhu MD⁵  Feng Wang MD⁶  Liang Chen MD⁷  Xiufang Lin MD¹  Yubi Lin MD¹ 

[1] The Cardiovascular Center, Department of Cardiology, Interventional Medical Center, Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University;These authors contributed equally to this manuscript.;BGI Education Center, University of Chinese Academy of Sciences;Reproductive Center, The Six Affiliated Hospital, Sun Yat-sen University;School of Medicine, Jinan University;Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangdong Geriatrics Institute;State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences ,(CAMS) and Peking Union Medical College

关键词: ion channelopathy;    KCNH2;    long QT syndrome;    SCN5A;    whole-exome sequencing;   

DOI  :  10.1111/anec.12889

来源: Wiley

【 摘 要 】

Introduction Long QT syndrome (LQTS) is a life-threatening inherited channelopathy, and prolonged QT intervals easily trigger malignant arrhythmias, especially torsades de pointes and ventricular fibrillation. Materials and methods The proband with overlapped phenotypes of LQTS and sinoatrial node dysfunction underwent some necessary examinations, including echocardiography, electrocardiogram (ECG), and Holter monitoring. Next, whole-exome sequencing was performed, and candidate genes were validated by Sanger sequencing. RNA secondary structure and protein physical-chemical parameter analyses were used to predict the possible structural change of the proteins induced by the mutations. Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and SCN5A p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Na v 1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index. Conclusions The digenic heterozygous KCNH2 and SCN5A mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.

【 授权许可】

Unknown