云南傈僳族、彝族不明原因猝死与LQTS及CPVT致病基因的相关性研究

Because of high mortality, high incidence and no specific control measure,the sudden unexplained death(SUD) in Yunnan Lisu and Yi minorities has become a serious public health problem. It was found that Yunnan SUD has the character of family aggregation and the characteristic ECG changes of long Q-T syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), which indicated that the etiology of Yunnan SUD may be related to LQTS and CPVT. Moreover, there are a large number of pathogenic gene mutations in the pathogenic gene KCNQ1, KCNH2 and SCN5A of LQTS and the pathogenic gene RYR2 of CPVT, which form some mutational hot zones. In the present study, the association between the Yunnan SUD of Lisu and Yi minorities and the pathogenic genes of LQTS and CPVT will be studied by the means of using case-control study and pedigree investigation, detecting the mutations in KCNQ1, KCNH2, SCN5A and RYR2 genes, and then identifying the pathogenicity of these mutational genes.The aim of this study is to explore the cause of death of the Yunnan SUD of Lisu and Yi minorities.

云南傈僳族、彝族不明原因猝死（sudden unexplained death，SUD）死亡人数多、发病率高，无防治措施，已成为严重的公共卫生问题。研究发现，云南SUD呈家庭聚集性，并有长Q-T综合征(long QT syndrome，LQTS）和儿茶酚胺敏感性多形性室性心动过速（catecholaminergic polymorphic ventricular tachycardia，CPVT）的心电图改变，提示其病因可能与LQTS、CPVT有关。LQTS致病基因KCNQ1、KCNH2、SCN5A和CPVT致病基因RYR2存在大量致病性突变，形成了多个突变热点区。本课题拟通过病例对照和家系调查研究，检测KCNQ1、KCNH2、SCN5A和RYR2基因突变热点区变异，进而明确变异基因的致病性，研究云南傈僳族、彝族SUD与LQTS及CPVT致病基因的相关性，探索云南傈僳族、彝族SUD死因。

云南不明原因猝死（yunnan sudden unexplained death, YNSUD）是指主要发生在云南的具有一定时间聚集性、空间聚集性和家庭或家族聚集性等特点的地方性不明原因猝死（sudden unexplained death, SUD）。前期研究发现，云南傈僳族、彝族SUD死亡人数多、发病率高，部分猝死病例及存活疑似病人存在长Q-T 综合征(long QT syndrome，LQTS）和儿茶酚胺敏感性多形性室性心动过速（catecholaminergic polymorphic ventricular tachycardia，CPVT）的心电图改变。我们首次提出“YNSUD应具有一定的遗传学基础”的科学假说。本项目对YNSUD者及其核心家系成员和高发病区人群，利用多种基因分析技术，进行了心脏疾病相关基因变异研究。结果：1.一起YNSUD家系的全基因组人重测序结果发现，HADH、NUP155、AKAP9基因有3个错义突变为两例YNSUD者共有而其存活直系亲属没有；2.来自14个家系的25例YNSUD核心家系成员全外显子测序发现CACNA2D1、TTN、MYH6等16个与心脏骤停、QT间期改变、心肌病等心脏疾病相关的基因变异。3.在90例散发性SUD和3例聚集性YNSUD中进行突变热点区测序，新发现KCNQ1（c. 575G>T，p.R192L）、KCNH2（c.1789T>A，p.Y597N)和KCNH2（c.1800C>A，p.S600R) 基因变异；4.在392例YNSUD高发病区组及532例邻村对照组人群中进行60个心脏疾病相关基因SNP位点的飞行质谱检测，结果病区组傈僳族TTN、DSG2、MTHFR、DMD、RNF207、GRID1等基因存在7个SNP位点等位基因频率和基因型频率均高于对照组；病区组彝族DSG2（rs201845396）位点的等位基因频率和基因型频率均高于对照组；5.病区组人群ECG检查，发现5例患者存在QT间期延长或LQTS，且具有RYR2、SCN5A、TTN等基因变异。本研究表明，云南傈僳族、彝族YNSUD及其高发地区人群存在LQTS、心肌病等多种心脏疾病相关基因变异，YNSUD的发生存在一定的遗传学基础，为进一步深入研究YNSUD的机制及其防治开辟了新的研究方向。