肥厚型心肌病患者的基因突变位点鉴定和基因型表型分析  

Genetic screening and genotype-phenotype correlation in a Chinese cohort with hypertrophic cardiomyopathy

作　　者：肖嫣[1] 卢超霞[2] 刘芳[2] 田涛[1] 杨坤璂 张莹[1] 孟旭[1] 范鹏 刘亚欣[1] 王林平[1] 张学[2] 周宪梁[1] XIAO Yan, LU Chao-xia, Liu Fang, TIAN Tao, YANG Kun-qi, ZHANG Ying, MENG Xu, FANG Peng, LIU Ya-xin, WANG Lin-ping, ZHANG Xue, ZHOU Xian-liang.(Department of Hypertension, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China)

机构地区：[1]中国医学科学院北京协和医学院国家心血管病中心阜外医院高血压中心心血管病国家重点实验室,北京市100037 [2]中国医学科学院基础医学研究所北京协和医学院基础学院医学遗传学系医学分子生物学国家重点实验室,北京市100005

出　　处：《中国分子心脏病学杂志》2018年第4期2571-2575,共5页Molecular Cardiology of China

基　　金：中央级公益性科研院所基本科研基金(2017-F05);中国医学科学院医学与健康科技创新工程(2016-I2M-002);国家重点研发计划(2016YFC0905101);北京市科技计划课题(Z151100003915078)

摘　　要：目的旨在明确肥厚性心肌病(HCM)的突变谱并探讨基因型与表型的关系。方法前瞻性纳入2010年11月至2012年11月在阜外医院确诊为肥厚型心肌病的71例患者,应用半导体靶向二代测序鉴定基因突变,对患者进行全面评估和随访,应用生存分析等明确基因型与短期预后的关系。结果 33例(46%)患者被检出34种突变位点,其中首次报道的突变位点占65%(22/34),MYH7和MYBPC3基因各占35%(12/34),多基因突变占12%(4/33)。与突变阴性患者相比较,突变阳性者的发病年龄早[(40±12)岁vs(49±11)岁,P=0.001];家族史和家族猝死史发生率高(52%vs 13%,P<0.001;50%vs 1%,P<0.001);非持续性室性心动过速多见(36%vs13%,P=0.022)。随访(36±8)个月,Kaplan-Meier生存分析显示突变阳性者较突变阴性患者心血管死亡发生率高(P=0.019)、心衰住院率高(P=0.037)和心脏性猝死发生率高(P=0.010)。除了年龄≤35岁的患者多见(39%vs 0%,P=0.041),MYH7突变携带者较MYBPC3突变携带者的表型和预后无统计学差异。在4例多基因突变携带者中,2例患者植入埋藏式心脏复律除颤器,其中1例发生适当放电;2例随访为终末期HCM并伴有左室血栓和心衰住院,其中1例列入心脏移植名单。结论囊括几乎所有致病基因的二代测序方法增加了基因突变的检出率。基因突变阳性预测不良预后,但与单个突变基因的类型无关。多基因突变可能预示左室收缩功能障碍。Objective To identify the genotype by overall HCM causal genes and to explore the genotype-phenotype correlation.Methods Patients diagnosed with HCM were prospectively included from Nov 2011 to Nov 2012 at Fuwai Hospital.Causal gene mutations were screened by Ion Torrent Sequencing for these patients.Survival analysis was used for genotype-phenotype correlation after comprehensive clinical evaluation and follow-up for HCM patients.Results Of the inclusive 71 patients,33（46%） carried 34 different mutations,65%（22/33） of them were novel.Of all mutations,the frequency of MYH7,MYBPC3 and multiple-gene mutations was 35%,35% and 12%,respectively.Compared to the mutationnegative patients,the mutation-positive patients had earlier age at symptoms onset（40±12 vs 49±11 years old,P=0.001）,and the more frequent presence of family history of HCM（52% vs 13%,P〈0.001）,family history of sudden death（50% vs 11%,P〈0.001）,and non-sustained ventricular tachycardia（36% vs 13%,P=0.022）.Kaplan-Meier analysis demonstrated that the survival free of cardiovascular death（P=0.019）,sudden cardiac death（P=0.010）,and heart failure admission（P=0.037） in mutation-positive patients were lower than those in mutation-negative patients.The frequency of ages less than 35 years old was higher in MYH7 carriers than in MYBPC3 carriers,but there is no difference between them on other clinical characteristics or prognosis.Among four patients with multiple-gene mutations,two patients implanted a cardiac cardioverter defibrillator with an appropriate discharge and two patients with end-stage HCM both had mural thrombus and heart failure admission with one waiting for heart transplantation.Conclusion Mutation-positive patients have worse prognosis irrelative to mono-mutation type.Multiple mutations may predict systolic dysfunction

关 键 词：肥厚型心肌病 基因 MYH7 MYBPC3 多基因突变 

分 类 号：R542.2[医药卫生—心血管疾病]