汉族肥厚型心肌病患者中Fabry病的基因突变鉴定和家系研究  

Genetic Screening and Genotype-phenotype Correlation of Fabry Disease in a Chinese Cohort with Hypertrophic Cardiomyopathy

作　　者：肖嫣[1] 孙洋[2] 张莹[1] 田涛[1] 赵然旭[2] 张迪[1] 孟旭[1] 范鹏 刘亚欣[1] 王林平[1] 卢超霞[3] 周宪梁[1] XIAO Yan;SUN Yang;ZHANG Ying;TIAN Tao;ZHAO Ran-xu;ZHANG Di;MENG Xu;FAN Peng;LIU Ya-xin;WANG Lin-ping;LU Chao-xia;ZHOU Xian-liang(Cardiovascular Department,National Center for Cardiovascular Disease,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100037;Department of Pathology,Fuwai Hospital,National Center for Cardiovascular Disease,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100037;National Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing 100005,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心内科,北京市100037 [2]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病理科,北京市100037 [3]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》2020年第3期3356-3360,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-TZGG-08);中央高校基本科研业务费专项基金(3332019048);国家自然科学基金(81400187)。

摘　　要：目的探讨基因检测在汉族肥厚型心肌病(hypertrophic cardiomyopathy,HCM)患者中Fabry病的基因突变情况及家系筛查中的应用,并分析基因型与表型的关系。方法应用半导体靶向二代测序平台筛查在阜外医院诊断为HCM的217例患者,应用Sanger测序验证先证者和家系内成员的GLA基因突变位点,收集GLA突变携带者的临床资料并进行基因型与表型关联分析。结果发现2例男性Fabry病先证者(在HCM中占比0.93%)。1例携带GLA基因错义突变c.887T>C(p.M296T),表现为迟发心脏型Fabry病;对其一家四代中的25个家庭成员进行家系突变筛查,结果发现有4个女性杂合突变携带者,其中1个确诊为HCM。另1例携带GLA基因错义突变c.758T>C(p.I253T),表现为经典型Fabry病,累及肾和神经系统。对其一家四代中的32个家系成员进行家系调查,发现2个女性杂合突变携带者和2个男性早发心脏性猝死。两例先证者经室间隔心肌切除术后梗阻解除,后者应用分子伴侣药物Migalastat治疗后肾功能稳定于31 ml/min。结论首次发现Fabry病在汉族HCM中并不少见,基因检测有助于早期鉴别诊断及筛查家系内突变携带者。GLA c.758T>C为恶性基因型,男性突变携带者猝死风险高危,室间隔心肌切除术和Migalastat有助于改善预后。Objective To identify the mutations of pathogenic gene of Fabry disease in Chinese HCM cohort and to explore the genotypephenotype correlation.Methods Causal gene mutations were screened by semiconductor-targeted next generation sequencing in 217 patients diagnosed with HCM prospectively included at Fuwai Hospital.Causal GLA gene mutations were verified by Sanger sequencing in probands and family members.Clinical characteristics were collected for genotype-phenotype analysis.Results Two cases of Fabry disease were found(0.93%in HCM).One case had a GLA mutation c.887 T>C(p.M296 T)with later-onset cardiac variant and family screening revealed four female heterozygotes,only one of them diagnosed with HCM.Another case had a GLA mutation c.758 T>C(p.I253 T)as classic phenotype combined with renal insufficiency and cerebral infarction;family screening revealed 2 female heterozygotes and 2 male sudden cardiac deaths.Conclusion Fabry disease is not uncommon in Chinese HCM.Genetic testing is helpful for early differential diagnosis and mutation carriers screening within families.Although mutation p.I253 T is a malignant genotype,ventricular septal myotomy and the molecular chaperone drug Migalastat help to improve the prognosis.

关 键 词：FABRY病 肥厚型心肌病 GLA 基因检测 Migalastat 

分 类 号：R542.2[医药卫生—心血管疾病]