全外显子组测序发现一家族性扩张型心肌病致病基因  

Identification of gene mutation associated with familial dilated cardiomyopathy by whole-exome sequencing

作　　者：周年伟 秦胜梅 刘阳[1,2,5] 赵维鹏 崔洁 潘翠珍[1,2,5] 陈瑞珍 王小林 舒先红[1,2,5] ZHOU Nian-wei;QIN Sheng-mei;LIU Yang;ZHAO Wei-peng;CUI Jie;PAN Cui-zhen;CHEN Rui-zhen;WANG Xiao-lin;SHU Xian-hong(Shanghai Institute of Medical Imaging,Shanghai 200032,China;Department of Echocardiography,Zhongshan Hospital,Fudan University,Shanghai 200032,China;3Department of Cardiology,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Department of Interventional Radiology,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Shanghai Institute of Cardiovascular Disease,Shanghai 200032,China)

机构地区：[1]上海市影像医学研究所,上海200032 [2]复旦大学附属中山医院心超室,上海200032 [3]复旦大学附属中山医院心内科,上海200032 [4]复旦大学附属中山医院介入治疗科,上海200032 [5]上海市心血管病研究所,上海200032

出　　处：《复旦学报（医学版）》2018年第2期164-168,共5页Fudan University Journal of Medical Sciences

基　　金：国家自然科学基金(81371576)

摘　　要：目的对一扩张型心肌病(dilated cardiomyopathy,DCM)家系行全基因组外显子测序以寻找该家系的致病基因。方法收集在复旦大学附属中山医院就诊的一位DCM患者及其家系成员的临床资料,采集相关家系成员外周血并抽提DNA,对该家系5名成员行全基因组外显子测序,寻找致病基因,用Sanger测序对家系其他成员进行验证。结果通过对家系患者与正常人测序结果比对分析,同时经过多个生物数据库数据过滤,发现LMNA基因6号外显子上存在的杂合突变c.961 C>T(p.Arg321Ter)为该家系的可能致病基因突变。LMNAc.961 C>T无义突变导致LMNA编码蛋白质过程提前终止,相应蛋白质功能异常,进而导致该家系中此突变基因的携带者出现心功能异常。结论本研究应用全基因组外显子测序从一DCM家系中发现其致病基因及突变位点:LMNAc.961 C>T(p.Arg321Ter),突变导致该家系相关成员心功能异常。此位点在汉族人群中尚属首次报道。Objective T o identify the disease-causing gene in a Chinese pedigree with familial dilated cardiomyopathy(DCM)by whole-exome sequencing.Methods After collecting the clinical data and extracting the whole blood genomic DNA of the 5 family members form a Chinese DCM pedigree,whole-exome sequencing was performed to search the causative genes.Familial co-segregation analysis among the pedigree was subsequently confirmed by traditional Sanger sequencing.Results We performed whole exome sequencing(W ES)on representative affected individuals and unaffected familial members from this pedigree.After comparison with variants identified in affected individuals and unaffected individuals,along with previously reported genetic mutations associated with DCM,we found that a heterozygous variant c.961C>T(p.Arg321Ter)in exon 6 of the LMNA gene in affected individuals matched the criteria to be the potential disease-causing gene,which was confirmed by Sanger sequencing.This stop-gain mutation leads to only a small part of LMNA-coding protein expressed,therefore we concluded that LMNA c.961C>Tshould be the causative mutation for this familial DCM case.Conclusions The nonsense mutation c.961C>T in gene LMNA identified by whole-exome sequencing might be the pathogenic mutation in this DCM pedigree.

关 键 词：扩张型心肌病 基因突变 全外显子测序 

分 类 号：Q987[生物学—遗传学]