云南省一少数民族家族性扩张型心肌病家系致病基因筛查及临床特征分析

Gene screening and phenotype analysis of a minority family with familial dilated cardiomyopathy in Yunnan Province

目的对云南省一傣族家族性扩张型心肌病(FDCM)家系进行基因测序,寻找该家系的致病基因,并分析基因型与临床表型的关系。方法入选2018年8月到云南省第一人民医院心血管内科就诊的一傣族FDCM家系,包括DCM患者3例及其家系成员共28名。详细询问先证者及该家系成员的病史,完善体格检查、常规心电图和超声心动图检查,同时对该家系成员采外周血,利用芯片捕获测序技术捕获遗传性心肌病及遗传性心律失常相关基因所有的外显子及剪切位点,应用高通量测序技术检测这些基因的突变情况。应用Sanger测序技术对检测到的变异位点进行验证,对其家系成员及220名来自于云南省第一人民医院体检中心的健康对照组人群进行检测,并分析其临床表型。结果对该家系DCM患者与正常人测序结果进行比对分析,同时经过多个生物数据库数据过滤,发现该家系中3例DCM患者(Ⅱ1、Ⅱ3、Ⅱ5)携带电压门控-钠通道α亚基(SCN5A)Arg1139Gln错义突变,先证者的母亲(I 2)、弟弟(Ⅱ7)和侄女(Ⅲ9)也检出相关基因突变位点,但无临床症状,心电图及超声心动图检查均未见明显异常。其余家系成员及健康对照人群均未检出上述基因突变位点。结论本研究发现云南省一傣族FDCM家系携带SCN5A基因Arg1139Gln错义突变,此位点在DCM家系中为首次报道,其可能与FDCM发病相关。

Objective To identify the potential pathogenic gene by using gene sequencing in a Dai nationality with familial dilated cardiomyopathy(FDCM)in Yunnan Province and to analyze the relationship between the genotype and the phenotype.Method A Dai nationality with FDCM including 3 patients with DCM and 28 family members admitted to the First People′s Hospital of Yunnan Province in August 2018 was enrolled.Data on medical history,physical examinations,electrocardiograms,and echocardiography were obtained.Peripheral blood was sampled for each person.The whole exons and splice sites of genes related to hereditary cardiomyopathy and hereditary arrhythmia were captured by chip capture sequencing technology.The mutations in these genes were detected by high-throughput sequencing technology.The mutations in proband were confirmed and detected in all family members as well as in 220 healthy controls by Sanger sequencing.The relationship between the genotype and the phenotype was analyzed in this pedigree.Results We performed whole exome sequencing(WES)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 the missense variant of Arg1139Gln in sodium channel protein type 5 subunit alpha isoform(SCN5A).This gene variation was detected in 3 symptomatic family members with DCM(Ⅱ1,Ⅱ3,Ⅱ5)and 3 carrier without DCM from the pedigree(Ⅰ2,Ⅱ7,Ⅲ9).No gene variation loci were detected in the other family members and the control group.Conclusions The missense variant Arg1139Gln in the gene SCN5A was identified in the minority FDCM pedigree in Yunnan Province,which was reported for the first time in DCM family and may be related to the incidence of FDCM.