家族性肥厚型心肌病致病突变检测及基因型表型关联分析

Identification of pathogenic mutations in familial hypertrophic cardiomyopathy and analysis of genotype-phenotype

目的研究中国人家族性肥厚型心肌病的致病基因突变位点,分析其基因型与表型的关系。方法利用目标区域重测序技术,对一个中国肥厚型心肌病家系先证者的64个与遗传性心肌病相关的基因进行筛查。Sanger测序验证可疑突变位点并筛查家系成员8例和正常个体100例,同时分析家系突变携带者4例的临床表型特点。结果本家系中包括先证者在内的4例存活家系成员携带MYBPC3基因c.1377del C突变,在100例正常对照中未发现此突变。携带者中有2例确诊为肥厚型心肌病,均表现为室间隔肥厚,另外2例为无症状携带者,心电图和超声心动图均未见异常。家系中有3例猝死,4例有晕厥史,3例发病年龄小于40岁,2例在40岁后发病。结论基因检测在肥厚型心肌病鉴别诊断和家系筛查中有重要的临床意义。

Objective To identify the mutations of pathogenic gene of familial hypertrophic cardiomyopathy （HCM） in China,and analyze the genotype-phenotype correlation. Methods A Chinese family with HCM was investigated. Targeted resequencing was performed in the proband based on a custom AmpliSeq panel which includes 64 candidate pathogenic genes for cardiomyopathies. Sanger sequencing was used to validate suspicious mutation sites and screened family members in 8 cases and 100 normal individuals,and analyzed the clinical phenotype of 4 cases of mutant carriers. The genotype-phenotype relationship in the family was analyzed. Results A frameshift mutation,c. 1377delC,was identified in the MYBPC3 gene in four alive family members,including the proband,which was not detected in 100 normal controls. Two mutation carriers were diagnosed with HCM,with the involvement of ventricular septum. The other two asymptomatic mutation carriers were found without positive finding in electrocardiogram and echocardiogram. In this pedigree,sudden cardiac death occurred in 3 family members,while syncope was presented in 4 members. Onset age less than 40 was observed in three members,while two members were diagnosed HCM after the age of 40. Conclusions Genetic test is very important in the differential diagnosis and pedigree screening of HCM.