β肌球蛋白重链基因Asn391Thr突变导致家族性肥厚型心肌病的基因型与临床表型分析

Genotype-phenotype Analysis in a Family with Hypertrophic Cardiomyopathy Caused by Asn391Thr Mutation in β-Myosin Heavy Chain Gene

目的研究家族性肥厚型心肌病(HCM)致病基因突变位点,分析基因型与临床表型的联系。方法利用靶向捕获加二代测序,对1个HCM家系的先证者进行26个致病基因的筛查。二代测序发现的突变,利用双脱氧末端终止法测序进行验证,并对家族中其他成员进行该突变位点的筛查,并分析其临床表型特点。结果遗传筛查发现先证者携带β肌球蛋白重链基因(MYH7)c.1172A>C(Asn391Thr)突变,该突变位于MYH7基因第12号外显子,导致β肌球蛋白重链的第391位氨基酸残基由天冬酰胺变为苏氨酸。该家系中接受调查的22例对象中8例携带MYH7基因Asn391Thr突变,其中6例患者均携带该突变,突变与疾病呈共分离,且在307名对照者中没有检出。携带者中有3例出现呼吸困难、心悸、胸痛、黑矇等心功能不全表现,所有患者发病年龄均小于40岁,其中Ⅱ9小于8岁(见图1)。家系中有4人早逝(<50岁),其中3人确诊为HCM。结论 MYH7基因Asn391Thr错义突变为HCM的一个恶性致病突变,携带该突变的患者应进行较积极的治疗和猝死预防。

Objective To identify the disease-causing mutations in familial hypertrophic cardiomyopathy and to analyze the relationship between the genotype and the phenotype. Methods Peripheral blood samples were collected from the 22 members of a Chinese pedigree with hypertrophic cardiomyopathy and 307 healthy controls. The coding exons and their flanking 5 bp intronic regions of 26 disease-causing genes of the proband were captured and sequenced by next generation sequencing. Identified mutation in proband was confirmed by Sanger capillary sequencing and analyzed in all the members of the pedigree as well as in the healthy controls. The relationship between the genotype and the phenotype was evaluated in this pedigree. Results A missense mutation （c.1172A〉C,p.Asn391Thr） in exon 12 of MYH7 gene were identified in 8 family members, including the proband. Six persons with this mutation are FHC patients. Three of the patients presented cardiac dysfunction, and four persons of this pedigree died of sudden death,three of them were diagnosed as HCM. Conclusion The Asn391Thr mutation of MYH7 gene is a malignant disease-causing mutation of HCM.Patients who carry this mutation should get effective treatment and prevent sudden death.