“良性”MYH7基因Val606Met突变导致恶性肥厚型心肌病

Previously Reported Benign Mutation Val606Met in MYH7 Gene Leads to Malignant Phenotype in A Chinese Pedigree with Hypertrophic Cardiomyopathy

目的研究汉族人群家族性肥厚型心肌病的致病基因突变位点,分析基因型与临床表型的关系。方法采集1个家族性肥厚型心肌病(HCM)家系成员的血液样本,并收集临床表型资料;对该家系先证者的28个HCM相关致病基因利用高通量测序进行靶向重测序;利用Sanger测序在家系成员中检测发现的致病突变位点;分析致病突变携带者的临床表型特点。结果高通量测序和Sanger测序发现并证实先证者携带β肌球蛋白重链基因(MYH7)Val606Met杂合错义突变,该突变在307名正常对照未检出;其他27个HCM相关致病基因中,未检出致病突变。家系遗传筛查发现3例HCM患者均携带MYH7基因Val606Met错义突变,该突变与HCM共分离。该家系3例HCM患者伴有心悸、胸痛、黑矇、晕厥等症状,先证者已经出现严重的心力衰竭,接受心脏移植后上述症状消失,生活质量明显改善。该家系另有2名成员在调查前发生心源性猝死。结论虽然有报道MYH7基因Val606Met错义突变为良性突变,但在本研究家系中,易导致早发心衰和猝死。因突变引起的终末期心衰接受心脏移植可能为最佳的治疗手段。

Objective To study the disease mutation in a Chinese pedigree with hypertrophic cardiomyopathy （HCM）, and to analyze the correlation between their genotype and phenotype. Methods The blood samples of the family members were collectedand the clinical phenotype data was gathered.The coding exons and their flanking intronic regions of 28previously reported disease genes were sequenced by targetedresequencing in the proband.The identified mutation were detected with Sanger sequencing in all family members.The genotype-phenotype correlation was analyzed in the family. Results A heterozygous missense mutation Val606Metin the 16th exon of beta myosin heavy chain gene （MYH7） gene was identified by targeted resequeneing, which was confirmed by Sanger sequencing. No disease mutations were detected in the other genes. Genetic screening found that all the three patients with HCM carried the mutation. This mutation was absent in 307 healthy controls. The clinical expression of the three HCM patients includedpalpitations, chest pain, amaurosis or/and syncope. The proband manifested severe congestive heart failure. Hergeneral condition rapidly improved after receiving heart transplantation and the quality of life was improved significantly.There were 2 members who were not investigated suffered sudden cardiac death. Conclusions Althoughpreviously reported as a benign mutation in this pedigrees, Val606Met mutation in MYH7 geneleaded to malignant clinical expression in this Chinese family, lincluding early heart failure and sudden death. Cardiac transplantation may be the best treatmentfor the end-stage heart failure due to HCM.