MYH7基因Glu931del突变导致恶性肥厚型心肌病

目的 本研究拟查明1个中国汉族肥厚型心肌病（HCM）家系的致病突变,并探讨基因型-表型关联。方法 利用二代测序技术,全面筛查家系先证者的28个HCM相关致病基因。通过Sanger测序,在家系中验证和筛查发现的可能致病突变,并对突变携带者进行表型分析。结果 二代测序发现先证者携带MYH7基因Glu931del杂合突变。家系筛查发现4名患者均携带该突变,突变与疾病共分离,该突变为此HCM家系的致病突变,常染色体显性遗传。Glu931del突变位于MYH7基因第23外显子,三个核苷酸缺失（c.2791_2793del GAG）,导致其所编码的心脏β-肌球蛋白重链的第931位谷氨酸缺失。MYH7基因第931位谷氨酸残基在不同物种间高度保守。临床表型分析发现,家系中4例患者的左心室最厚厚度在19mm-30mm之间,静息状态均无明显左室流出道梗阻,表现为胸痛、心悸和呼吸困难,并伴黑曚或有晕厥史。该家系另有两例患者在家系筛查前发生猝死,确诊年龄分别为5岁和6岁,死亡年龄均为16岁。该家系随访12年,HCM临床症状进展较快,1例患者左心室最大厚度由7mm发展为30mm,两例患者心功能进展为NYHA分级Ⅲ/Ⅳ级。结论 MYH7基因Glu931del突变导致的HCM表型较严重,易发生猝死和心衰,但也存在较大的表型异质性。二代高通量测序可以用于HCM致病基因的全面筛查。

Malignant Clinical Expression in A family with Hypertrophic Cardiomyopathy Caused by Glu931del Mutation in MYH7 Gene

Objective This study aimed to identify the disease mutation in a family with hypertrophic cardiomyopathy （HCM） and analyze the relationship between genotype and phenotype. Methods The coding exons and their flanking intronic regions of 28 HCM-causing genes were screened by next generation sequencing in the proband. The identified mutation was measured in all the familial members and the clinical expressions of the mutation carriers were analyzed. Results A mutation, Glu93 ldel in MYH7 gene, was identified in the proband. Familial analysis found that all the 4 patients in this family carried this mutation. The mutation located ill the 23rd exon of MYH7 gene, resulted in a deletion of 3 nucleic acids （c.2791_2793delGAG） and thereby missing of the 931st amino acid of cardiaci3-myosin heavy chain. The 931st amino acid was highly conserved among various species. Clinical analysis revealed that the maximum left ventricle thickness of the patients arranged from 19ram to 30 mm. Patients expressed chest pain, palpitation and dyspnea. All the patients have a history of amaurosis or syncope. Tow patients died of sudden cardiac death at 16 years old before the recruitment of the family. During a follow-up of 12 years, a relatively rapid progress of the clinical expression was observed in the mutation carriers. The maximum left ventricle wall thickness of a young carrier developed from 7 mm to 30 mm, and the NYHA class of another 2 patients progressed to NYHA Ⅲ/ Ⅳ . Conclusion Glu931del mutation in MYH7 gene causes malignant HCM. The carriers of this mutation have high risk for sudden cardiac death and heart failure. Next generation sequencing can be used in the genetic testing of HCM.