β肌球蛋白重链基因变异致肥厚型心肌病家系遗传基因变异分析

Analysis of genetic mutations of familial hypertrophic cardiomyopathy caused byβ-myosin heavy chain gene mutations

目的探讨β肌球蛋白重链基因(MYH7)变异致肥厚型心肌病(HCM)的家系遗传基因变异。方法纳入2018年8月于首都医科大学附属北京安贞医院就诊的HCM先证者及其2名家系成员。完善先证者及其家系成员的临床资料及病史信息。利用先证者外周血进行全外显子测序,利用Sanger测序在家系内对候选致病位点进行验证。依据美国医学遗传学与基因组学学会(ACMG)遗传变异分类标准与指南进行致病性判定。结果先证者超声心动图结果示化学消融术后,室间隔增厚,回声增强,左心室舒张功能减低。发病男性(先证者侄子)超声心动图结果提示非对称性肥厚型梗阻性心肌病。先证者哥哥自述无临床症状,未行超声心动图及心电图等临床检查。先证者、发病男性(先证者侄子)及先证者哥哥均存在MYH7基因c.C599T(p.A200V)错义变异。根据ACMG遗传变异分类标准与指南将变异位点判定为疑似致病变异(PM1+PM2+PP2+PP3+PP5)。结论HCM先证者及2名家系成员均存在MYH7基因c.C599T错义变异,该变异为该家系HCM发病原因。

Objective To investigate the familial inheritance and genetic mutations of hypertrophic cardiomyopathy(HCM)caused byβ-myosin heavy chain gene(MYH7)mutations.Methods A proband with HCM and two family members who received treatment at Beijing Anzhen Hospital,Capital Medical University were included in August 2018.The clinical data and medical history of the proband and his family members were completed.Whole-exome sequencing was performed on the proband′s peripheral blood,and Sanger sequencing was conducted to validate the candidate pathogenic site within the family.The pathogenicity of the mutations was determined according to the genetic mutation classification criteria and guidelines of the American College of Medical Genetics and Genomics(ACMG).Results The echocardiography results of the proband showed that there was thickening of the interventricular septum,enhanced echo and reduced left ventricular diastolic function after the chemical ablation.The echocardiography results of the male patient(the nephew of the proband)revealed an asymmetrical hypertrophic obstructive cardiomyopathy.The brother of the proband reported no clinical symptoms and had not been clinically evaluated by means of echocardiography,electrocardiography or other exams.The c.C599T(p.A200V)missense mutation of the MYH7 gene was identified in the proband,the onset male(nephew of the proband)and the brother of the proband.Based on the genetic mutation classification criteria and guidelines of the ACMG,the mutation sites was designated as suspected pathogenic mutations(PM1+PM2+PP2+PP3+PP5).Conclusion The c.C599T(p.A200V)missense mutation of the MYH7 gene was identified in the proband with HCM and two family members,which was identified as the pathogenic cause of HCM in this family.