一个肥厚型心肌病家系患者的表型和MYH7基因变异分析  

Analysis of phenotype and MYH7 gene variant in a family of patients with hypertrophic cardiomyopathy

作　　者：赵雪丽 王博 朱晓丽 杨倩利 刘莹 邵虹 左蕾 罗云 王月 刘丽文 Zhao Xueli;Wang Bo;Zhu Xiaoli;Yang Qianli;Liu Ying;Shao Hong;Zuo Lei;Luo Yun;Wang Yue;Liu Liwen(Hypertrophic Cardiomyopathy Center of Xijing Hospital of Air Force Medical University,Multi Disciplinary Consultation Center of Hypertrophic Cardiomyopathy of Shaanxi Province,Department of Ultrasonography,Xijing Hospital of Air Force Medical University,Xi′an,Shaanxi 710032,China;Department of Radiology,Xijing Hospital of Air Force Medical University,Xi′an,Shaanxi 710032,China;Electrocardiogram Unit,Xijing of Hospital of Air Force Medical University,Xi′an,Shaanxi 710032,China)

机构地区：[1]空军军医大学第一附属医院肥厚型心肌病诊治中心,陕西省肥厚型心肌病多学科会诊中心,空军军医大学第一附属医院超声医学科,西安710032 [2]空军军医大学第一附属医院放射科,西安710032 [3]空军军医大学第一附属医院心电图室,西安710032

出　　处：《中华医学遗传学杂志》2022年第8期873-876,共4页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(82001831,82071931,8190175);陕西省自然科学基础研究青年项目(2020JQ-463);陕西省国际合作一般项目(2019KW-076);西京医院学科助推项目(XJZT19MJ01,XJZT10Z03)。

摘　　要：目的对1个肥厚型心肌病家系(hypertrophic cardiomyopathy,HCM)进行表型和MYH7基因变异分析,明确其可能的致病原因,为其临床诊断提供依据。方法对1个HCM家系先证者进行96个遗传性心肌病相关基因全外显子靶向高通量测序,应用Sanger测序在家系成员和300名正常对照者中对可疑变异进行验证,在家系中进行基因型与临床表型的共分离分析。应用Clustal X软件进行变异基因在物种间的序列保守性分析,并采用相关生物信息学软件对变异进行致病性分析和功能预测。结果在先证者及12名家系成员中,6人的MYH7基因存在c.4124A>G(p.Tyr1375Cys)杂合变异,其中5人确诊为HCM患者,1人未达到HCM诊断标准,但出现心电图异常。在300正常对照中未检出该变异。序列保守性分析显示MYH7基因的p.Tyr1375Cys变异位于高度保守区域,生物信息学分析预测该变异可能影响蛋白功能,为有害变异。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南,MYH7基因c.4124A>G(p.Tyr1375Cys)变异判定为可能致病(PM2+PP1_Moderate+PP3+PP5)。结论MYH7基因c.4124A>G(p.Tyr1375Cys)变异可能是该家系的主要致病基因,基因检测结果对HCM家系患者早期诊断具有重要的意义。Objective To analyze the clinical phenotype and MYH7 gene variant in a Chinese pedigree affected with hypertrophic cardiomyopathy(HCM).Methods The proband was screened for variant of 96 cardiomyopathy-associated genes by exonic amplification and high-throughput sequencing.Candidate variant was verified by Sanger sequencing among 300 healthy controls as well as family members of the proband.Co-segregation analysis of genotypes and clinical phenotypes was carried out for the pedigree.Clustal X software was used to analyze the sequence conservation of the variant among various species,and its pathogenicity was predicted by using bioinformatics software.Results 6 out of 12 members from this pedigree were found to harbor heterozygous c.4124A>G(p.Tyr1375Cys)variant of the MYH7 gene,among whom five were diagnosed with HCM.The remaining one had failed to meet the diagnostic criteria for HCM,but had abnormal ECG.The same variant was not found in the 300 healthy controls.Amino acid sequence analysis showed that the variant is located in a highly conserved region,and bioinformatics analysis predicted that this variant may affect protein function and has a deleterious effect.Based on the American College of Medical Genetics and Genomics(ACMG)guidelines,the variant was predicted to be likely pathogenic(PM2+PP1_Moderate+PP3+PP5).Conclusion The c.4124A>G(p.Tyr1375Cys)variant of the MYH7 gene probably underlay the pathogenesis in this pedigree.Above finding has important value for the early diagnosis of patients with HCM.

关 键 词：肥厚型心肌病 MYH7基因 基因变异 表型 

分 类 号：R542.2[医药卫生—心血管疾病]