1例肥厚型心肌病家系的产前诊断和遗传分析  

Prenatal diagnosis and genetic analysis of a family with hypertrophic cardiomyopathy

作　　者：张晓康 荣伽玲 何思颖 杨国华[3] 梁宾 向阳 罗晶[1] 李梦兰 马建鸿[2,4] ZHANG Xiaokang;RONG Jialing;HE Siying;YANG Guohua;LIANG Bin;XIANG Yang;LUO Jing;LI Menglan;MA Jianhong(Department of Clinical Laboratory,Zhongnan Hospital of Wuhan University,Wuhan 430071,Hubei;Department of Obstetrics and Gynecology,Zhongnan Hospital of Wuhan University,Wuhan 430071,Hubei;School of Basic Medicine Science,Wuhan University,Wuhan 430071,Hubei;Prenatal Diagnosis and Eugenics Clinical Medical Research Center of Hubei Province,Wuhan 430071,Hubei,China)

机构地区：[1]武汉大学中南医院检验科,武汉430071 [2]武汉大学中南医院妇产科,武汉430071 [3]武汉大学基础医学院,武汉430071 [4]湖北省产前诊断与优生临床医学研究中心,武汉430071

出　　处：《临床检验杂志》2019年第11期865-870,共6页Chinese Journal of Clinical Laboratory Science

基　　金：湖北省卫健委创新团队项目(WJ2019C002);湖北省卫生计生委面上项目(WJ2017M003)

摘　　要：目的对1例肥厚型心肌病(HCM)家系的孕妇进行产前诊断和遗传分析,探讨HCM致病基因突变与临床表型的联系。方法搜集该先证者及其家系成员临床资料,提取先证者外周血DNA、羊水细胞DNA、经培养的羊水细胞DNA,二代测序(NGS)筛查先证者的致病基因位点,PCR扩增产物直接测序验证HCM致病候选基因MYH7和MYBPC3的可疑致病突变序列,并检测羊水细胞潜在的致病突变。用遗传学数据资料和Mutation taster、PolyPhen-2、ANTHEPROT等生物信息学软件预测突变的致病性。结果测序结果显示先证者存在MYH7 c.1988G>A(p.Arg663His)和MYBPC3 c.151G>A (p.Ala51Thr)杂合突变,其父亲表型正常且未检出异常突变,其表型正常的母亲仅携带MYBPC3 c.151G>A杂合突变。胎儿仅存在MYH7 c.1988G>A杂合突变,而MYBPC3无异常变异。突变效应预测和蛋白质结构功能分析显示这2种错义突变分别影响蛋白质的疏水性和抗原性,且遗传学数据资料显示MYH7 c.1988G>A为明确致病性突变。结论先证者MYH7 c.1988G>A为新发致病性突变或由于其父母为生殖嵌合所致,MYBPC3 c.151G>A突变可能促进HCM的发生。胎儿虽然仅携带MYH7 c.1988G>A,但其表型可能仍为HCM。Objective To explore the relationship between HCM pathogenic gene mutations and clinical phenotypes by analyzing the prenatal diagnosis and genetic characteristics of a pregnant woman from a family with hypertrophic cardiomyopathy(HCM). Methods The clinical data of the proband and her family members was collected. The DNA was extracted from the peripheral blood, amniotic fluid cells and cultured amniotic fluid cells of proband. Next generation sequencing(NGS) was utilized for screening pathogenetic loci of the proband. The suspected mutation sequences of HCM pathogenic candidate genes MYH7 and MYBPC3 were directly sequenced after PCR. Pathogenicity prediction of amniotic fluid cells was performed by using genetic data and bioinformatics software, such as Mutation taster, PolyPhen-2 and ANTHEPROT. Results The sequencing results showed that heterozygous mutations of MYH7 c.1988 G>A(p.Arg663 His) and MYBPC3 c.151 G>A(p.Ala51 Thr) were found in the proband. The phenotype of her father was normal, and no abnormal mutations were detectable. Her mother also showed normal phenotype but carried MYBPC3 c.151 G>A heterozygous mutation. Only MYH7 c.1988 G>A heterozygous mutation was found in the fetus and no abnormal variation of MYBPC3 was showed. The prediction of mutation effect and analysis of protein structure and function revealed that the two missense mutations could affect the hydrophobicity and antigenicity of the protein. The genetic data demonstrated MYH7 c.1988 G>A was defined as a pathogenic mutation. Conclusion MYH7 c.1988 G>A should be a newly generated pathogenic mutation in the proband, or caused by reproductive chimerism of her parents. MYBPC3 c.151 G>A mutation may promote the occurrence of HCM. Although the fetus only carries MYH7 c.1988 G>A, her phenotype may still display as HCM.

关 键 词：肥厚型心肌病 产前诊断 MYH7 MYBPC3 

分 类 号：R446.11[医药卫生—诊断学] R542.2[医药卫生—临床医学]