MYBPC3基因G12101A和MYH7基因G15391A突变与肥厚型心肌病临床表型

The genotype-phenotype correlation of MYH7 gene G15391A mutation and MYBPC3 gene G12101A mutation in familial hypertrophic cardiomyopathy

目的研究中国人家族性肥厚型心肌病（HCM）的致病基因突变位点，分析基因型与临床表型的相互关系。方法在2个中国汉族HCM家系中进行心脏肌钙蛋白T基因（TNNT2）、心脏肌球蛋白结合蛋白C基因（MYBPC3）和心脏β-肌球蛋白重链基因（MYH7）的突变筛查，聚合酶链式反应（PCR）扩增基因功能区外显子片段并对PCR产物进行测序分析。结果在ZZJ家系接受调查的8名成员中有4名成员携带MYBPC3基因G12101A杂合突变，该突变位点位于MYBPC3基因的21号外显子并使668位的精氨酸（R）转换为组氨酸（H），携带该突变的家族成员发病年龄较晚且均无梗阻及晕厥史。在FHL家系接受调查的6名成员中有3名成员携带MYH7基因G15391A杂合突变，该突变位点位于MYH7基因的23号外显子并使930位的谷氨酸（E）转换为赖氨酸（K），该突变导致的临床表型呈现发病年龄早、梗阻率高以及外显率高的特点。两家系成员TNNT2基因未发现突变，且正常对照组相同位置未发现异常。结论MYBPC3基因和MYH7基因是我国家族性HCM的致病基因，MYBPC3基因G12101A突变所致HCM临床症状相对较轻，而MYH7基因G15391A突变所致HCM临床症状出现早、进展较快且预后较差，是一种恶性突变。

Objective To reveal genotype-phenotype correlation of disease-causing gene mutations in Chinese hypertrophic cardiomyopathy （HCM） pedigree. Methods Peripheral venous blood samples were collected from two Chinese HCM families and 120 healthy subjects were recruited as normal control. The full encoding exons and flanking sequences of the cardiac troponin T gene （ TNNT2）, beta-myosin heavy chain gene （MYH7） and myosin binding protein C gene （MYBPC3） were amplified with the polymerase chain reaction method, DNA sequencing was used to detect the mutation. Results In ZZJ family, mutation G12101A was identified in exon 21 of MYBPC3 gene in 4 family members [ the arginine （R） converted to histidine （H） ]. In this pedigree, three out of eight family members were diagnosed as HCM and with a penetrance of 75%. In FHL family, mutation G15391A was identified in exon 23 of MYH7 gene in 3 family members [ the glutamic acid （E） converted to lysine （K）1. In this pedigree, three out of six family ,members were diagnosed as HCM and with a penetrance of 100%. Echocardiography showed obstruction of left ventricular outflow tract in two out of the three HCM patients. Conclusions Our results showed that the G12101A mutation of MYBPC3 gene is the causal mutation of familial HCM with mild phenotype. The G15391A mutation of MYH7 gene is the causal mutation of familial HCM with malignant phenotype and a penetrance of 100%. Screening mutations in the MYH7 gene should be viewed as a reasonable procedure in obstructive HCM patients.