肥厚型心肌病家系中MYBPC3-D1149fs*40新发突变的基因型及临床表型研究

Genotype-phenotype correlation for a novel MYBPC3-D1149fs*40 mutation identified in familial hypertrophic cardiomyopathy

关键词:  心肌病  肥厚性  MYBPC3  基因型  表型

Key words:  cardiomyopathy  hypertrophic  MYBPC3  genotype  phenotype

摘要:

目的 探讨肥厚型心肌病（hypertrophic cardiomyopathy， HCM)家系中新发现的MYBPC-D1149fs*40突变的基因型与临床表型关系。方法 应用全外显子测序技术检测先证者与HCM相关的基因，采用Sanger测序验证可疑突变并筛查家系成员，进行基因型和临床表型共分离分析。利用ClustalX软件分析突变在不同物种间的保守性，使用SIFT、Polyphen_2等生物信息学软件预测该突变位点的致病性。结果 本家系共筛查亲属7位，其中经临床确诊HCM患者3人，均表现为不对称性室间隔肥厚，平均室间隔厚度（16.1+1.2） mm，均不伴有流出道梗阻。确诊的3例均携带突变MYBPC3 c.3445（exon31）delG（p.Asp1149fs*40），在该家系的另4位临床表型正常的成员中未检测到相同突变位点。该突变在dbSNP、千人基因组等中均未见报道，种间保守性分析表明该突变氨基酸在多物种中高度保守，生物信息学分析预测此为有害突变。结论 该家系中携带MYBPC3-D1149fs*40的成员均为HCM患者，另4位临床表型正常的成员未检测到该突变位点，推测该突变可能是该HCM家系的致病突变。

Abstract:

Objective To analyze the genotype-phenotype correlation of a novel MYBPC-D1149fs*40 mutation identified in familial hypertrophic cardiomyopathy(HCM). Methods Genes associated with HCM were detected in the proband by exonic amplification and high throughput sequencing. Suspected mutations were verified by Sanger sequencing among family members of the proband， and genotype-phenotype correlation was co-isolated and analyzed. The conservation of the detected mutations across species were analyzed with ClustalX software, and the pathogenicity was predicted with SIFT, PolyPhen-2 and other software. Results Hypertrophic cardiomyopathy was diagnosed in 3 of the 7 family members. They had asymmetric hypertrophy of the interventricular septum with a average thickness of （16.1+1.2） mm and no left ventricular outflow tract obstruction was observed. Genetic testing showed that 3 of them carried a c.3 445（exon 31） delG（p.Asp1149fs*40） mutation of the MYBPC gene, while the remaining 4 family members were phenotypically normal and did not carry the gene mutation. The mutation had not been recorded by the dbSNP, 1 000 genomes and other databases. Conservation analysis showed that the mutation was highly conserved， and bioinformatics analysis forecasted that the mutation was pathogenic. Conclusion Family members carrying the p.D1149fs*40 mutation of the MYBPC3 gene are all HCM patients, and those without the mutation were phenotypically normal, which suggests that the p.D1149fs*40 mutation of the MYBPC3 gene may be the pathogenic mutation for familial hypertrophic cardiomyopathy.