目标基因捕获测序技术鉴定肥厚型心肌病致病突变的研究

目的:利用目标基因靶向捕获高通量测序方法鉴定肥厚型心肌病(hypertrophic cardiomyopathy,HCM)致病突变,并进行基因型-临床表型的分析,以期对临床诊治提供参考依据。方法:连续收集10例HCM患者血液与临床资料。提取全血基因组DNA、文库制备,靶向富集8个编码肌小节蛋白的HCM的致病基因,并行高通量测序。结果:10例患者平均年龄为(46±7.9)岁,女性占50%]中,4例患者发现5个基因突变位点。双突变(TNNT2 R286H和MYH7 R663H)携带者具有HCM家族史,发病早,左心室重度肥厚,心电图呈现传导阻滞。MYBPC3 D770N和MYBPC3 S236G突变携带者发病年龄晚,左心室肥厚程度较轻。MYH7 R869C突变携带者年龄大,左心室肥厚程度较重,心电图呈现明显左心室肥大证据。结论:对10例HCM患者利用目标基因捕获测序技术筛选出5个致病突变。携带不同突变的患者其临床表型不一致,这对患者的预后和治疗提供了有利的依据。

The research of identification of pathogenic mutations associated with hypertrophic cardiomyopathy by targeted capture and high throughput sequencing technique

Objective:To identify pathogenic mutations associated with hypertrophic cardiomyopathy(HCM) by targeted capture and high throughput sequencing technique,and to study the genotype-phenotype correlation.Methods:Whole blood and clinical data from ten patient with HCM were collected.Genomic DNA was extracted and library was prepared.Exomes of patients with 8 HCM-related genes encoding sarcomere protein were captured and sequenced.Results:① Mutation was detected in 4 out of 10 HCM patients mean age,(46 ±7.9) years;female,50%].② The patient with double mutations(TNNT2 R286H and MYH7 R663H) was younger with more severe hypertrophy and severe arrhythmias.③ MYBPC3 D770N or MYBPC3 S236G mutation could lead to mild phenotype.④ MYH7 R869C carrier presented at an old onset age and more serious myocardial hypertrophy.Conclusion:Five pathogenic mutations were identified among 10 HCM cases by targeted capture and high throughput sequencing technique.Different clinical phenotypes in different mutation carriers provide evidence for prognosis and treatment of HCM.