全外显子组测序技术在32例肺动脉高压患者中的应用

Application of Whole Exome Sequencing Technology in 32 Cases of Pulmonary Hypertension

目的探讨肺动脉高压(PH)在中国人群中的遗传性病因及特点,深入分析该疾病的基因型与临床表型之间的关系。方法选取有PH相关疾病表型的32例患者进行全外显子组基因序列捕获,利用Illumina Novaseq6000的标准操作流程进行测序,通过生物信息学的方法并根据美国医学遗传学和基因组学会(ACMG)指南对先证者的变异位点进行致病性评估,同时对受检者及其双亲的致病性变异位点进行一代验证。结果患者的平均发病年龄为25岁,其中20~40岁的患者占所有受检者的56.3%(18/32)。检测到6个基因含有致病性变异位点,分别为BMPR2、LDLR、ACVRL1、PROC、MMACH、DLL4,全外显子组测序(WES)的阳性检出率为43.8%(14/32)。结论WES作为临床诊断PH的一个有效辅助手段,在由基因变异引起的临床表型复杂疾病的早期识别和个体化精准用药中有重要意义。

Objective To investigate the etiology and characteristics of genetic pathogenicity of pulmonary hypertension(PH)in Chinese population,and to analyze the relationship between genotype and clinical phenotype of the disease.Methods Thirty-two patients with phenotypes associated with PH were selected for full exome gene sequence capture,sequenced using the Illumina Novaseq6000 standard protocol,and pathogenicity assessment of proband variant sites by bioinformatics methods and according to American College of Medical Genetics and Genomics(ACMG)guidelines.And validated variations predicted to be damaging by Sanger Sequencing.Results The average age of onset was approximately 25 years old,with 56.3%(18/32)of the subjects in the 20-40 age group.Six genes were found to contain pathogenic mutation sites,namely BMPR2,LDLR,ACVRL1,PROC,MMACH,DLL4.The positive detection rate of whole exome sequencing(WES)was 43.8%(14/32).Conclusion WES is an effective adjunct to clinical diagnosis of pulmonary hypertension.It is of great significance in the early identification and individualized precise use of clinical phenotypic complex diseases caused by genetic variation.