基于全外显子测序和生信分析的PRKAG2心脏综合征家系研究

Family Study of PRKAG2 Syndrome Based on Whole Exome Sequencing and Bioinformatics Analysis

目的:对一个家族性心肌肥厚家系成员进行临床资料收集及致病基因筛查,挖掘家族性心肌肥厚的致病基因,探究临床症状的分子生物学基础。方法:收集该家系成员包括病史、体格检查、心电图、超声心电图在内的临床资料,绘制家系系谱图。采集先证者及家系成员外周血,提取DNA,对先证者行全外显子测序,筛查到可疑突变后,用Sanger测序验证突变真实性以及其他家系成员是否携带相应突变。根据全外显子测序结果进行验证性分析和探索性分析。结果:先证者(II-6)和其儿子(III-4)携带PRKAG2 c.1589A>G(p.His530Arg)错义突变,存在家系共分离。先证者II-6一共339个可疑突变,涉及172个蛋白编码基因,致病可能性较高且评级在D以上的基因突变共4个。先证者儿子III-4一共361个可疑突变,涉及176个蛋白编码基因,致病性较高的突变共7个。结论:家系为PRAKG2心脏综合征家系,发现PRAKG2基因第1589位点腺嘌呤突变为鸟嘌呤,其编码蛋白中530位组氨酸被替换为精氨酸。此突变位点在国内未见报道。家系B中II-6患者比III-4患者有更严重的临床表现可能和PI3K-Akt信号通路相关。

Objective Collect clinical data and screen pathogenic genes for members of a family with familial myocardial hypertrophy,to explore the pathogenic genes and molecular biological basis of myocardial hypertrophy and other clinical symptoms.Methods Collecting the familial clinical data including medical history,physical examination,electrocardiogram and echocardiogram.Collecting the peripheral blood of the proband and family members,extracting DNA,and performing target sequence capture high-throughput sequencing of the proband.After screening suspicious mutation,using Sanger sequencing to verify the authenticity of the mutation and discern if other family members carry the identical mutation.And use the sequencing results for confirmatory and exploratory bioinformatic analysis.Result Proband II-6 and her son all carry the c.1589A>G(p.His530Arg)heterozygous mutation of PRKAG2.A total of 14 pathways were enriched using the confirmatory bioinformatics analysis method,and no pathways related to mitral valve morphology were found.Using exploratory bioinformatic analysis method,fitting 27 related genes with abnormal mitral valve morphology,found that PI3K-Akt pathway is related to PRKAG2 cardiac syndrome in related pathways,and there are 31 mutations in 14 pathway genes in II-6 patients,III-4 patients have 23 mutations in 15 genes.Conclusions It’s a family of PRAKG2 cardiac syndrome.It was found that adenine at position 1589 of PRAKG2 gene was mutated to guanine,and histidine at position 530 in the encoded protein was replaced with arginine.The mutation sites have not been reported in China.II-6 patients have more severe clinical manifestations than III-4 patients,which may be related to PI3K-Akt signaling pathway.