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摘要: 目的:对收集的1例血脂异常家系的致病基因进行全外显子测序,确定其突变基因位点。方法:收集在我院就诊的1例血脂异常患者及其家系成员的临床资料,采集患者及相关家系成员外周血样本并提取基因组DNA,利用目标外显子捕获技术和二代测序技术对先证者的与血脂异常有关的基因进行基因突变筛查,并使用Sanger测序法验证可疑突变位点并筛查患者家系成员和100例健康人,确定该家系患者的致病突变基因,使用Polyphen2、MutationTaster、SIFT和Provean这4种软件进行突变基因功能检测,并利用Swiss-Model软件分析突变前后的蛋白质三维结构模型。结果:在受检人样品中检测到LPL基因的纯合变异c.1322+1G>A(编码区第1322+1位核苷酸由G变为A),在其子女样品中检测到LPL基因同位点的杂合变异。4种预测软件均预测该突变为有害突变,Swiss-Model软件结果显示该突变位点导致442位的缬氨酸突变为终止密码子,可能影响蛋白质的剪切和活化功能。结论:本研究应用全外显子测序技术在一血脂异常家系中发现LPL基因新的突变位点:LPL c.1322+1G>A。该突变可能是患者家系发生高三酰甘油血症的致病因素,且可能导致更严重的冠心病。此位点目前在我国人群中少见文献报道。Abstract: Objective:To sequence the pathogenic genes of a family with hyperlipidemia by full exon sequencing,and determine the mutation loci.Method:We collected the clinical data of a hyperlipidemia patient and her family members in our hospital,peripheral blood samples from patients and related family members were collected and genomic DNA were extracted.The gene mutations associated with hyperlipidemia in the proband were screened by target exon capture and second-generation sequencing techniques.Suspicious mutation sites were identified by Sanger sequencing,and the patients' family members and 100 healthy persons were screened to identify the pathogenic mutations in the proband.Polyphen2,MutationTaster,SIFT and Provean were used to detect the function of mutant genes,and Swiss-Model software was used to analyze the three-dimensional protein structure model before and after mutation.Result:The homozygous variation C.1322+1 G>A of LPL gene was detected in the tested samples(the nucleotide of coding site 1322+1 was changed from G to A),and heterozygous variation of LPL gene was detected in the offspring samples.The four prediction softwares predicted that the mutation was a harmful mutation.The Swiss-Model software results showed that the mutation site lead to the mutation of valine at position 442 as a stop codon,which may affect the protein's cleavage and activation function.Conclusion:In this study,a new mutation of LPL gene,LPL C.1322+1 G>A,is found in a hyperlipidemia family by using exon sequencing technique.The mutation may be a pathogenic factor of hypertriglyceridemia in the family,and may lead to more severe coronary atherosclerotic heart disease.This locus is rarely reported in Chinese population.
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Key words:
- familial /
- hyperlipidemia /
- total exon sequencing /
- gene mutation /
- homozygous mutation
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