应用全外显子组测序技术鉴定1个白化病家系致病基因HPS1

Whole exome sequencing for identifying HPS1 as causative gene in a pedigree with albinism

目的采用全外显子组测序鉴定1个常染色体隐性遗传白化病家系患者的致病基因,探讨其发病机制。方法采集先证者及其家系成员外周血并提取其基因组DNA,对先证者进行全基因外显子组测序,并结合序列变异生物信息学分析方法,鉴定其致病基因,利用Sanger测序对基因突变位点验证。结果全外显子组测序结果显示,先证者HPS1基因存在由c.1276_1279dupGGAG(p.Asp427fs)移码突变和c.398+5G>A剪切位点变异组成的复合杂合突变,而其表型正常的父亲为c.1276_1279dupGGAG(p.Asp427fs)杂合突变,表型正常的母亲为c.398+5G>A杂合突变。结论该白化病先证者由HPS1基因c.1276_1279dupGGAG和c.398+5G>A复合杂合突变导致,此患者被诊断为Hermansky-Pudlak综合征1型。外显子测序技术可以快速准确地筛查白化病候选基因,并明确其具体临床亚型,有利于临床医师积极干预患者潜在并发症以及改善患者生存质量。

Objective In this study,whole exome sequencing was used to identify disease-causing genes for a pedigree with autosomal recessive albinism and pathogenesis mechanism.Methods Genomic DNA was extracted from peripheral blood samples of proband and other family members.Whole exome sequencing was performed for proband.The disease-causing mutations were determined by whole exome sequencing with sequence variation bioinformatics analysis,and the mutations were identified by Sanger sequencing.Results Proband was diagnosed with compound heterozygous mutations in HPS1gene,including c.1276_1279dupGGAG(p.Asp427fs)mutation and c.398+5G>A mutation.The frameshifting mutation was inherited from father,and the splicing mutation was inherited from mother.Conclusions The compound heterozygous c.1276_1279dupGGAG and c.398+5G>A mutations of HPS1gene are identified as causative mutations for albinism in this family.The proband is diagnosed as Hermansky-Pudlak syndrome1subtype.The whole exome sequencing can be a new and efficient method to determine specific disease gene and subtype in albinism,and it can improve the treatment and patients'live quality.