RPGRIP1基因新突变致Leber先天性黑矇一家系

Novel mutations of RPGRIP1 gene in a family with Leber congenital amaurosis

目的确定1个汉族Leber先天性黑矇(LCA)家系的致病基因突变。方法回顾性研究。2018年10月在河南省立眼科医院就诊的LCA一家系1例患者和3名家系成员纳入研究。详细询问患者病史并行物体注视性质、追随试验、裂隙灯显微镜、散瞳验光、眼底照相及全视野ERG检查;家系成员行BCVA、裂隙灯显微镜联合前置镜、验光、眼底照相及全视野ERG检查。采集先证者及其兄长、父母的外周静脉血5 ml,提取全基因组DNA。应用包含441个致病基因的遗传眼病捕获芯片进行靶向捕获富集高通量测序以获得致病基因及突变。对可疑致病突变位点通过Sanger进行验证,并行生物信息学分析确定基因突变位点的致病性。结果患者表现为自幼不追物但有明显畏光和眼球震颤;双眼眼前节及眼底无异常;全视野ERG检查可见双眼视锥、视杆系统功能严重下降。基因检测结果显示,患者RPGRIP1基因存在c.1635dupA和c.3565C>T两个突变。其中,RPGRIP1 c.1635dupA为新发突变。RPGRIP1基因c.1635dupA和c.3565C>T构成复合杂合突变。生物信息学分析结果显示,c.3565C>T为致病突变,c.1635dupA为可能致病突变。结论RPGRIP1基因新发突变c.1635dupA与c.3565C>T构成复合杂合突变可能是本家系的致病原因。

Objective To identify the pathogenic gene mutations in a family with Leber congenital amaurosis(LCA).Methods In October 2018,1 patient and 3 normal family members from a LCA family was enrolled in this retrospective study.Detailed medical history of proband was obtained and fixation test,cycloplegic refraction,slit-lamp,fundus color photography and full-field ERG were performed.And other family members underwent BCVA,refraction slit-lamp,fundus biomicroscopy with the slit lamp,fundus color photography and full-field ERG.The family was investigated with a specific hereditary eye disease enrichment panel which contained 441 known pathogenic genes and based on targeted exome capture technology first to indentify the potential pathogenic genes and mutations.Then the potential pathogenic mutations were conformed by Sanger sequencing.Finally,the results were analyzed via bioinformatics analysis.Results The proband showed no trace object from childhood,but had obvious photophobia and nystagmus.No positive changes were found in the anterior segment,vitreous and retina in both eyes.Both cone and rod system function decreased significantly in full-field ERG in both eyes.Gene tests showed the proband carried both RPGRIP1 c.1635dupA and c.3565C>T,which composited a heterozygous mutation.Bioinformatics analysis showed RPGRIP1 c.1635dupA was a pathogenic mutation,and RPGRIP1 c.3565C>T which was a novel potential pathogenic mutation in LCA.Conclusion The compound heterozygous mutation,c.1635dupA and c.3565C>T in RPGRIP1 may be responsible for the pathogenesis in this Chinese Han LCA pedigree.