RS1基因突变的X连锁视网膜劈裂症家系基因型和表型分析

A phenotype-genotype study of X-linked retinoschisis in RS1 mutations

目的检测3个X连锁视网膜劈裂症(XLRS)家系的致病基因,探讨其基因型和表型特征。方法采用横断面研究方法,纳入2017年10月至2019年3月在宁夏眼科医院就诊的3个先天性视网膜劈裂家系,收集患者和家系成员的临床资料,采集受检者外周血,完善眼科检查并进行临床分期,通过Panel测序筛选致病基因,利用软件工具对突变进行保守性分析、致病性分析和蛋白质结构预测,并根据ACGM指南分析突变的致病性。结果3个家系共5例青年患者,黄斑光相干断层扫描(OCT)均出现典型的黄斑区视网膜劈裂腔,表现为视网膜劈裂症Ⅰ期;1例中年患者表现为视网膜劈裂症Ⅲ期的黄斑萎缩改变;Panel测序分别发现RS1基因突变c.668G>A、c.618G>A和外显子1缺失,其中C223和W206在哺乳动物中高度保守,软件预测突变具有致病性且蛋白质结构改变;外显子1缺失突变没有进行保守性分析和蛋白结构的预测。根据ACGM指南分析3个突变均为致病性变异。结论RS1基因突变c.668G>A/p.C223Y、c.618G>A/p.W206X和外显子1缺失均为中国XLRS家系的致病性突变。Panel测序联合致病性预测软件工具的应用对遗传性视网膜疾病的诊断及致病基因的确定有重要作用。

Objective To describe the characteristics of genotype and phenotype in 3 families with X-linked retinoschisis(XLRS)due to RS1 mutations.Methods A cross-sectional approach was adopted.Three XLRS families at the Ningxia Eye Hospital from October 2017 to March 2019 were included.Clinical data and peripheral blood of patients and related families were collected and clinically staged were formulated through a comprehensive eye examination.The disease-causing genes screened by panel sequencing underwent conservative analysis,pathogenicity analysis and protein structure prediction by software tools.Analysis of the mutations pathogenicity was performed according to the American College of Medical Genetics and Genomics guidelines.The research was approved by Medical Ethics Committee of the People's Hospital of Ningxia Hui Autonomous Region and followed the Declaration of Helsinki.Written informed consent was obtained from each participant.Results Total 5 young male patients and 1 middle-aged patient in these three families.The optical coherence tomography(OCT)findings of 5 young patients showed typical macular retinoschisis,which were characterized by stage I of XLRS.One middle-aged patient(Ⅱ-9)showed a stageⅢlesion of macular atrophy.The mutations of c.668G>A,c.618G>A and exon 1 deletion in RS1 gene were found in the three families.C223 and W206 were verified to be highly conserved in mammals and were predicted to be pathogenic mutations by software and the change of protein structure.Conservation analysis and prediction of protein structure were not performed for the mutation of exon 1 deletion.All the mutations were pathogenic variants according to the ACGM guidelines.Conclusions Mutations of c.668G>A/p.C223Y,c.618G>A/p.W206X and exon 1 deletion in RS1 gene are pathogenic mutations in Chinese XLRS families.The combination of Panel sequencing with pathogenicity analysis and protein structure prediction have important effect to diagnosis and identify the causative genes for the hereditary retinal diseases.