宁夏地区一遗传性视网膜色素变性五代家系基因型和临床表型分析

Genotype and clinical phenotype analysis of a five-generation Ningxia family with autosomal dominant retinitis pigmentosa pedigree

目的研究宁夏地区1个常染色体显性遗传视网膜色素变性(adRP)5代家系患者的致病基因突变及临床表型特征。方法家系调查研究。收集1个adRP家系患者及其家系成员病史资料,进行详细的眼科检查,抽取3例患者和1名正常家系成员及300名正常对照者外周静脉血,提取DNA,运用全外显子测序(WES)芯片进行检测,对检测结果进行生物信息学分析,运用PCR和直接测序在家庭成员和正常对照组中进行验证,最终确定致病性突变位点,并对临床表型和基因型间的关系进行分析。结果通过WES技术和优化的生物信息学分析技术证实,PRPF 31基因的c.C1048T(p.Q350X)无义突变为该家系的致病基因突变。该家系患者的主要临床特征为5~6岁发病,均以夜盲为首发症状;病情进展较为迅速,视功能均严重受损,同时合并后囊下白内障,眼底和视网膜电图(ERG)均呈现典型的RP改变。结论PRPF 31基因的c.C1048T(p.Q350X)无义突变为该家系的致病基因突变,该突变在中国人群中首次报道,该突变可引起的临床表型包括发病年龄早、病情进展较为迅速、合并后囊下白内障及视功能严重受损等。

Objective To identify the pathogenic mutation in a five￣generation Ningxia family with autosomaldominant retinitis pigmentsoa (adRP) and to analyze its associated clinical phenotype. Methods One adRPpedigree was recruited for this study. All the patients and family members received complete ophthalmic examinations.DNA was abstracted from peripheral blood of three patients,one normal family member and 300 normal controls.Using whole exome sequencing(WES)chip and bioinformatics analysis to screen the candidate disease-causing mutations.PCR and direct sequencing were used to confirm the disease-causing mutations.Genotype-phenotype correlation was also analyzed.This study followed the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of People's Hospital of Ningxia Hui Autonomous Region(No.20160204).Results PRPF 31 c.C1048T(p.Q350X)nonsense mutation was identified as the disease-causing mutation for this family by WES chip,PCR and direct sequencing.This family demonstrated early onset of the disease by presenting nyctalopia from 5 to 6 years,performed rapid disease progression,severely impaired visual function and posterior subcapsular cataract.The fundus presentations and electroretinogram(ERG)results showed typical RP progressions.Conclusions PRPF 31 c.C1048T(p.Q350X)nonsense mutation is the disease-causing mutation of this family.This mutation is first reported in Chinese with distinct phenotypes in the present family,including early onset of the disease,rapid disease progression,severely impaired visual function and posterior subcapsular cataract.