近亲结婚家系遗传性视网膜疾病的基因突变频谱研究

项目名称： 近亲结婚家系遗传性视网膜疾病的基因突变频谱研究

项目编号： No.81460093

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 庄文娟

作者单位： 宁夏医科大学

项目金额： 47万元

中文摘要： 遗传性视网膜疾病（HRD）是一组具有高度遗传和临床异质性、以原发性视网膜退行性改变为主要病理变化、视功能严重受损为主要临床表型的最常见致盲眼病。目前尚无有效治疗方法，且复杂多样交互重叠的临床表型使得部分HRD的临床诊断不可确定。探索分子遗传学病因是降低HRD群体发病率并为基因治疗提供靶向位点的前提。本课题拟在前期视网膜色素变性遗传学研究基础上利用本地丰富的遗传资源，收集近亲结婚HRD家系，采用目标序列捕获测序筛查致病性基因突变，发现已知基因的新突变及可疑致病基因突变；未检测出致病突变的家系则采用全基因组外显子测序发现新的致病基因，利用生物信息系统评估候选突变的致病性，并制作相应的细胞模型研究致病基因及突变的功能和发病机制，从而丰富我国HRD的致病基因图谱；同时分析基因型与临床表型的对应关系，提升临床与基因诊断的水平和效率；在此基础上推进本地区遗传性眼病基因诊断中心及专业遗传咨询体系的建立。

中文关键词： 遗传性视网膜疾病；近亲结婚；基因突变；基因诊断

英文摘要： Hereditary retinal dystrophies (HRD) consist of a number of severe retinal degenerative diseases with great genetic and clinical heterogeneities, which can lead to severe visual impairments or even blindness. However, there is no effective treatment by far and the phenotypic overlaps and variability in presentation of HRD often make clinical diagnosis uncertain and complicated. Identifying genetic causes is essential to lower the prevalence of HRD and to provide target site for gene therapy of HRD. Based on the prior genetic research associated with retinitis pigmentosa, making use of our rich genetic resources, the HRD pedigrees are collected in consanguineous families and then the causative genes/mutations of HRD are sequenced using targeted genes capture with next-generation high throughput sequencing. Furthermore the novel gene mutations are discovered by using of exome sequencing in undetected causative mutations pedigrees by targeted genes capture with NGS. Then the hereditary conservation and pathogenicity of candidate mutations are evaluated by corresponding biological analysis system and the cell models are established for investigating the function and pathogenesis of causing genes and mutations. Thus, the gene mutations spectrum of Chinese HRD will be enriched. Meanwhile, the relationship of genotype and phenotype are analyzed to promote the efficiency in clinical and gene diagnosis. On this basis, we will promote the establishment the center of gene diagnosis and the system of genetic counseling in Ningxia.

英文关键词： hereditary retinal dystrophies;consanguineous marriage;gene mutation;gene diagnosis