中国人群中视网膜色素变性的研究

The main goal of this proposal is to identify multiple novel genes underlying Retinitis Pigmentosa (RP) and get a better idea of the mutation spectrum in Chinese RP patients based on large data set. RP is highly genetic heterogeneous with the molecular basis for about 50% of RP patients remain unknown. To achieve comprehensive and accurate diagnosis for this disease, it is essential to identify the remaining disease genes. Furthermore, subsequent studies of these novel disease genes will lead to new insights of disease mechanisms as well as for developing new diagnosis and treatment methods. Retinitis Pigmentosa is the most common form of retinal degeneration and affects 1 in 4,000 people around the world. Patients with RP lose vision because rods and cones die throughout the retina. The age of onset of RP can vary from birth (LCA), to infancy (juvenile RP) and early adulthood (adult onset RP). Consistent with these highly variable clinical phenotypes, the inheritance of RP is also complex, including autosomal dominant (ad), autosomal recessive (ar), and X-linked recessive (xr). In addition, digenic (controlled by two genes) and mitochondrial forms have also been described. Different retinal dystrophies often share many common features and many known RP disease genes, such as CRX, CRB1, IMPDH1, RDH12, RPE65, TULP1, and SPATA7, have also been linked to other clinical appearances, including LCA and Cone Rod Dystrophy. Similar phenomena have been observed with many known RP genes. These observations indicate that the mechanisms underlying RP are often shared among many forms of retinal diseases, including neurologic and developmental disorders, intellectual disabilities, hearing impairment, short stature and other skeletal anomalies, and kidney disease. Indeed, several genes that are associated with syndromic diseases have recently been linked to nonsyndromic RP, such as CEP290, Ush2A, and NPHP5. Due to its clinically and genetically heterogeneous nature, it is difficult to identify compounds that can treat all RP patients effectively. Translational medicine that relies on molecular biology, pharmacogenomics, and genetics offers an attractive alternative. To achieve this goal, we have established a large collection of RP patient families, including 18 families with at least 9 affected members in each family. In addition, about 100 smaller families with two or more affected members have also been collected. To systematically identify multiple novel RP disease genes in this collection, we propose to use a combination of regional and whole exome sequencing (WES), bioinformatics, statistics, and functional studies.

视网膜色素变性(Retinitis Pigmentosa, RP)是视网膜疾病中的最常见一种疾病，在世界范围内的患病率约为1/4000，患者最初表现为夜盲，视野范围逐渐缩小，最终导致失明。视网膜色素变性具有高度的异质性，目前为止已发现有52个 基因上的突变会导致该疾病，而这52个基因仅能解释大约50%视网膜色素变性患者的致病原因，因而对于视网膜色素变性疾病还有很大的研究空间。申请人将对433名中国视网膜色素变性患者进行以下的分析研究： A.利用外显子富集结合二代测序的方法对视网膜色素变性患者进行已知基因上突变的检测，建立中国人群视网膜色素变性的突变频谱； B.建立视网膜色素变性患者临床表型与基因型的相关性，提高诊断的准确率； C.寻找视网膜色素变性的新基因，初步探索致病机理。

眼遗传病是一组由于基因缺陷导致的眼部疾病， 临床常见的眼遗传病有视网膜变性；先天性青光眼；先天性白内障；遗传性视神经病变等单纯眼遗传疾病以及累及眼部的一些综合征。 遗传方式包括常染色体显性遗传；常染色体隐性遗传； X性连锁遗传；双基因遗传及线粒体遗传等。由于眼遗传病存在高度异质性，为眼遗传病的临床诊断和分子检测带来了巨大的挑战。随着人类基因组参考序列的完成、基因芯片和高通量测序等技术的问世以及生物信息技术对海量生物数据的高效分析和处理技术的发展，近几年来单基因遗传病的分子诊断效率快速提高，技术方法取得了很大的突破，为患者和临床医师的遗传咨询提供了技术保障，更为将来的基因治疗奠定了良好的基础。在众多基因组技术中，尤以二代测序（next-generation sequencing，NGS）技术以其特有的优势在包括眼遗传病在内的单基因遗传病的研究中发挥着重要作用，已越来越多地用于眼遗传病的分子检测。本项研究对大量的眼遗传病样本进行目标区域富集以及高通量测序，以确定受检者的致病原因。同时，在此基础上，对研究的实验方法，数据分析方法进行不断地改进完善。对于模块检测阴性的样本，利用全外显子或全基因组检测，以期待发现染色体结果变化，非编码区的致病突变以及发现新的致病基因。