The goal of this project is to identify novel genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause Retinitis Pigmentosa (RP), one of the most common forms of inherited retinal degeneration that affects an estimated 100,000 people in the United States alone, will be identified by combining whole exome sequencing with genetic mapping. Mutations in known RP genes account for about 50% of all cases in the European population, suggesting that many additional RP genes remain to be identified. To identify additional RP disease genes, we have collected more than 500 patient families with autosomal recessive RP (arRP) from around the world. Screen for mutations in known arRP disease genes suggests that about 300 of these families are likely to carry mutations in novel RP disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause RP. In this proposal, we will identify the underlying mutations in these patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies.
Our Specific Aims are to: 1. Whole exome sequencing of RP families to identify novel RP disease genes 2. Confirmation and discovery of novel RP genes by screening a 1300-patient cohort 3. Phenotype genotype analysis of RP families and continued enrollment Discovery of novel RP genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in RP disease genes also cause other retinal dystrophies, isolation of additional RP disease genes will provide important insights into the molecular mechanisms underlying both RP and retinal dystrophies in general.
|Wang, Jun; Zhao, Li; Wang, Xia et al. (2018) GRIPT: a novel case-control analysis method for Mendelian disease gene discovery. Genome Biol 19:203|
|Eblimit, Aiden; Zaneveld, Smriti Agrawal; Liu, Wei et al. (2018) NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype. Exp Eye Res 173:32-43|
|Li, Huajin; Jones, Evan M; Li, Hui et al. (2018) Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants. Ophthalmic Genet 39:569-576|
|Zaneveld, Smriti Agrawal; Eblimit, Aiden; Liang, Qingnan et al. (2018) Gene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice. Hum Gene Ther :|
|Dharmat, Rachayata; Eblimit, Aiden; Robichaux, Michael A et al. (2018) SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium. J Cell Biol 217:2851-2865|
|DuPont, Mariana; Jones, Evan M; Xu, Mingchu et al. (2018) Investigating the disease association of USH2A p.C759F variant by leveraging large retinitis pigmentosa cohort data. Ophthalmic Genet 39:291-292|
|Xu, Mingchu; Xie, Yajing Angela; Abouzeid, Hana et al. (2017) Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet 100:592-604|
|Yuan, Zhisheng; Li, Baiyu; Xu, Mingchu et al. (2017) The phenotypic variability of HK1-associated retinal dystrophy. Sci Rep 7:7051|
|Soens, Zachry T; Branch, Justin; Wu, Shijing et al. (2017) Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. Hum Mutat 38:1521-1533|
|Jones, Kaylie D; Wheaton, Dianna K; Bowne, Sara J et al. (2017) Next-generation sequencing to solve complex inherited retinal dystrophy: A case series of multiple genes contributing to disease in extended families. Mol Vis 23:470-481|
Showing the most recent 10 out of 43 publications