Inherited retinal degenerations (IRD) are the leading cause of irreversible blindness in young adults in the United States. The genetic basis of recessive IRD is known only in about 50% of cases. Furthermore, little is known about the molecular mechanism underlying these diseases. Cures are currently unavailable for these diseases. However, gene therapy clinical trials for Leber's congenital amaurosis have been reported to be successful and gene-based pre-clinical studies of IRD treatments were found to be effective. Nevertheless, the lack of information on the underlying cause of IRD in the remaining half of cases and the paucity of knowledge on the pathways leading to these diseases impedes the development of therapies to treat these conditions. Until recently, the search for the genetic cause of IRD was limited to the coding region comprising 3% of the genome leaving the remaining 97% unexplored. In addition, prioritization and interpretation of candidate variants has been challenging due to the lack of efficient methodologies. In this proposal we aim to identify the genetic cause of disease in the remaining 50% of cases and understand the pathways involved in causing IRD. To achieve our goals, we will build on the opportunity we have to sequence the whole genomes (WGS) of 500 individuals from IRD pedigrees and the exome sequences (WES) generated on 54 pedigrees in the previous grant cycle, representing 230 unrelated pedigrees/patients. We propose to analyze the WGS and WES to identify the novel genes and associated pathways leading to IRD pathology by: (1) identifying putative candidate variants in both coding and non-coding regions, (2) using computational analysis that integrates existing data; publicly available genomes, epigenomes, transcriptomes and other large data sets relevant to IRD; and experimental data including the molecular expression profiles of relevant retinal cells differentiated from patient induced pluripotent stem cells (hiPSC) and (3) performing molecular and biochemical analyses of putative causal variants using patient iPSC based disease-in-dish models and CRISPR-Cas9 system based genome edited mouse models. These studies will provide a molecular profile of the IRD genome, identify novel genes involved in causing IRD, enhance our understanding of the biological pathways leading to retinal degeneration, and establish a molecular-network based approach for finding causal variants in patients with IRD. These studies will also enable the development of genetic tests for patients and precision medicine strategies based on pathways associated with RD pathology.

Public Health Relevance

The goal of this proposal is to examine coding and non-coding variants in the genomes of 230 pedigrees to identify novel genes and associated pathways involved in causing IRD using a comprehensive knowledge network-based analysis. The outcomes will enable genetic testing and pave the way for the development of therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
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Shen, Grace L
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Chekuri, Anil; Guru, Aditya A; Biswas, Pooja et al. (2018) IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. Hum Genet 137:447-458
Villanueva, Adda; Biswas, Pooja; Kishaba, Kameron et al. (2018) Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent. Ophthalmic Genet 39:73-79
Biswas, Pooja; Naeem, Muhammad Asif; Ali, Muhammad Hassaan et al. (2018) Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree. Adv Exp Med Biol 1074:219-228
Li, Lin; Jiao, Xiaodong; D'Atri, Ilaria et al. (2018) Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. PLoS Genet 14:e1007504
Branham, Kari; Guru, Aditya A; Kozak, Igor et al. (2018) Identification of Novel Deletions as the Underlying Cause of Retinal Degeneration in Two Pedigrees. Adv Exp Med Biol 1074:229-236
Panopoulos, Athanasia D; D'Antonio, Matteo; Benaglio, Paola et al. (2017) iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types. Stem Cell Reports 8:1086-1100
Panopoulos, Athanasia D; Smith, Erin N; Arias, Angelo D et al. (2017) Aberrant DNA Methylation in Human iPSCs Associates with MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics. Cell Stem Cell 20:505-517.e6
Biswas, Pooja; Duncan, Jacque L; Ali, Muhammad et al. (2017) A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Hum Mol Genet 26:4741-4751
Biswas, Pooja; Duncan, Jacque L; Maranhao, Bruno et al. (2017) Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association. Physiol Genomics 49:216-229
Gustafson, Kevin; Duncan, Jacque L; Biswas, Pooja et al. (2017) Correction: Gustafson et al., Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree. Genes 2017, 8, 210. Genes (Basel) 8:

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