Abstract
Presentation Description :
Inherited retinal diseases (IRD) represent a major cause of blindness affecting two million of people worldwide. Significant advances in the genomic underpinnings of IRD have culminated in novel therapies for IRD. To be eligible for gene-specific interventions, an unequivocal molecular diagnosis of IRD is imperative. Despite this progress, there are important knowledge gaps that hamper a molecular diagnosis in half of the cases. As we have demonstrated an emerging role for complex structural variants (SVs) and defects in non-coding regions such as cis-regulatory elements (CREs) in IRD, we hypothesize that these may explain unsolved IRD cases and may represent novel targets for intervention.
We have established a multi-omics framework for the interpretation of non-coding variation in IRD. We established a genome-wide multi-omics retinal regulatory database, RegRet, which can be used for the identification of candidate CREs. Using in situ Hi-C we mapped 3D genome architecture of human neural retina and RPE, required to link CREs to their target genes. We assessed the conservation of topologically associating domains (TADs) at retinal disease loci in retina versus clinically accessible tissues (fibroblasts, lymphoblastoid cells), revealing both conserved and retina-specific 3D topologies. These chromatin interaction maps delineate the search space for genomic studies and advance the interpretation of the impact of SVs on the 3D genome. Furthermore, we illustrate how the integration of in silico predictions, in vitro and in vivo enhancer assays can be used to interpret non-coding SNVs.
Overall, our multi-omics approach offers a unique opportunity to accelerate the diagnosis of unsolved IRD and to find novel targets for intervention. Finally, this approach is also relevant for other rare eye diseases.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.