Inherited retinal degeneration (RD) is responsible for 5% of blindness worldwide. Genetic
studies have revealed underlying molecular defects in ~50% of individuals with RD, most of
which are located in the coding portion of the genome. The advent of next-generation sequencing (NGS) has revolutionized the genetic landscape. However, the massive amount of
data produced by NGS hampers disease gene identification, requiring powerful prioritization
strategies. In addition, there is accumulating evidence that an important fraction of genetic defects reside outside the coding regions. These are missed by genomic approaches such as exome sequencing. To overcome this, our project aims to:
(i) Integrate genomics and transcriptomics NGS-based approaches, in order to uncover
both coding and non-coding changes.
(ii) Develop an extensive filtering strategy for NGS data analysis in RD, based on retinaspecific data - such as retinal expression sets of coding and non-coding RNAs and
cis-regulatory mapping data of the retinal transcription factors CRX and OTX2 -
combined with generic data based on homozygosity mapping.
This integrated approach will be applied on 50 consanguineous families with Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (ARRP), the most severe and most common RDs, respectively. We expect that this project will push forward the limits of gene discovery in RDs, and will lead to the identification of coding and unconventional noncoding mutations in at least several new RD genes for LCA or ARRP.