Center for Medical Genetics Center for Medical Genetics


  • Research focus

Integrated genomics for gene identification in inherited retinal degeneration


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 approaches such as exome sequencing.


To overcome this, our research 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 retina- specific data - such as retinal expression sets of coding and non-coding RNAs and cis-regulatory mapping data of the retinal transcription factors CRX, NRL and OTX2 - combined with generic data based on homozygosity mapping in recessive families (e.g. consanguineous families) or linkage analysis in dominant families.
This integrated approach will be applied on families with RD. This research will result in gene discovery in RD, and will lead to the identification of coding and unconventional non-coding mutations new RD genes.

Exploring the role of non-coding variation in hereditary blindness: Stargardt disease as a model


Inherited retinal dystrophies (RDs) affect more than 2 million people worldwide. The underlying molecular defects have been found in ~50% of individuals with RD, mostly located in the coding portion of the genome. There is accumulating evidence however that an important fraction of genetic defects reside outside the exome. A striking example is a recurrent deep intronic mutation of CEP290, accounting for 15% of congenital blindness in Europe and amenable to antisense oligonucleotide (AON)-mediated gene therapy.
Another emerging model for non-coding variation in hereditary blindness is Stargardt disease (STGD), the most frequent RD ultimately leading to legal blindness. The inheritance of STGD is autosomal recessive and it is caused by mutations in the single disease gene ABCA4. Interestingly, only 60% of STGD cases can be explained by bi-allelic coding ABCA4 mutations, leaving 40% of cases unexplained. We and others have strong arguments for the contribution of non-coding changes of the ABCA4 locus to these cases. As gene therapies for STGD are emerging, elucidating its molecular pathogenesis is of utmost importance.


It is our aim to (i) functionally dissect the regulatory landscape of ABCA4; (ii) uncover non-coding variation of the ABCA4 locus in a subset of STGD patients with a single coding ABCA4 mutation; (iii) functionally study the effects of non-coding variations of the ABCA4 locus; (iv) explore AON-mediated rescue for a subset of non-coding mutations.

Last updated: 08 December 2015 - 17:36
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