Over 200 disease genes and loci account for ~50% of cases, leaving dozens of genes awaiting discovery. In addition to non-syndromic RDs, there is a wide range of complex RDs, with accompanying phenotypes varying from red blood cell to skeletal aberrations. A subset of complex RDs has been classified as ciliopathies, a broad spectrum of severe phenotypes caused by mutations in ciliary genes. Intriguingly, a majority of families with retinal ciliopathies display inter- and/or intrafamilial clinical variability, which is presumed to be caused by modifier alleles in other ciliary genes, affecting the interaction with and function of the primary disease gene.

This research grant is part of a larger project aiming to identify such modifier alleles, to explore their mechanism of action and to elucidate ciliary protein networks in vivo. In specific, this research grant focuses on the following objectives:

1. Identification of the primary disease gene in complex RDs. This will be addressed by the characterization of ZBTB25 as a new disease gene for complex RDs.
2. Identification of novel modifier alleles in ciliopathies. In specific, exome sequencing will be performed in two families segregating a ciliopathy with intrafamilial variability.

As a result, this project will contribute to a more refined prognosis of retinal ciliopathies and provide novel basic insights in ciliary biology.