Blindness Genetics

Genes for IRDs were identified through positional cloning, candidate gene analysis, homozygosity mapping and next-generation sequencing (NGS). In this way >80% of the genetic causes were identified. In my team we found 9 of 22 genes implicated in arCD or arCRD, 6 of 21 genes mutated in arLCA, and 13 of 55 genes involved in arRP. In addition, we discovered 2 of 5 genes mutated in familial exudative vitreoretinopathy.

To identify the remaining causes for IRDs, we employ whole exome sequencing (WES) and whole genome sequencing (WGS). In addition we search for deep-intronic variants by analyzing the RNA of genes that are expressed exclusively in the retina. To obtain retinal RNA from patients, we reprogram fibroblasts into induced pluripotent stem cells and differentiate them into photoreceptor progenitor cells; for more info, see: https://www.radboudumc.nl/en/research/radboud-technology-centers/stem-cells. These studies will pinpoint the molecular defects and will enable a more accurate recurrence risk estimate.

Moreover, gathering such molecular data will result in a better clinical classification which will aid in a more accurate prognosis, and might identify patients that are eligible for future clinical gene therapy trials. It is our aim to identify the remaining causative retinal dystrophy genes and genetic defects underlying retinal dystrophy in the Netherlands before 2025.