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The research of my lab focusses on the identification of genetic causes underlying non-syndromic retinal diseases and syndromic diseases comprising retinal dystrophy in the clinical spectrum, such as Usher syndrome (USH) leading to deaf-blindness. Genes for inherited retinal diseases (IRDs) were identified through positional cloning, candidate gene analysis, homozygosity mapping and next-generation sequencing (NGS). In this way, for only 60-70% of all IRDs and USH cases the genetic cause has been identified. The large number of genes underlying IRDs illustrates the high genetic heterogeneity, currently >280 causative genes (RetNet; https://sph.uth.edu/retnet/). While in the early days of genetic studies findings were made relatively easy with multiple families with mutations in the same gene, now this low-hanging fruit is gone. Now, the era has come where usually the supporting evidence is only a single family is found with pathogenic variants in a candidate gene.
The mission of my team is to ‘solve the unsolved IRD-cases through genomics and transcriptomic approaches’ by using 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 PBMCs from blood into induced pluripotent stem cells and differentiate them into photoreceptor progenitor cells. Moreover, by studying structural variants through innovative technologies and approaches we hope to investigate the contribution of the ectopic expression mechanism to the pathogenicity of IRDs. These studies will pinpoint the molecular defects and will enable 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 with the ultimate goal to enable development a genetic therapeutic strategies to inhibit, stop or prevent the progression of disease in the future.