Genetic findings of inherited retinal diseases in France

Abstract

Inherited retinal diseases (IRDs) are a major cause of retinal degeneration leading to progressive blindness with limited therapeutic options. The last decades have seen promising therapeutic development urging for a better characterization and understanding of IRDs. The genetics of IRDs is heterogeneous but the advent of high throughput sequencing including whole genome sequencing have greatly accelerated our capacity to identify their genetic cause, which is a prerequisite for adequate genetic counselling and developing innovative treatments. The success rate in detecting the genetic cause is however far from being complete with about 30% of cases that remains unresolved. Since the establishment of our group in 2007, we are working on a large cohort of patients (more than 8000 cases) with annual growth of 800 cases clinically investigated at the rare disease center REFERET of the Quinze‐Vingts hospital, Paris, France. By analysing >1000 cases with IRDs we delivered prevalence data and genotype–phenotype correlations of known gene defects. Furthermore, our group was successful in identifying 8 novel gene defects and novel phenotype–genotype associations in non‐syndromic and syndromic IRDs. Using Sanger sequencing, targeted next generation sequencing and whole exome sequencing we detect in ~70% of the cases with IRDs the underlying gene defect. Subsequently, the remaining cases are analysed by whole genome sequencing (WGS) and either identify missed structural and deep intronic variants in known genes or novel candidate genes. One challenge with current genomic‐based technologies is the capacity to unravel numerous genetic variants that are difficult to interpret in the context of the disease. Therefore, there is a need to conduct systematic studies associated with relevant functional validation to better decipher underlying gene defects that will lead to an enhanced understanding of the disease and improve patients' care. To validate the pathogenic role of a novel candidate gene and to further investigate the pathogenic mechanism, we developed a pipeline combining WGS, functional assays and disease modelling using induced pluripotent stem cells and more recently using zebrafish modelling. This revealed selected genetically unresolved families on which WGS analysis was performed and functional assays were initiated.