Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy

PURPOSE:Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian decent with only few reports of North African descent. METHODS:Genome, targeted next-generation and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium (RPE) cells and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS:Here we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in four independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the RPE and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin associated (SOUBA) domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the SOUBA domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION:Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.