Identification of a new gene for Autosomal Recessive Retinitis Pigmentosa (arRP)

Abstract

Purpose: : Retinitis pigmentosa (RP) is a severe, clinically and genetically heterogeneous retinal disease that inexorably leads to blindness. Mutations in over 50 genes currently explain ~50% of patients. Our goal is to identify the remaining RP genes. We identified a consanguineous French-Canadian family with arRP and aimed to identify the causal gene.

Methods: : We performed APEX (Asper Ophthalmics) technology to exclude ~500 arRP mutations in ~20 genes. Homozygosity mapping (by SNP genotyping), next generation sequencing and exome capture and Sanger sequencing were used to identify all the genetic variations in the family. We then use a pipeline approach, combining co-segregation, retinal expression, exclusion from 500 normal controls and known SNP changes to narrow down the number of variants. We then screened an additional 150 RP patients and 100 more severe ciliopathy patients. The phenotype was investigated using best-corrected visual acuity (VA), Goldmann visual fields (GVF), slit-lamp biomicroscopy, funduscopy, ERG (Diagnosys LLC), in-vivo retinal architecture (Heidelberg engineering), renal ultrasound and biochemical studies.

Results: : Initially, we identified a novel mutation in WDR19, p.L710S, c.2129T>C, which cosegregates perfectly in 2 families. The residue is strictly conserved down to Caenorhabditis elegans. WDR19 is a ciliary protein. We then discovered that most of the probands developed renal cysts with normal kidney function. We then hypothesized that more severe WDR19 mutations may lead to more severe ciliopathy phenotypes. We subsequently found nonsense, splice site, missense and frameshift mutations in WDR19 in patients with Senior-Loken disease (p.L214FfsX5, c.407-2A>G, p.T261LfsX18, p.A30P, p.E103G, p.R272C and p.G109E).

Conclusions: : We have successfully identified a new gene for arRP and a new gene for Senior Loken disease. We are currently investigating the full extent of the mutation spectrum and severity. Our findings are crucial in expanding the current understanding of childhood blindness and identifying new causal genes, new proteins and novel retinal pathways. This work suggests novel avenues for therapeutic interventions.

Keywords: gene/expression • retina • retinal degenerations: hereditary