Genetic Heterogeneity Among Patients with Pericentral Retinitis Pigmentosa

Abstract

Purpose: Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery (Sandberg et al, AJO, 2005). Mutations in the TOPORS gene have been described in selected pericentral RP families (e.g. Selmer et al, Acta Ophthalmol, 2010). This study was performed to further define the overall mutation spectrum in patients with this phenotype. It remains to be determined to what extent pericentral RP could have similar genetic causes as typical RP, or whether the different phenotype of pericentral RP is a reflection of mutations in novel genes or pathways.

Methods: We identified a cohort of 34 patients from separate families with pericentral RP based on a comprehensive analysis of their retinal phenotype. DNA samples were collected from these patients, along with 14 samples from affected and unaffected relatives. A multistage gene discovery approach was used, starting with selective exon capture and next generation sequencing (NGS) to sequence 196 genes previously associated with inherited retinal degenerations. Then the samples without mutations in known genes underwent analyses of copy number variation (CNV) for deletion detection, followed by whole exome sequencing for novel gene discovery.

Results: The selective exon capture/NGS approach provided a mean depth of coverage of the targeted sequences of >124 fold, and >97% of the targeted sequences were covered with ≥10x depth. Mutations provisionally responsible for disease were found in 5 of the first 12 patients analyzed. These include mutations in RHO (4 patients) and PDE6B (1 patient). No mutations were found in TOPORS. Two mutations have been previously identified in patients with more common forms of typical RP and four mutations appeared to be novel. Sequencing analyses in the remainder of the samples is ongoing.

Conclusions: Initial results suggest that some patients with pericentral RP have mutations in the same genes that cause more common forms of typical RP. Further molecular genetic subtyping of the entire cohort, including ongoing whole exome sequencing, will better define the genetic heterogeneity that appears to exist within this clinical phenotype.

Keywords: 696 retinal degenerations: hereditary • 695 retinal degenerations: cell biology • 539 genetics