Clinical and Genetic Analysis of a European Cohort with Pericentral Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.

Keywords: USH2A; inherited retinal dystrophies; next generation sequencing; pericentral retinitis pigmentosa.

Figure 1

Ophthalmic features of pericentral RP. (a) Goldmann visual field of a representative pericentral RP patient showing the typical pericentral scotomas and preserved peripheral field. (b) Composite fundus photograph showing the typical retinal phenotype with sparing of far periphery. (c) Fundus autofluorescence (FAF) image illustrating hypo-autofluorescence within and beyond the vascular arcades.

Figure 2

Frequency of causative genes in the pericentral RP cohort. (a) Relative frequency of retinopathy genes mutated in the 23 familial cases with pericentral RP. (b,c) Prevalence for causative variants in genes associated also with syndromic retinopathies and in genes involved in ciliary function.

Figure 3

Example of intrafamiliar phenotypic variability. (a) Pedigree of family n. 3. (b) Sanger sequencing traces of the two variants in exon 8 and exon 14 of the PDE6B gene in the two affected siblings (II:1, II:2) of family n. 3. (c) Composite fundus photograph of the proband (II:2, P4) and his 6 years older affected sister (II:1), revealing typical features of pericentral RP (left hand side) and sector RP (right hand side), respectively.