The Genetic Basis of Pericentral Retinitis Pigmentosa—A Form of Mild Retinitis Pigmentosa

Abstract

Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.

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

“…Consistent with previous reports [21], we found that pericentral RP is a rather uncommon RP subtype and has extensive genetic heterogeneity. Genetic defects underlying pericentral RP are overall overlapping those causing mild forms of typical RP, as previously suggested [4]. While previous studies [3][4][5] found pericentral RP cases almost exclusively in the context of non-syndromic forms, we observed a high prevalence of pericentral RP within the syndromic RP group, mainly in Usher syndrome.…”

“…Genetic defects underlying pericentral RP are overall overlapping those causing mild forms of typical RP, as previously suggested [4]. While previous studies [3][4][5] found pericentral RP cases almost exclusively in the context of non-syndromic forms, we observed a high prevalence of pericentral RP within the syndromic RP group, mainly in Usher syndrome. In agreement, variants in USH2A were detected in over 40% of the solved cases in our cohort.…”

“…In agreement, variants in USH2A were detected in over 40% of the solved cases in our cohort. A high frequency of USH2A mutations among cases with pericentral RP has not been previously reported [4,5,22,23]. Different studies identified RHO [4,24] or ABCA4 [5] defects as the most common cause.…”

“…Specifically, Matsui et al included only subjects with non-syndromic retinal degenerations, while Grondahl et al analyzed only four genes (RHO, RP1, PRPH2 and IMPDH1) that did not comprise USH2A. Our cohort can be directly compared to the study of Comander et al which recruited 45 cases with pericentral RP without excluding syndromic forms [4]. In that report, USH2A gene defects were identified in 14.3% of solved cases, whereas mutations in the HGSNAT gene (typically responsible for Mucopolysaccharidosis type IIIC [25]) were a relatively common cause of pericentral RP [4].…”

Characterizing variants of unknown significance in rhodopsin: a functional genomics approach

“…The variants that were pathogenic by the functional assay were not uniformly predicted to be damaging based on computational predictions alone ( Table 2). Both of the subjects with the G18D mutation and the one subject with the G101V mutation had a phenotype of pericentral retinitis pigmentosa, as described in further detail (Comander, 2017).…”