Abstract
PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR.
Highlights
Retinitis pigmentosa (RP) is a common type of inherited retinal degenerations (IRD) characterized by impaired dark adaptation and night blindness, progressive visual field defects and pigmentary retinopathy, affecting approximately one in 3,500–4,000 people worldwide (Berger et al, 2010; Traboulsi, 2010; Sundaram et al, 2012; Zhang, 2016)
Genotype–phenotype correlation was investigated by statistical analyses on different groups of patients with likely pathogenic variants of RPGR according to the variants in certain regions
Among the 46 likely pathogenic variants, nine missense variants, one in-frame variant and 17 truncation variants were located in exon1-14, and the remaining 19 truncation variants were located in ORF15 (Table 1)
Summary
Retinitis pigmentosa (RP) is a common type of inherited retinal degenerations (IRD) characterized by impaired dark adaptation and night blindness, progressive visual field defects and pigmentary retinopathy, affecting approximately one in 3,500–4,000 people worldwide (Berger et al, 2010; Traboulsi, 2010; Sundaram et al, 2012; Zhang, 2016). X-linked RP is one of the most severe forms of human retinal degeneration (Bird, 1975). Variants in retinitis pigmentosa GTPase regulator (RPGR, OMIM 312610) account for 70–80% (Sharon et al, 2003; Pelletier et al, 2007; Shu et al, 2007) of X-linked RP cases. This protein localizes to the connecting cilium in photoreceptors and is thought to play a role in protein transport (Roepman et al, 2000; Hong et al, 2003)
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