Retinal Disease Variability in Female Carriers of RPGR Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters

<i>Objectives:</i> We sought to investigate the visual function, retinal features, and genotype-phenotype correlations of an Australian cohort of <i>RPGR</i> carriers. <i>Methods:</i> In this cross-sectional study, we evaluated <i>RPGR</i> carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. <i>RPGR</i> carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype-phenotype relationships in the RPGR carriers were investigated. <i>Results:</i> Thirty-five female <i>RPGR</i> carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for <i>RPGR</i> carriers and controls, respectively (<i>p</i> = 0.26). Most <i>RPGR</i> carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1-7° of the retina differed between phenotypes of <i>RPGR</i> carriers. On average, <i>RPGR</i> carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all <i>p</i> < 0.05) compared to those with exon 1-14 variants. <i>Conclusions:</i> Female <i>RPGR</i> carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in <i>RPGR</i> carriers. The genetic variant alone did not influence retinal phenotype; however, <i>RPGR</i> carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1-14 variants.