Phenotypic Manifestations in Female Carriers of RPGR ORF15 Variants Causing X-Linked Cone Dystrophy

Importance: Recent insights into impaired glutamylation caused by distal truncating variants in RPGR ORF15 and its association with the cone-dominated phenotype have provided the first molecular evidence of a genotype-phenotype correlation in male individuals with X-linked RPGR-related retinal dystrophy, though this correlation remains unexplored in female carriers. Objective: To characterize the clinical phenotype in female carriers of RPGR variants causing X-linked cone dystrophy in hemizygous male individuals. Design, Setting, and Participants: This case-control study was conducted at a specialist genetics clinic from May to December 2024. A total of 11 patients were examined, including female carriers with RPGR variants causing cone dystrophy (n = 7) and age-similar female carriers of RPGR variants causing rod-cone dystrophy as controls (n = 4). Exposures: RPGR variants associated with X-linked cone dystrophy in hemizygous male individuals. Main Outcomes and Measures: Results of ophthalmic examination, multimodal retinal imaging, and functional testing. Results: Seven female carriers aged 11 to 71 years were identified from RPGR cone dystrophy pedigrees. Visual acuity ranged from 6/4.8 to 6/7.5 (Snellen, 20/16 to 20/25), and 4 of the 7 participants experienced photophobia. Myopia and high cylindrical powers were common (6/7 [86%]), with myopia greater than -6.00 D in 2 patients. Fundus autofluorescence imaging revealed a diffuse, granular hyperautofluorescence pattern limited to the posterior pole, compared with the typical spoke pattern that extended into the far periphery in female carriers from RPGR rod-cone pedigrees. Green reflectance imaging most sensitively detected an abnormality in the form of an en face tapetallike sheen, which colocalized with a hyperreflective outer retinal band observed on optical coherence tomography. Ultra-widefield retinal imaging demonstrated no peripheral abnormalities. A mosaic pattern of reduced retinal sensitivity was found within the central 20° on microperimetry, which did not correlate with features observed on retinal imaging. Normal rod responses were measured on electroretinography, but average cone responses were 60.1% of the lower normal limit compared with 36% in male probands. Conclusions and Relevance: This study identified a distinct phenotype in female carriers of RPGR variants causing X-linked cone dystrophy. In this cohort, the phenotype was consistent with mild cone dysfunction and anatomical macular changes. Depending on X-inactivation skew and rate of disease progression, some female carriers may be suitable for emerging gene therapies currently in clinical trials for affected male individuals.