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

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.

To characterize the clinical phenotype in female carriers of RPGR variants causing X-linked cone dystrophy in hemizygous male individuals.

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).

RPGR variants associated with X-linked cone dystrophy in hemizygous male individuals.

Results of ophthalmic examination, multimodal retinal imaging, and functional testing.

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.

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.