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

Area of Science:

• Ophthalmology
• Genetics
• Retinal Dystrophy

Background:

• X-linked retinitis pigmentosa (XLRP) is a leading cause of inherited blindness in males.
• RPGR variants, particularly in ORF15, are a common cause of XLRP, often leading to cone-rod dystrophy.
• Genotype-phenotype correlations are established in males, but the phenotype in female carriers remains largely uncharacterized.

Purpose of the Study:

• To define the clinical and imaging phenotype of female carriers of RPGR variants associated with X-linked cone dystrophy.
• To compare the phenotype of female carriers of cone dystrophy-associated RPGR variants with those of rod-cone dystrophy-associated RPGR variants.

Main Methods:

• A case-control study involving 7 female carriers of RPGR variants causing cone dystrophy and 4 female carriers of RPGR variants causing rod-cone dystrophy.
• Ophthalmic examinations, multimodal retinal imaging (fundus autofluorescence, green reflectance, optical coherence tomography, ultra-widefield imaging), and functional testing (microperimetry, electroretinography) were performed.

Main Results:

• Female carriers of cone dystrophy-associated RPGR variants presented with mild visual acuity reduction, photophobia, myopia, and significant astigmatism.
• Retinal imaging revealed a distinct granular hyperautofluorescence limited to the posterior pole and a tapetal-like sheen.
• Cone function was reduced (60.1% of lower normal limit), while rod function remained normal, differentiating them from rod-cone dystrophy carriers.

Conclusions:

• Female carriers of RPGR variants causing X-linked cone dystrophy have a distinct phenotype characterized by mild cone dysfunction and macular abnormalities.
• This phenotype differs from that seen in carriers of RPGR variants causing rod-cone dystrophy.
• The findings suggest that some female carriers may be candidates for gene therapies targeting RPGR-related retinal dystrophies.