Clinical and Genetic Landscape of RPGR ‐Associated Retinal Dystrophies in Portugal: Insights From the Nationwide IRD ‐ PT Registry

Background Retinitis pigmentosa GTPase regulator ( RPGR )‐associated retinal dystrophies are among the most severe inherited retinal diseases (IRDs), yet population‐level data from Southern Europe remain scarce. Methods This nationwide, multicentre study characterises the clinical and genetic spectrum of RPGR ‐associated disease in Portugal, integrating multimodal imaging, standardised phenotyping and curated molecular analysis. Results A total of 103 individuals from 40 families (58 males; 45 heterozygous females) were identified using the IRD‐PT registry. Males predominantly manifested X‐linked retinitis pigmentosa (82.8%) with childhood/adolescence onset (mean 13.1 ± 8.8 years), whereas cone/cone‐rod dystrophy (17.2%) presented later in life. Visual acuity in males (mean 0.65 ± 0.54 logMAR) matched international cohorts, showing an age‐dependent decline. Female heterozygotes demonstrated striking variability: although central vision was generally preserved (mean 0.39 ± 0.55 logMAR), fundus autofluorescence (FAF) revealed a wide spectrum from normal to male‐pattern disease. FAF severity correlated strongly with visual acuity, with male‐pattern heterozygotes showing significantly reduced visual acuity. Interocular asymmetry was present in 20.5% of females. Twenty‐nine distinct RPGR variants were identified, including 11 novel; truncating variants predominated, particularly within ORF15, accounting for 63% of genetically confirmed cases. Genotype–phenotype relationships aligned with established patterns, with distal RPGR variants associated with cone‐dominant disease and proximal variants with rod‐cone dystrophy. Conclusions This study provides the first nationwide overview of RPGR ‐associated disease in Portugal, expanding the mutational landscape and reinforcing the clinical utility of FAF phenotyping in female heterozygotes. These findings support harmonised phenotyping and full‐length RPGR sequencing to improve diagnosis, counselling, and readiness for emerging gene‐based therapies.