Genotypic and phenotypic landscape of novel RPGR variants in patients from Western Canada

To evaluate the breadth of RPGR gene variants in a cohort of Canadian inherited retinal dystrophy patients.

A retrospective cohort analysis.

We evaluated 54 subjects in Western Canada with an inherited retinal dystrophy diagnosis and confirmed variants in the RPGR gene.

Clinical information collected included family history, age, sex, and ethnicity. All participants underwent a full ophthalmic examination, wide-field colour fundus photography, fundus autofluorescence imaging, and visual field testing. Pathogenicity of variants was assessed by comparison to genetic databases of disease-causing variants and in silico modelling.

Correlation of genotype with clinical phenotype established a conclusive molecular diagnosis in 34/54 cases (62.9%), with either retinitis pigmentosa (31 cases), cone-rod dystrophy (1 case) or macular dystrophy (2 cases). In the remaining cases, 18 novel RPGR variants were identified comprising 3 nonsense, 5 frameshift, 6 duplications/deletions, 3 missense and 1 splicing variant. Using in silico modelling, 3 novel variants were classified as pathogenic, and 6 were classified as likely pathogenic, increasing the diagnostic rate to 79.6%. Only 3.8% of the cohort were South Asian compared to the local population statistic of 13.5%. Ten of 13 female RPGR carriers were symptomatic and displayed moderate-to-severe phenotypic characteristics.

Through genetic testing, we identified 18 novel RPGR variants, of which 9 were determined to be pathogenic or likely pathogenic. RPGR variants were not a significant cause of retinal dystrophy in South Asians. Female RPGR carriers with visual deficits are likely to be a significant cohort for future RPGR gene therapy trials or treatment modalities.