Retrospective Natural History Study of RPGR-Related Cone- and Cone-Rod Dystrophies While Expanding the Mutation Spectrum of the Disease

Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGR(ORF15)) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, the characteristics and progression of RPGR-related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype–phenotype correlations specifically in RPGR(ORF15)-related CD/CRDs. This retrospective longitudinal study included 34 index patients and two affected relatives with a molecular diagnosis of RPGR-related CD/CRDs. Patients were recruited at the “Quinze-Vingts” Hospital, Paris, France and screened for mutations in RPGR(ORF15) at the Institut de la Vision, Paris, France. We identified 29 distinct variants, of which 27 were truncating. All were located in the 3′ half of the RPGR(ORF15) transcript. Twenty of them were novel. Fifteen subjects were affected by CD, the remaining had CRD. When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. To our knowledge, this is the largest described study of a cohort of CD/CRD patients affected by RPGR(ORF15) variants. Longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages.