Defining a Novel RPGR Phenotype of Sector Retinitis Pigmentosa With Cone Dystrophy

Purpose: RPGRORF15-associated retinal degeneration is characterized by clinical and genetic heterogeneity: Proximal mutations typically result in rod-cone dystrophy, distal mutations in cone-dominated disease, and mutations within open-reading frame 15 (ORF15) in either phenotype. This study characterizes an intermediate phenotype in which patients exhibit a combination of cone dystrophy and incomplete (sectoral) rod-cone dystrophy associated with mutations in the ORF15 region and explores potential mechanistic explanations. Methods: A multinational, multicenter, observational, cross-sectional case series was conducted using databases from RPGR-related retinal dystrophy clinical trial referral centers. Patients with molecularly confirmed RPGR-related cone dystrophy or RPGR-related cone-rod dystrophy were studied. Individuals exhibiting a mixed phenotype of cone dystrophy and sectoral retinitis pigmentosa were identified. In silico analyses assessed the impact of identified mutations on RPGR transcript expression and protein structure. Results: Fourteen patients exhibited a cone dystrophy phenotype with bilateral, symmetrical regions of outer retinal atrophy distributed along the inferior vascular arcades and extending nasally. All harbored ORF15 mutations within a defined transitional zone. All of the mutations were predicted to produce truncated proteins with partial or complete loss of function. Additionally, several were predicted to disrupt splicing regulatory elements. Conclusions: An intermediate phenotype consisting of a cone dystrophy with sectoral retinitis pigmentosa development was characterized. These patients may benefit from full-length RPGR gene therapy. Furthermore, we demonstrate that this rare presentation closely resembles the phenotype observed in some patients with loss-of-function TTLL5-associated cone dystrophy with sectoral involvement.