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

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.

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.

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.

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.