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Importance: Pathogenic variants in retinitis pigmentosa GTPase regulator (RPGR) gene typically lead to a severe form of X-linked retinitis pigmentosa, which is associated with early severe vision loss. Objective: To investigate an X-linked retinal degeneration family with atypical preservation of visual acuity in the presence of a novel deep intronic splice site RPGR c.779-5T>G variant. Design, Setting, and Participants: In this case series, 3 members of an X-linked retinal degeneration family were studied by in-depth phenotyping and genetic screening at a single center. Data were collected and analyzed from November 2018 to March 2020. Main Outcomes and Measures: Data were collected on full ophthalmic history, examination, and retinal imaging. A full retinitis pigmentosa gene panel was analyzed by next-generation sequencing. The pathogenicity of the RPGR c.779-5T>G variant was assessed by in silico splice prediction tools and by purpose-designed in vitro splicing assay. Results: An 84-year-old man was referred with clinical diagnosis of choroideremia and possible inclusion into a gene therapy trial. He presented with late-stage retinal degeneration and unusually preserved visual acuity (78 and 68 ETRDS letters) that clinically resembled choroideremia. His 23-year-old grandson was still in early stages of degeneration but showed a very different clinical picture, typical of retinitis pigmentosa. Next-generation sequencing identified a sole RPGR c.779-5T>G variant of undetermined pathogenicity in both cases. The daughter of the proband showed an RPGR carrier phenotype and was confirmed to carry the same variant. The molecular analysis confirmed that the RPGR c.779-5T>G variation reduced the efficiency of intron splicing compared with wild type, leading to a population of mutant and normal transcripts. The predicted consequences of the pathogenic variant are potential use of an alternative splice acceptor site or complete skipping of exon 8, resulting in truncated forms of the RPGR protein with different levels of glutamylation. Conclusions and Relevance: These results support the importance of careful interpretation of inconsistent clinical phenotypes between family members. Using a molecular splicing assay, a new pathogenic variant in a noncoding region of RPGR was associated with a proportion of normal and hypomorphic RPGR, where cones are likely to survive longer than expected, potentially accounting for the preserved visual acuity observed in this family.

Original publication




Journal article


JAMA Ophthalmol

Publication Date