Jasmina Cehajic-Kapetanovic, Michelle E. McClements, Jennifer Whitfield, Morag Shanks, Penny Clouston, Robert E. MacLaren | JAMA Ophthalmoly | 2020 September 4 | Vol 138, Issue 11 | 1151-58  | doi:10.1001/jamaophthalmol.2020.3634
Key Question
"Can a mild RPGR phenotype be explained by impaired splicing caused by a novel pathogenic variant?"
ResultsÂ
"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 RelevanceÂ
"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."
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