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Marco Nassisi, Giuseppe De Bartolo, Saddek Mohand-Said, Christel Condroyer, Aline Antonio, Marie-Elise Lancelot, Kinga Maria Bujakowska, Vasily M. SMIRNOV, Thomas Pugliese, John Neidhardt, Jose Alain Sahel, Christina Zeitz, Isabelle S Audo; Genotype-phenotype correlation and disease modeling in RPGR-related cone and cone-rod dystrophies.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):138 – A0318.
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© ARVO (1962-2015); The Authors (2016-present)
Variants in the retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal isoform opening reading frame-15 (RPGRORF15) have been associated with rod-cone (RCD), cone and cone-rod dystrophies (CD and CRD). While RPGR-related RCD is well understood, the characteristics and progression of RPGR-related CD/CRD were less frequently investigated. Here, we report the genotyping and genotype-phenotype correlation of a large cohort of patients with RPGR-related CD/CRD.
34 index patients and 2 affected relatives were recruited at the “Quinze-Vingts” Hospital, Paris, France. Genetic screening was performed through direct Sanger sequencing of the RPGRORF15. Phenotypic data were collected retrospectively.
29 distinct variants in RPGRORF15 were identified, of which 27 were frameshift or nonsense and 24 were located towards the 3’ end of the RPGRORF15 transcript. 20 variants are novel sequence alterations. 15 subjects were affected by CD and 19 were diagnosed with CRD. Mean age at last examination was 43,97 ± 11,24 years. Best corrected visual acuity (BCVA) was 0.97 ± 0.71 LogMAR (20/200 Snellen equivalent). The most important predictors of BCVA seem related to morphologic data, with a significant correlation found for the central retinal thickness (β coeff. -0.523, p=0.003), autofluorescence (β coeff. 0.353, p=0.044) and peripapillary sparing (β coeff. -0.376, p=0.031). When analyzing longitudinal data, progressive decline of BCVA was noted, with more than 60% of the patients reaching a BCVA ≥ 1 LogMar in the best eye during their sixth decade of life.
We confirmed that RPGRORF15 variants associated with CD/CRD phenotypes are mostly located within the 3' end of the transcript (C-terminal part of the protein). Several imaging parameters may be useful as prognostic factors in these patients, although prospective longitudinal studies will be needed to confirm these results. The longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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