The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene

Mays Talib, Mary J van Schooneveld, Caroline Van Cauwenbergh, Jan Wijnholds, Jacoline B Ten Brink, Ralph J Florijn, Nicoline E Schalij-Delfos, Gislin Dagnelie, Maria M van Genderen, Elfride de Baere, Magda A Meester-Smoor, Julie de Zaeytijd, Frans P M Cremers, L Ingeborgh van den Born, Alberta A Thiadens, Carel B Hoyng, Caroline C Klaver, Bart P Leroy, Arthur A Bergen, Camiel J F Boon

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Abstract

Purpose: The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations.

Methods: This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families.

Results: Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter).

Conclusions: RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

Original languageEnglish
Pages (from-to)4123-4133
Number of pages11
JournalInvestigative Ophthalmology & Visual Science
Volume59
Issue number10
DOIs
Publication statusPublished - 2018

Keywords

  • Journal Article

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