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

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)4123-4133
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number10
DOIs
StatePublished - Aug 1 2018

Fingerprint

Heterozygote
Pedigree
Genes
Visual Acuity
Mutation
Retinitis Pigmentosa
Myopia
Phenotype
Visual Fields
Retina
Exons
Cohort Studies
Retrospective Studies

Keywords

  • Disease progression
  • Gene therapy
  • Retinitis pigmentosa
  • Retinitis pigmentosa GTPase regulator

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Talib, M., van Schooneveld, M. J., Van Cauwenbergh, C., Wijnholds, J., Ten Brink, J. B., Florijn, R. J., ... Boon, C. J. F. (2018). The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene. Investigative Ophthalmology and Visual Science, 59(10), 4123-4133. https://doi.org/10.1167/iovs.17-23453

The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene. / Talib, Mays; van Schooneveld, Mary J.; Van Cauwenbergh, Caroline; Wijnholds, Jan; Ten Brink, Jacoline B.; Florijn, Ralph J.; Schalij-Delfos, Nicoline E.; Dagnelie, Gislin; van Genderen, Maria M.; De Baere, Elfride; Meester-Smoor, Magda A.; De Zaeytijd, Julie; Cremers, Frans P.M.; van den Born, L. Ingeborgh; Thiadens, Alberta A.; Hoyng, Carel B.; Klaver, Caroline C.; Leroy, Bart P.; Bergen, Arthur A.; Boon, Camiel J.F.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 10, 01.08.2018, p. 4123-4133.

Research output: Contribution to journalArticle

Talib, M, van Schooneveld, MJ, Van Cauwenbergh, C, Wijnholds, J, Ten Brink, JB, Florijn, RJ, Schalij-Delfos, NE, Dagnelie, G, van Genderen, MM, De Baere, E, Meester-Smoor, MA, De Zaeytijd, J, Cremers, FPM, van den Born, LI, Thiadens, AA, Hoyng, CB, Klaver, CC, Leroy, BP, Bergen, AA & Boon, CJF 2018, 'The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene', Investigative Ophthalmology and Visual Science, vol. 59, no. 10, pp. 4123-4133. https://doi.org/10.1167/iovs.17-23453
Talib, Mays ; van Schooneveld, Mary J. ; Van Cauwenbergh, Caroline ; Wijnholds, Jan ; Ten Brink, Jacoline B. ; Florijn, Ralph J. ; Schalij-Delfos, Nicoline E. ; Dagnelie, Gislin ; van Genderen, Maria M. ; De Baere, Elfride ; Meester-Smoor, Magda A. ; De Zaeytijd, Julie ; Cremers, Frans P.M. ; van den Born, L. Ingeborgh ; Thiadens, Alberta A. ; Hoyng, Carel B. ; Klaver, Caroline C. ; Leroy, Bart P. ; Bergen, Arthur A. ; Boon, Camiel J.F. / The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 10. pp. 4123-4133.
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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.",
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T1 - The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene

AU - Talib, Mays

AU - van Schooneveld, Mary J.

AU - Van Cauwenbergh, Caroline

AU - Wijnholds, Jan

AU - Ten Brink, Jacoline B.

AU - Florijn, Ralph J.

AU - Schalij-Delfos, Nicoline E.

AU - Dagnelie, Gislin

AU - van Genderen, Maria M.

AU - De Baere, Elfride

AU - Meester-Smoor, Magda A.

AU - De Zaeytijd, Julie

AU - Cremers, Frans P.M.

AU - van den Born, L. Ingeborgh

AU - Thiadens, Alberta A.

AU - Hoyng, Carel B.

AU - Klaver, Caroline C.

AU - Leroy, Bart P.

AU - Bergen, Arthur A.

AU - Boon, Camiel J.F.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Disease progression

KW - Gene therapy

KW - Retinitis pigmentosa

KW - Retinitis pigmentosa GTPase regulator

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