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

doi:10.1167/iovs.17-23453

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

Medical retina and Uveitis

Research output: Contribution to journal › Article › Research › peer-review

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 language	English
Pages (from-to)	4123-4133
Number of pages	11
Journal	Investigative ophthalmology & visual science
Volume	59
Issue number	10
DOIs	https://doi.org/10.1167/iovs.17-23453
Publication status	Published - 1 Aug 2018

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Child
Child, Preschool
Eye Proteins/genetics
Female
Heterozygote
Humans
Middle Aged
Myopia/complications
Phenotype
Retinal Pigment Epithelium/pathology
Retinitis Pigmentosa/genetics
Retrospective Studies
Visual Acuity/physiology
Young Adult

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Talib, M., van Schooneveld, M. J., Van Cauwenbergh, C., Wijnholds, J., Ten Brink, J. B., Florijn, R. J., Schalij-Delfos, N. E., Dagnelie, G., van Genderen, M. M., De Baere, E., Meester-Smoor, M. A., De Zaeytijd, J., Cremers, F. P. M., van den Born, L. I., Thiadens, A. A., Hoyng, C. B., Klaver, C. C., Leroy, B. P., Bergen, A. A., & Boon, C. J. F. (2018). The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene. Investigative ophthalmology & visual science, 59(10), 4123-4133. https://doi.org/10.1167/iovs.17-23453

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title = "The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene",

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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Eye Proteins/genetics, Female, Heterozygote, Humans, Middle Aged, Myopia/complications, Phenotype, Retinal Pigment Epithelium/pathology, Retinitis Pigmentosa/genetics, Retrospective Studies, Visual Acuity/physiology, Young Adult",

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

year = "2018",

month = aug,

day = "1",

doi = "10.1167/iovs.17-23453",

language = "English",

volume = "59",

pages = "4123--4133",

number = "10",

}

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 & visual science, vol. 59, no. 10, pp. 4123-4133. https://doi.org/10.1167/iovs.17-23453

TY - JOUR

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 - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Child

KW - Child, Preschool

KW - Eye Proteins/genetics

KW - Female

KW - Heterozygote

KW - Humans

KW - Middle Aged

KW - Myopia/complications

KW - Phenotype

KW - Retinal Pigment Epithelium/pathology

KW - Retinitis Pigmentosa/genetics

KW - Retrospective Studies

KW - Visual Acuity/physiology

KW - Young Adult

U2 - 10.1167/iovs.17-23453

DO - 10.1167/iovs.17-23453

M3 - Article

C2 - 30105367

VL - 59

SP - 4123

EP - 4133

IS - 10

ER -

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

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Keywords

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