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

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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.

Originele taal-2	Engels
Pagina's (van-tot)	4123-4133
Aantal pagina's	11
Tijdschrift	Investigative Ophthalmology & Visual Science
Volume	59
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1167/iovs.17-23453
Status	Gepubliceerd - 2018

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10.1167/iovs.17-23453

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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 = "Journal Article",

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",

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

language = "English",

volume = "59",

pages = "4123--4133",

journal = "Investigative Ophthalmology & Visual Science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

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, nr. 10, blz. 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 et al.
In: Investigative Ophthalmology & Visual Science, Vol. 59, Nr. 10, 2018, blz. 4123-4133.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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

Y1 - 2018

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 - Journal Article

U2 - 10.1167/iovs.17-23453

DO - 10.1167/iovs.17-23453

M3 - Article

C2 - 30105367

SN - 0146-0404

VL - 59

SP - 4123

EP - 4133

JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

IS - 10

ER -

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

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