Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss

Emmanuelle Souzeau; Melanie Hayes; Tiger Zhou; Owen M. Siggs; Bronwyn Ridge; Mona S. Awadalla; James E H Smith; Jonathan B. Ruddle; James E. Elder; David A. Mackey; Alex W. Hewitt; Paul R. Healey; Ivan Goldberg; William H. Morgan; John Landers; Andrew Dubowsky; Kathryn P. Burdon; Jamie E. Craig

doi:10.1001/jamaophthalmol.2015.0980

Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss

Emmanuelle Souzeau^*, Melanie Hayes, Tiger Zhou, Owen M. Siggs, Bronwyn Ridge, Mona S. Awadalla, James E H Smith, Jonathan B. Ruddle, James E. Elder, David A. Mackey, Alex W. Hewitt, Paul R. Healey, Ivan Goldberg, William H. Morgan, John Landers, Andrew Dubowsky, Kathryn P. Burdon, Jamie E. Craig

^*Corresponding author for this work

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

16 Citations (Scopus)

Abstract

IMPORTANCE: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. OBJECTIVE: To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. MAIN OUTCOMES AND MEASURES: Identification and characterization of CYP1B1 sequence variants. RESULTS: We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F_1,126 = 5.90; P = .02; partial η_p² = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F_1,122 = 7.18; P = .008; η_p² = 0.06) than patients without CYP1B1 pathogenic variants. CONCLUSIONS AND RELEVANCE: Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.

Original language	English
Pages (from-to)	826-833
Number of pages	8
Journal	JAMA Ophthalmology
Volume	133
Issue number	7
DOIs	https://doi.org/10.1001/jamaophthalmol.2015.0980
Publication status	Published - 1 Jul 2015

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10.1001/jamaophthalmol.2015.0980

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Souzeau, E., Hayes, M., Zhou, T., Siggs, O. M., Ridge, B., Awadalla, M. S., Smith, J. E. H., Ruddle, J. B., Elder, J. E., Mackey, D. A., Hewitt, A. W., Healey, P. R., Goldberg, I., Morgan, W. H., Landers, J., Dubowsky, A., Burdon, K. P., & Craig, J. E. (2015). Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss. JAMA Ophthalmology, 133(7), 826-833. https://doi.org/10.1001/jamaophthalmol.2015.0980

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title = "Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss",

abstract = "IMPORTANCE: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. OBJECTIVE: To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. MAIN OUTCOMES AND MEASURES: Identification and characterization of CYP1B1 sequence variants. RESULTS: We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. CONCLUSIONS AND RELEVANCE: Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.",

author = "Emmanuelle Souzeau and Melanie Hayes and Tiger Zhou and Siggs, {Owen M.} and Bronwyn Ridge and Awadalla, {Mona S.} and Smith, {James E H} and Ruddle, {Jonathan B.} and Elder, {James E.} and Mackey, {David A.} and Hewitt, {Alex W.} and Healey, {Paul R.} and Ivan Goldberg and Morgan, {William H.} and John Landers and Andrew Dubowsky and Burdon, {Kathryn P.} and Craig, {Jamie E.}",

year = "2015",

month = jul,

day = "1",

doi = "10.1001/jamaophthalmol.2015.0980",

language = "English",

volume = "133",

pages = "826--833",

journal = "JAMA Ophthalmology",

issn = "2168-6165",

publisher = "American Medical Association",

number = "7",

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Souzeau, E, Hayes, M, Zhou, T, Siggs, OM, Ridge, B, Awadalla, MS, Smith, JEH, Ruddle, JB, Elder, JE, Mackey, DA, Hewitt, AW, Healey, PR, Goldberg, I, Morgan, WH, Landers, J, Dubowsky, A, Burdon, KP & Craig, JE 2015, 'Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss', JAMA Ophthalmology, vol. 133, no. 7, pp. 826-833. https://doi.org/10.1001/jamaophthalmol.2015.0980

TY - JOUR

T1 - Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss

AU - Souzeau, Emmanuelle

AU - Hayes, Melanie

AU - Zhou, Tiger

AU - Siggs, Owen M.

AU - Ridge, Bronwyn

AU - Awadalla, Mona S.

AU - Smith, James E H

AU - Ruddle, Jonathan B.

AU - Elder, James E.

AU - Mackey, David A.

AU - Hewitt, Alex W.

AU - Healey, Paul R.

AU - Goldberg, Ivan

AU - Morgan, William H.

AU - Landers, John

AU - Dubowsky, Andrew

AU - Burdon, Kathryn P.

AU - Craig, Jamie E.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - IMPORTANCE: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. OBJECTIVE: To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. MAIN OUTCOMES AND MEASURES: Identification and characterization of CYP1B1 sequence variants. RESULTS: We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. CONCLUSIONS AND RELEVANCE: Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.

AB - IMPORTANCE: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. OBJECTIVE: To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. MAIN OUTCOMES AND MEASURES: Identification and characterization of CYP1B1 sequence variants. RESULTS: We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. CONCLUSIONS AND RELEVANCE: Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.

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Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss

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