Emmanuelle Souzeau1, Melanie Hayes2, Tiger Zhou1, Owen M Siggs1, Bronwyn Ridge1, Mona S Awadalla1, James E H Smith3, Jonathan B Ruddle4, James E Elder5, David A Mackey6, Alex W Hewitt7, Paul R Healey8, Ivan Goldberg9, William H Morgan10, John Landers1, Andrew Dubowsky2, Kathryn P Burdon11, Jamie E Craig1. 1. Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia. 2. SA Pathology, Flinders Medical Centre, Adelaide, Australia. 3. Department of Ophthalmology, Macquarie University, Royal North Shore Hospital, Sydney, Australia4Department of Ophthalmology, Children's Hospital at Westmead, Sydney, Australia. 4. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. 5. Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia. 6. Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 7. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia7Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia8Menzies Institute fo. 8. Centre for Vision Research, Department of Ophthalmology, Westmead Millennium Institute, University of Sydney, Sydney, Australia. 9. Discipline of Ophthalmology, University of Sydney and Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia. 10. Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia. 11. Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
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.
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.
Authors: Emmanuelle Souzeau; Kathryn P Burdon; Bronwyn Ridge; Andrew Dubowsky; Jonathan B Ruddle; Jamie E Craig Journal: BMC Med Genet Date: 2016-04-14 Impact factor: 2.103
Authors: Tiger Zhou; Emmanuelle Souzeau; Shiwani Sharma; John Landers; Richard Mills; Ivan Goldberg; Paul R Healey; Stuart Graham; Alex W Hewitt; David A Mackey; Anna Galanopoulos; Robert J Casson; Jonathan B Ruddle; Jonathan Ellis; Paul Leo; Matthew A Brown; Stuart MacGregor; David J Lynn; Kathryn P Burdon; Jamie E Craig Journal: PLoS One Date: 2017-03-06 Impact factor: 3.240
Authors: Julia V Stingl; Stefan Diederich; Heidi Diel; Alexander K Schuster; Felix M Wagner; Panagiotis Chronopoulos; Fidan Aghayeva; Franz Grehn; Jennifer Winter; Susann Schweiger; Esther M Hoffmann Journal: J Clin Med Date: 2021-12-21 Impact factor: 4.241