title: Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: SA Pathology, Flinders Medical Centre, Adelaide, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hayes
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Tiger
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Siggs
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Ridge
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Mona S
authors.initials: MS
authors.lastname: Awadalla
authors.affiliation: Department of Ophthalmology, Macquarie University, Royal North Shore Hospital, Sydney, Australia4Department of Ophthalmology, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: James E H
authors.initials: JE
authors.lastname: Smith
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.affiliation: Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Elder
authors.affiliation: Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: 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.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Centre for Vision Research, Department of Ophthalmology, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.affiliation: Discipline of Ophthalmology, University of Sydney and Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia.
authors.forename: William H
authors.initials: WH
authors.lastname: Morgan
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Landers
authors.affiliation: SA Pathology, Flinders Medical Centre, Adelaide, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dubowsky
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001315:Australia; D002648:Child; D015331:Cohort Studies; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D015994:Incidence; D007429:Intraocular Pressure / Q000235:genetics / Q000502:physiology; D008297:Male; D009154:Mutation; D012042:Registries; D018570:Risk Assessment; D012607:Scotoma / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D012720:Severity of Illness Index; D012737:Sex Factors; D014794:Visual Fields / Q000235:genetics*; D055815:Young Adult
chemical_list: C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1