Souzeau, E and Hayes, M and Zhou, T and Siggs, OM and Ridge, B and Awadalla, MS and Smith, JEH and Ruddle, JB and Elder, JE and Mackey, DA and Hewitt, AW and Healey, PR and Goldberg, I and Morgan, WH and Landers, J and Dubowsky, A and Burdon, KP and Craig, JE, Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss, JAMA Ophthalmology, 133, (7) pp. 826-833. ISSN 2168-6165 (2015) [Refereed Article]
Copyright 2015 American Medical Association
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.
|Item Type:||Refereed Article|
|Research Division:||Medical and Health Sciences|
|Research Group:||Ophthalmology and Optometry|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Hearing, Vision, Speech and Their Disorders|
|Author:||Mackey, DA (Professor David Mackey)|
|Author:||Hewitt, AW (Dr Alex Hewitt)|
|Author:||Burdon, KP (Associate Professor Kathryn Burdon)|
|Web of Science® Times Cited:||3|
|Deposited By:||Menzies Institute for Medical Research|
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