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Prevalence of FOXC1 variants in individuals with a suspected diagnosis of primary congenital glaucoma


Siggs, OM and Souzeau, E and Pasutto, F and Dubowsky, A and Smith, JEH and Taranath, D and Pater, J and Rait, JL and Narita, A and Mauri, L and Del Longo, A and Reis, A and Chappell, A and Kearns, LS and Staffieri, SE and Elder, JE and Ruddle, JB and Hewitt, AW and Burdon, KP and Mackey, DA and Craig, JE, Prevalence of FOXC1 variants in individuals with a suspected diagnosis of primary congenital glaucoma, JAMA Ophthalmology, (January) pp. E1-E8. ISSN 2168-6165 (2019) [Refereed Article]


Copyright Statement

Copyright 2019 American Medical Association.

DOI: doi:10.1001/jamaophthalmol.2018.5646


Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma.

Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma.

Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017.

Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them.

Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome.

Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
UTAS Author:Mackey, DA (Professor David Mackey)
ID Code:131185
Year Published:2019
Web of Science® Times Cited:19
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-03-06
Last Modified:2022-08-29
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