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dc.contributor.authorSiggs, Owen Men_US
dc.contributor.authorSouzeau, Emmanuelleen_US
dc.contributor.authorPasutto, Francescaen_US
dc.contributor.authorDubowsky, Andrewen_US
dc.contributor.authorSmith, James E Hen_US
dc.contributor.authorTaranath, Deepa Aen_US
dc.contributor.authorPater, John Brianen_US
dc.contributor.authorRait, Julian Len_US
dc.contributor.authorNarita, Andrewen_US
dc.contributor.authorMauri, Luciaen_US
dc.contributor.authorDel Longo, Alessandraen_US
dc.contributor.authorReis, Andreen_US
dc.contributor.authorChappell, Angela Jen_US
dc.contributor.authorKearns, Lisa Aen_US
dc.contributor.authorStaffieri, Sandra Een_US
dc.contributor.authorElder, James Een_US
dc.contributor.authorRuddle, Jonathan Ben_US
dc.contributor.authorHewitt, Alex Wen_US
dc.contributor.authorBurdon, Kathryn Penelopeen_US
dc.contributor.authorMackey, David Aen_US
dc.contributor.authorCraig, Jamie Een_US
dc.date.accessioned2019-01-22T03:19:07Z
dc.date.available2019-01-22T03:19:07Z
dc.date.issued2019-01-17
dc.identifier.issn2168-6165
dc.identifier.urihttp://hdl.handle.net/2328/38873
dc.description© 2019 American Medical Association. Reproduced in accordance with the publisher's Public Access policy. This author accepted manuscript is made available following 12 month embargo from date of publication (January 2019) in accordance with the publisher’s archiving policyen_US
dc.description.abstractImportance 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.en_US
dc.language.isoenen_US
dc.publisherAmerican Medical Associationen_US
dc.relationhttp://purl.org/au-research/grants/nhmrc/1023911en_US
dc.rights© 2019 American Medical Associationen_US
dc.titlePrevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucomaen_US
dc.typeArticleen_US
dc.relation.grantnumbernhmrc/1023911en_US
dc.identifier.doihttps://doi.org/10.1001/jamaophthalmol.2018.5646en_US
dc.rights.holderAmerican Medical Associationen_US
local.contributor.authorOrcidLookupSiggs, Owen M: https://orcid.org/0000-0003-2840-4851en_US
local.contributor.authorOrcidLookupSouzeau, Emmanuelle: https://orcid.org/0000-0002-2015-6577en_US
local.contributor.authorOrcidLookupCraig, Jamie E: https://orcid.org/0000-0001-9955-9696en_US


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