Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma

© 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 policyImportance 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

Fastpac visual field screening

Publishers' version is restricted in accordance with the Taylor & Francis policy.In epidemiology, screening for visual field defects has traditionally been expensive, time consuming and laborious. To achieve cost-and time effective visual field screening, a faster algorithm has been developed for the Humphrey perimeter called Fastpac, which is designed to achieve threshold perimetry in two-thirds the time of the standard algorithm.We compared Fastpac and conventional full-threshold 24-2 fields obtained in 39 eyes of 36 participants. We divided the participants' fields into normal (14) and glaucomatous (25) visual field groups, and compared the test times, number of questions asked and statistical parameters generated for each field for Fastpac as compared to the standard algorithm.Then we divided the participants' fields into Fastpac and standard fields and again compared the test times, number of questions and statistical parameters.Finally we asked trained observers to judge the fields as being normal or abnormal, in a masked fashion, and found a high degreee of agreement between the fields generated by Fastpac and standard.Fastpac offers accurate full-threshold screening in two-thirds the time of the conventional algorithm and would be very useful for large scale prevalence studies in ophthalmic epidemiology

Five-year incidence of open-angle glaucoma: the Visual Impairment Project

Publisher version is restricted access in accordance with the publisher's policy. The original publication is available at http://www.ncbi.nlm.nih.gov/pubmed/12045042Purpose: To determine the incidence of open-angle glaucoma (OAG) in Melbourne, Victoria, Australia.Design: Population-based cohort study.Participants: Total of 3271 participants aged 40 years and older from Melbourne, Victoria, Australia.Main Outcome Measures: Five-year incidence of OAG. Methods: Particpants were recruited through a cluster random sampling from nine urban clusters. Baseline examination was conducted from 1992 through 1994, and the follow-up data were collected from 1997 through 1999. Each participant both at baseline and follow-up underwent a standardized ophthalmic examination including intraocular pressure measurement, visual field assessment, cup-to-disc ratio measurement, and paired stereo photographs of the optic disc. Glaucoma was assessed by a consensus group of six ophthalmologists that included two glaucoma specialists. Glaucoma was diagnosed as possible, probable, or definite. Results: The overall incidence of definite OAG was 0.5% (95% confidence limits [CL], 0.3, 0.7); probable and definite incidence of OAG was 1.1% (95%CL, 0.8, 1.4); and possible, probable, and definite OAG incidence was 2.7% (95% CL, 1.8, 3.7). The incidence of possible, probable, and definite OAG increases significantly as age increases (P<0.001). The incidence of definite OAG increases from 0% of participants aged 40 to 49 years to 4.1% of participants aged 80 years and older. The incidence of probable and definite OAG increases from 0.2% of participants 40 to 49 years to 5.4% o participants aged 80 years and older. The incidence of possible, probable, and definiete OAG increases from 0.5% of participants aged 40 to 49 years to 11% of participants aged 80 years and older. A nonsignificant but higher incidence of definite OAG among men was observed in this study when compared with women (odds ratio 2.2%; 95% CL, 0.9, 5.0). Fifty percent of the definite OAG participants were undiagnosed. Conclusion: The incidence of OAG increases significantly with age. The undiagnosed cases suggest the need to develop novel community screening strategies for glaucoma

Comparison between Fastpac and conventional Humphrey perimetry

Publisher's version is restricted access in accordance with the publisher's policy.As part of the Melbourne Visual Impairment Project, a substudy was performed to determine the efficacy of the newly released Fastpac program for the Humphrey Field Analyser. A comparison was performed of the Fastpac and conventional full threshold 24-2 fields obtained in 39 eyes of 36 participants. Also a comparison study was performed of the standard and non-standard 80-point screening tests to the standard 24-2 full threshold test in 23 eyes of 23 participants.In the full threshold comparison there was 100% agreement between the two with Fastpac being 32% to 39% faster than standard. In the 80-point screening test comparison, nonstandard was no faster than standard. Sensitivities were 17/17 (1.0) for nonstandard and 15/18 (0.83) for standard, as compared with the standard 24-2 full threshold test.Fastpac software offers accurate screening and threshold testing in less time than the standard algorithm

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. CORRECTION: Please note a corrigendum has been published by teh authors on 12 Oct 2017, and appears below.Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes