Owen M Siggs1, Emmanuelle Souzeau1, Francesca Pasutto2, Andrew Dubowsky3, James E H Smith4,5,6, Deepa Taranath1, John Pater1, Julian L Rait7,8, Andrew Narita9, Lucia Mauri10, Alessandra Del Longo11, André Reis2, Angela Chappell1, Lisa S Kearns7,8, Sandra E Staffieri7,8,12, James E Elder12,13, Jonathan B Ruddle7,8,12, Alex W Hewitt7,8,14, Kathryn P Burdon1,14, David A Mackey14,15, Jamie E Craig1. 1. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. 2. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. SA Pathology, Flinders Medical Centre, Adelaide, Australia. 4. Department of Ophthalmology, Children's Hospital at Westmead, Sydney, Australia. 5. Discipline of Ophthalmology, University of Sydney, Sydney, Australia. 6. Department of Ophthalmology, Macquarie University, Sydney, Australia. 7. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. 8. Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia. 9. Geelong Eye Centre, Geelong, Australia. 10. Medical Genetics Unit, Department of Laboratory Medicine, l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy. 11. Pediatric Ophthalmology Unit, l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy. 12. Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia. 13. Department of Paediatrics, University of Melbourne, Melbourne, Australia. 14. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 15. Centre for Ophthalmology and Visual Science and Lions Eye Institute, University of Western Australia, Perth, Australia.
Abstract
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.
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.
Authors: Owen M Siggs; Mona S Awadalla; Emmanuelle Souzeau; Sandra E Staffieri; Lisa S Kearns; Kate Laurie; Abraham Kuot; Ayub Qassim; Thomas L Edwards; Michael A Coote; Erica Mancel; Mark J Walland; Joanne Dondey; Anna Galanopoulous; Robert J Casson; Richard A Mills; Daniel G MacArthur; Jonathan B Ruddle; Kathryn P Burdon; Jamie E Craig Journal: Clin Genet Date: 2020-03-05 Impact factor: 4.438
Authors: Mallika Prem Senthil; Lachlan S W Knight; Deepa Taranath; David A Mackey; Jonathan B Ruddle; Mark Y Chiang; Owen M Siggs; Emmanuelle Souzeau; Jamie E Craig Journal: Cornea Date: 2022-03-30 Impact factor: 3.152
Authors: Elena Lang; Samuel Koller; Luzy Bähr; Marc Töteberg-Harms; David Atac; Françoise Roulez; Angela Bahr; Katharina Steindl; Silke Feil; Wolfgang Berger; Christina Gerth-Kahlert Journal: Transl Vis Sci Technol Date: 2020-06-30 Impact factor: 3.283
Authors: Emmanuelle Souzeau; Owen M Siggs; Francesca Pasutto; Lachlan S W Knight; Luis A Perez-Jurado; Lesley McGregor; Shannon Le Blanc; Christopher P Barnett; Jan Liebelt; Jamie E Craig Journal: Am J Med Genet A Date: 2020-11-24 Impact factor: 2.578