Mona S Awadalla1, John H Fingert2, Benjamin E Roos2, Simon Chen3, Richard Holmes4, Stuart L Graham5, Mark Chehade6, Anna Galanopolous6, Bronwyn Ridge7, Emmanuelle Souzeau7, Tiger Zhou7, Owen M Siggs7, Alex W Hewitt8, David A Mackey8, Kathryn P Burdon9, Jamie E Craig7. 1. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. Electronic address: mona.awadalla@flinders.edu.au. 2. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa. 3. Vitreoretinal Unit, Vision Eye Institute, Sydney, Australia. 4. Palmerston North Hospital, Palmerston North, New Zealand. 5. Australian School of Advanced Medicine, Macquarie University, Sydney, Australia. 6. South Australian Institute of Ophthalmology, Royal Adelaide Hospital, Adelaide, Australia. 7. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. 8. Lions Eye Institute, Perth, Australia. 9. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia; Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Abstract
PURPOSE: To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. DESIGN: A retrospective cohort study. METHODS: DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. RESULTS: Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. CONCLUSION: We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.
PURPOSE: To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. DESIGN: A retrospective cohort study. METHODS: DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. RESULTS: Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucomapatients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucomapatient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. CONCLUSION: We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucomapatients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.
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