Original article
Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

https://doi.org/10.1016/j.ajo.2014.09.044Get rights and content

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.

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.

Section snippets

Methods

Approval of this retrospective cohort study was obtained from the Southern Adelaide Clinical Human Research Ethics Committee. This study has been conducted in accordance with the Declaration of Helsinki and its subsequent revisions. The committee prospectively approved the recruitment of individuals and family members with primary open-angle glaucoma and its subtypes, the collection of blood or saliva samples for deoxyribonucleic acid extraction, the screening for genetic mutations, the data

Results

TBK1 copy number variations were detected in 4 of 334 Australian cases with normal-tension glaucoma (1.2%) using quantitative polymerase chain reaction assays (Figure 1). Three unrelated probands, GFMC524, AG604, and AG624, were found to have 3 copies of the gene (1 extra dose), while AG724 participant was found to carry 4 total copies of TBK1 (2 extra doses). No copy number variations were detected in any of the unaffected controls. This rate is similar to previously published data where

Discussion

Primary open-angle glaucoma is known to be a genetically heterogeneous disease. Recently, Fingert and associates identified a large duplication within a novel locus (GLC1P) to be associated with primary open-angle glaucoma and its subtype, normal-tension glaucoma, located on chromosome 12q14.15 Although the overlapping duplication encompassed 4 genes (TBK1, XPOT, RASSF3, and GNS), TBK1 was considered the strongest candidate gene for normal-tension glaucoma by virtue of its biology and the

Dr Mona S. Awadalla is a Postdoctoral Fellow at Flinders University, Australia. She earned her MBBS degree in 2007 from Alexandria University, Egypt, and her PhD degree in 2013 from Flinders University. Dr Awadalla main areas of scientific interest are genetics, nanophthalmos and glaucoma.

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    Dr Mona S. Awadalla is a Postdoctoral Fellow at Flinders University, Australia. She earned her MBBS degree in 2007 from Alexandria University, Egypt, and her PhD degree in 2013 from Flinders University. Dr Awadalla main areas of scientific interest are genetics, nanophthalmos and glaucoma.

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