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Original Investigation | Ophthalmic Molecular Genetics

TBK1 Gene Duplication and Normal-Tension Glaucoma

Robert Ritch, MD1; Ben Darbro, MD, PhD2,3; Geeta Menon, MD4; Cheryl L. Khanna, MD5; Frances Solivan-Timpe, BS3,6; Ben R. Roos, BS3,6; Mansoor Sarfarzi, PhD7; Kazuhide Kawase, MD8; Tetsuya Yamamoto, MD8; Alan L. Robin, MD9,10,11; Andrew J. Lotery, MD12; John H. Fingert, MD, PhD3,6
[+] Author Affiliations
1Einhorn Clinical Research Center, New York Eye and Ear Infirmary, New York
2Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City
3Institute for Vision Research, University of Iowa, Iowa City
4Department of Ophthalmology, Frimley Part Hospital, Surrey, United Kingdom
5Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
6Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City
7Department of Surgery, University of Connecticut Health Center, Farmington
8Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan
9Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland
10Department of International Health, Johns Hopkins University, Baltimore, Maryland
11Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
12Southampton Eye Unit, Southampton General Hospital, Southampton, United Kingdom
JAMA Ophthalmol. 2014;132(5):544-548. doi:10.1001/jamaophthalmol.2014.104.
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Importance  Normal-tension glaucoma (NTG) is a common cause of vision loss.

Objective  To investigate the role of TANK binding kinase 1 (TBK1) gene duplications in NTG to gain insights into the causes of glaucoma that occurs at low intraocular pressure (IOP).

Design, Setting, and Participants  In this multicenter case-control study, we investigated patients who met the criteria for NTG, including glaucomatous optic neuropathy, visual field defects, and maximum recorded untreated IOP of 21 mm Hg or less, and matched controls. Participants (N = 755) were recruited from Southampton, United Kingdom (180 patients and 178 controls), Rochester, Minnesota (65 patients and 12 controls), New York, New York (96 patients and 16 controls), and Iowa City, Iowa (208 controls).

Main Outcomes and Measures  Detection of TBK1 gene duplications and comparison of the extent of the identified DNA that is duplicated with prior TBK1 copy number variations associated with NTG.

Results  A TBK1 gene duplication was detected in 1 of 96 patients (1.0%) from New York and none of the controls. Analysis of duplication borders with comparative genome hybridization demonstrated that this patient has a novel duplication that has not been previously reported. No gene duplications were detected in any of the other cohorts of patients or controls.

Conclusions and Relevance  Duplication of the TBK1 gene is a rare cause of NTG. The identification of another case of NTG attributed to TBK1 gene duplication strengthens the case that this mutation causes glaucoma.

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Figure 1.
TBK1 Gene Duplications

The position and extent of each of the detected TBK1 gene duplications and their relationship to flanking genes are shown using the current human genome build (hg19).18,19 Duplications in normal-tension glaucoma pedigrees GGO-441, GGA-416, GGA-1159, and GGJ-414 were previously reported (using the hg18 genome build). kbp indicates kilobase pair.

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Figure 2.
Patient GGR-590-1 Clinical Data

A, Disc photographs at 56 years of age that demonstrate significant cupping. Humphrey visual field tests (24-2 Swedish Interactive Thresholding Algorithm Standard) performed at 53 years of age (B), 56 years of age (C), 59 years of age (D), and 64 years of age (E) demonstrate progressive glaucomatous visual field loss despite maximum intraocular pressure of 12 mm Hg in both eyes.

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