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Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma


Zhou, T and Souzeau, E and Siggs, OM and Landers, J and Mills, R and Goldberg, I and Healey, PR and Graham, S and Hewitt, AW and Mackey, DA and Galanopoulos, A and Casson, RJ and Ruddle, JB and Ellis, J and Leo, P and Brown, MA and MacGregor, S and Sharma, S and Burdon, KP and Craig, JE, Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma, Investigative Ophthalmology and Visual Science, 58, (3) pp. 1537-1544. ISSN 0146-0404 (2017) [Refereed Article]


Copyright Statement

Copyright 2017 The Authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (

DOI: doi:10.1167/iovs.16-21049


Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG.

Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes.

Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.3110-16).

Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

Item Details

Item Type:Refereed Article
Keywords:exome sequencing, OPTN, CYP1B1, LTBP2, MYOC
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
UTAS Author:Mackey, DA (Professor David Mackey)
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
ID Code:117997
Year Published:2017
Web of Science® Times Cited:9
Deposited By:Menzies Institute for Medical Research
Deposited On:2017-06-30
Last Modified:2018-06-05
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