Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/105317
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Type: Journal article
Title: Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma
Author: Zhou, T.
Souzeau, E.
Siggs, O.
Landers, J.
Mills, R.
Goldberg, I.
Healey, P.
Graham, S.
Hewitt, A.
Mackey, D.
Galanopoulos, A.
Casson, R.
Ruddle, J.
Ellis, J.
Leo, P.
Brown, M.
Macgregor, S.
Sharma, S.
Burdon, K.
Craig, J.
Citation: Investigative Ophthalmology and Visual Science, 2017; 58(3):1537-1544
Publisher: Association for Research in Vision and Ophthalmology
Issue Date: 2017
ISSN: 0146-0404
1552-5783
Statement of
Responsibility: 
Tiger Zhou, Emmanuelle Souzeau, Owen M. Siggs, John Landers, Richard Mills, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Anna Galanopoulos, Robert J. Casson, Jonathan B. Ruddle, Jonathan Ellis, Paul Leo, Matthew A. Brown, Stuart MacGregor, Shiwani Sharma, Kathryn P. Burdon, Jamie E. Craig
Abstract: 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 = 6.31×10−16). 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.
Keywords: Exome sequencing; OPTN; CYP1B1; LTBP2; MYOC
Rights: Copyright 2017 The Authors. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
RMID: 0030066613
DOI: 10.1167/iovs.16-21049
Grant ID: http://purl.org/au-research/grants/nhmrc/1023911
http://purl.org/au-research/grants/nhmrc/1107098
http://purl.org/au-research/grants/nhmrc/1065433
Appears in Collections:Medicine publications

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