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

Zhou, Tiger, Souzeau, Emmanuelle, Siggs, Owen M., Landers, John, Mills, Richard, Goldberg, Ivan, Healey, Paul R. , Graham, Stuart, Hewitt, Alex W, Mackey, David A., Galanopoulos, Anna, Casson, Robert J., Ruddle, Jonathan B., Ellis, Jonathan, Leo, Paul, Brown, Matthew A., Macgregor, Stuart, Sharma, Shiwani, Burdon, Kathryn P. and Craig, Jamie E. (2017) Contribution of mutations in known Mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma. Investigative Ophthalmology & Visual Science, 58 3: 1537-1544. doi:10.1167/iovs.16-21049

Author Zhou, Tiger
Souzeau, Emmanuelle
Siggs, Owen M.
Landers, John
Mills, Richard
Goldberg, Ivan
Healey, Paul R.
Graham, Stuart
Hewitt, Alex W
Mackey, David A.
Galanopoulos, Anna
Casson, Robert J.
Ruddle, Jonathan B.
Ellis, Jonathan
Leo, Paul
Brown, Matthew A.
Macgregor, Stuart
Sharma, Shiwani
Burdon, Kathryn P.
Craig, Jamie E.
Title Contribution of mutations in known Mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma
Journal name Investigative Ophthalmology & Visual Science   Check publisher's open access policy
ISSN 1552-5783
Publication date 2017-03-01
Sub-type Article (original research)
DOI 10.1167/iovs.16-21049
Open Access Status DOI
Volume 58
Issue 3
Start page 1537
End page 1544
Total pages 8
Place of publication Rockville, MD, United States
Publisher Association for Research in Vision and Ophthalmology
Language eng
Formatted 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 ninetythree 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 = 6.31310-16).

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.
Keyword CYP1B1
Exome sequencing
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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