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

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

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    12 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)1537-1544
    Number of pages8
    JournalInvestigative Ophthalmology and Visual Science
    Volume58
    Issue number3
    DOIs
    Publication statusPublished - Mar 2017

    Bibliographical note

    Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

    Keywords

    • exome sequencing
    • OPTN
    • CYP1B1
    • LTBP2
    • MYOC

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