Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Tiger Zhou, Emmanuelle Souzeau, Owen Siggs, John Landers, Richard Mills, Ivan Goldberg, Paul Healey, Stuart Graham, Alex Hewitt, David Mackey, Anna Galanopoulos, Robert Casson, Jonathan Ruddle, Jonathan Ellis, Paul Leo, Matthew Brown, Stuart Macgregor, Shiwani Sharma, Kathryn Burdon, Jamie Craig

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

Keywords

  • CYP1B1
  • Exome sequencing
  • LTBP2
  • MYOC
  • OPTN

Fingerprint Dive into the research topics of 'Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma'. Together they form a unique fingerprint.

Cite this