title: Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Tiger
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Siggs
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Landers
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Mills
authors.affiliation: University of Sydney Discipline of Ophthalmology, Sydney, Australia 3Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: University of Sydney Discipline of Ophthalmology, Sydney, Australia 4Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Graham
authors.affiliation: University of Tasmania Menzies Institute for Medical Research, Hobart, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: University of Western Australia Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: University of Adelaide, Discipline of Ophthalmology & Visual Sciences, Adelaide, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Galanopoulos
authors.affiliation: University of Adelaide, Discipline of Ophthalmology & Visual Sciences, Adelaide, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Casson
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ellis
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Leo
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia 6University of Tasmania Menzies Institute for Medical Research, Hobart, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000328:Adult; D017668:Age of Onset; D001315:Australia / Q000453:epidemiology; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D005136:Eye Proteins; C502341:WDR36 protein, human; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human