title: Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.
abstract: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases).
  
  
  
  Retrospective clinical and molecular study.
  
  
  
  Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma.
  
  
  
  Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist.
  
  
  
  Glaucoma clinical parameters and age at presentation.
  
  
  
  At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant.
  
  
  
  Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Souzeau
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.
authors.forename: Kien Hou
authors.initials: KH
authors.lastname: Tram
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Witney
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, Melbourne, Australia; and Ophthalmology, University of Melbourne, Department of Surgery, Melbourne, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.affiliation: Ophthalmology and Vision Science, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, Australia; Discipline of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Sydney, Australia.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Graham
authors.affiliation: Discipline of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Sydney, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Healey
authors.affiliation: Discipline of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Sydney, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, Melbourne, Australia; and Ophthalmology, University of Melbourne, Department of Surgery, Melbourne, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. Electronic address: jamie.craig@flinders.edu.au.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D005902:Glaucoma, Open-Angle / Q000175:diagnosis* / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009798:Ocular Hypertension / Q000175:diagnosis / Q000235:genetics; D010808:Physical Examination; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D012307:Risk Factors; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin