title: Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry.
abstract: OBJECTIVE
  To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort.
  
  
  METHODS
  Cross-sectional study using a national disease registry.
  
  
  METHODS
  One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma.
  
  
  METHODS
  Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation.
  
  
  METHODS
  Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG.
  
  
  RESULTS
  This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers.
  
  
  CONCLUSIONS
  The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention.
  
  
  BACKGROUND
  The author(s) have no proprietary or commercial interest in any materials discussed in this article.
authors: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.
authors: Emmanuelle
authors: E
authors: Souzeau
authors: Kathryn P
authors: KP
authors: Burdon
authors: Andrew
authors: A
authors: Dubowsky
authors: Scott
authors: S
authors: Grist
authors: Bronwyn
authors: B
authors: Usher
authors: Jude T
authors: JT
authors: Fitzgerald
authors: April
authors: A
authors: Crawford
authors: Alex W
authors: AW
authors: Hewitt
authors: Ivan
authors: I
authors: Goldberg
authors: Richard A
authors: RA
authors: Mills
authors: Jonathan B
authors: JB
authors: Ruddle
authors: John
authors: J
authors: Landers
authors: David A
authors: DA
authors: Mackey
authors: Jamie E
authors: JE
authors: Craig
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D044362:Australasia / Q000453:epidemiology; D003430:Cross-Sectional Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D016133:Polymerase Chain Reaction; D015995:Prevalence; D012042:Registries; D014794:Visual Fields / Q000502:physiology; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin