title: Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.
abstract: OBJECTIVE
  To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP).
  
  
  METHODS
  Cross-sectional genetic study.
  
  
  METHODS
  Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania.
  
  
  METHODS
  Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing.
  
  
  RESULTS
  From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy.
  
  
  CONCLUSIONS
  The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Craig
authors.forename: P N
authors.initials: PN
authors.lastname: Baird
authors.forename: D L
authors.initials: DL
authors.lastname: Healey
authors.forename: A I
authors.initials: AI
authors.lastname: McNaught
authors.forename: P J
authors.initials: PJ
authors.lastname: McCartney
authors.forename: J L
authors.initials: JL
authors.lastname: Rait
authors.forename: J L
authors.initials: JL
authors.lastname: Dickinson
authors.forename: L
authors.initials: L
authors.lastname: Roe
authors.forename: J H
authors.initials: JH
authors.lastname: Fingert
authors.forename: E M
authors.initials: EM
authors.lastname: Stone
authors.forename: D A
authors.initials: DA
authors.lastname: Mackey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018389:Codon, Nonsense; D003430:Cross-Sectional Studies; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D015987:Effect Modifier, Epidemiologic; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D018740:Genetic Heterogeneity; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005973:Glutamine; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009898:Optic Disk / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D013648:Tasmania / Q000453:epidemiology; D014794:Visual Fields; D000099179:Myocilin
chemical_list: D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D005973:Glutamine; D006023:Glycoproteins; D000099179:Myocilin