title: Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations.
abstract: OBJECTIVE
  We identified families with autosomal dominant optic atrophy (ADOA), determined the number and type of OPA1 mutations, and investigated the phenotypic variation and penetrance in ADOA Australian pedigrees.
  
  
  METHODS
  Cross-sectional genetics study.
  
  
  METHODS
  Probands were identified on the basis of characteristic clinical features of ADOA. We screened the OPA1 gene using single-strand conformational polymorphism, heteroduplex analysis (SSCP/HA), or by direct sequencing. Penetrance for pedigrees in which a mutation of OPA1 had been identified was calculated initially using all recruited individuals, and subanalysis was performed using only those families for which there was total recruitment of siblings.
  
  
  RESULTS
  A total of 406 patients from 17 pedigrees were recruited, and OPA1 mutations were identified in 11/17 (65%) of these. The mean age at clinical examination was 38.2 +/- 19.9 years (median age, 35 years; range, four to 83 years). The median best-corrected visual acuity in OPA1-mutation carriers was 20/70 (range, 20/16 to hand movements [HM]). The penetrance in Australian ADOA pedigrees in the families with complete sibling recruitment was 82.5%. On the other hand, overall penetrance for all individuals harboring an OPA1 mutation was 88%.
  
  
  CONCLUSIONS
  OPA1 mutations were identified in 11/17 (65%) of the ADOA pedigrees in this study. The penetrance in our cohort was lower than originally described (82.5% vs 98%) but higher than some recent studies since the availability of genotyping. It is anticipated that this figure would be even lower as more asymptomatic individuals are identified. There are likely to be other genetic and environmental modifiers influencing disease penetrance.
authors.affiliation: Ocular Diagnostic Clinic, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Cohn
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.forename: Catherine
authors.initials: C
authors.lastname: Potter
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Towns
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020180:Heteroduplex Analysis; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D014792:Visual Acuity
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human