title: OPA1 analysis in an international series of probands with bilateral optic atrophy.
abstract: OBJECTIVE
  To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada.
  
  
  METHODS
  OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 82 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were assessed for pathogenicity by in silico analysis. Segregation of the identified variants was performed in available first degree relatives.
  
  
  RESULTS
  A total of 29 heterozygous mutations evaluated as pathogenic were identified in 42 probands, of these seven were novel. In two probands, only variants of unknown significance were found. 76% of pathogenic mutations observed in 30 (71%) of 42 probands were evaluated to lead to unstable transcripts resulting in haploinsufficiency. Three probands with the following disease-causing mutations c.1230+1G>A, c.1367G>A and c.2965dup were documented to suffer from hearing loss and/or neurological impairment.
  
  
  CONCLUSIONS
  OPA1 gene screening in patients with bilateral optic atrophy is an important part of clinical evaluation as it may establish correct clinical diagnosis. Our study expands the spectrum of OPA1 mutations causing dominant optic atrophy and supports the fact that haploinsufficiency is the most common disease mechanism.
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.|Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Liskova
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Tesarova
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Dudakova
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Stepanka
authors.initials: S
authors.lastname: Svecova
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Kolarova
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzik
authors.affiliation: Cardiff Eye Unit, University Hospital of Wales, Cardiff, UK.|School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Seto
authors.affiliation: Cardiff Eye Unit, University Hospital of Wales, Cardiff, UK.|School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
authors.forename: Marcela
authors.initials: M
authors.lastname: Votruba
mesh_terms: D002170:Canada; D018153:Czech Republic; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D005821:Genetic Techniques; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D006113:United Kingdom
chemical_list: D004247:DNA; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
keywords: 
  OPA1
  ; DOA plus syndrome; dominant optic atrophy; haploinsufficiency; novel mutations