title: Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact.
abstract: BACKGROUND
  Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA.
  
  
  OBJECTIVE
  To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA.
  
  
  METHODS
  Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available.
  
  
  RESULTS
  This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease.
  
  
  CONCLUSIONS
  This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, and Pediatric Haemato-Oncology Service, Hospital Materno-Infantil Vall d'Hebron, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Castella
authors.forename: Roser
authors.initials: R
authors.lastname: Pujol
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: José A
authors.initials: JA
authors.lastname: Casado
authors.forename: Maria
authors.initials: M
authors.lastname: Talavera
authors.forename: Teresa
authors.initials: T
authors.lastname: Ferro
authors.forename: Arturo
authors.initials: A
authors.lastname: Muñoz
authors.forename: Julián
authors.initials: J
authors.lastname: Sevilla
authors.forename: Luis
authors.initials: L
authors.lastname: Madero
authors.forename: Elena
authors.initials: E
authors.lastname: Cela
authors.forename: Cristina
authors.initials: C
authors.lastname: Beléndez
authors.forename: Cristina Díaz
authors.initials: CD
authors.lastname: de Heredia
authors.forename: Teresa
authors.initials: T
authors.lastname: Olivé
authors.forename: José Sánchez
authors.initials: JS
authors.lastname: de Toledo
authors.forename: Isabel
authors.initials: I
authors.lastname: Badell
authors.forename: Jesús
authors.initials: J
authors.lastname: Estella
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Dasí
authors.forename: Antonia
authors.initials: A
authors.lastname: Rodríguez-Villa
authors.forename: Pedro
authors.initials: P
authors.lastname: Gómez
authors.forename: María
authors.initials: M
authors.lastname: Tapia
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinés
authors.forename: Ángela
authors.initials: Á
authors.lastname: Figuera
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D002873:Chromosome Fragility; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005199:Fanconi Anemia / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009030:Mosaicism; D010641:Phenotype
chemical_list: D003432:Cross-Linking Reagents; D004852:Epoxy Compounds; D016685:Mitomycin; C007366:diepoxybutane