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Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact
  1. Maria Castella1,2,
  2. Roser Pujol1,2,
  3. Elsa Callén1,2,
  4. Maria J Ramírez1,2,
  5. José A Casado2,3,
  6. Maria Talavera4,
  7. Teresa Ferro4,
  8. Arturo Muñoz5,
  9. Julián Sevilla6,
  10. Luis Madero6,
  11. Elena Cela7,
  12. Cristina Beléndez7,
  13. Cristina Díaz de Heredia8,
  14. Teresa Olivé8,
  15. José Sánchez de Toledo8,
  16. Isabel Badell9,
  17. Jesús Estella10,
  18. Ángeles Dasí11,
  19. Antonia Rodríguez-Villa12,
  20. Pedro Gómez12,
  21. María Tapia13,
  22. Antonio Molinés14,
  23. Ángela Figuera15,
  24. Juan A Bueren2,3,
  25. Jordi Surrallés1,2
  1. 1Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona Spain
  2. 2Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
  3. 3Hematopoiesis and Gene Therapy Division, CIEMAT, Madrid, Spain
  4. 4Medical Genetics Department, Hospital Ramón y Cajal, Madrid, Spain
  5. 5Pedriatic Oncology Service, Hospital Ramón y Cajal, Madrid, Spain
  6. 6Pedriatic Haematology Service, Hospital Niño Jesús, Madrid, Spain
  7. 7Pedriatic Onco-Haematology Service, Hospital Gregorio Marañón, Madrid, Spain
  8. 8Pedriatic Haemato-Oncology Service, Hospital Materno-Infantil Vall d'Hebron, Barcelona, Spain
  9. 9Pedriatic Haematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  10. 10Haematology Service, Hospital Sant Joan de Deu, Esplugues, Spain
  11. 11Pedriatic Haematology Service, Hospital Universitario la Fe, Valencia, Spain
  12. 12Hematology Service, Hospital Reina Sofía, Córdoba, Spain
  13. 13Hematology Service Hospital General de La Palma, Santa Cruz de La Palma, Spain
  14. 14Haematology Service, Hospital Materno Infantil, Las Palmas, Spain
  15. 15Haematology Service, Hospital La Princesa, Madrid, Spain
  1. Correspondence to Professor Jordi Surrallés, Group of Genome Instability and DNA Repair. Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Campus de Bellaterra s/n, 08193 Bellaterra, Barcelona, Spain; jordi.surralles{at}


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.

  • Diagnostics tests
  • genetics
  • cytogenetics
  • haematology (including blood transfusion)

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  • Funding This work was funded by the Generalitat de Catalunya (SGR0489-2009), the La Caixa Fundation Oncology Program (BM05-67-0), Fundación Genoma España, the Spanish Ministry of Science and Innovation (projects FIS PI06-1099, CB06/07/0023, SAF2006-3440, SAF2009-11936, SAF2009-07164 and PLE 2009-0100), the Commission of the European Union (project RISC-RAD FI6R-CT-2003-508842 and VII FWP PERSIST 222878), and the European Regional Development Funds. CIBERER is an initiative of the Instituto de Salud Carlos III.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Universitat Autonoma de Barcelona Ethical Committee on Human Research.

  • Provenance and peer review Not commissioned; externally peer reviewed.