Chromosome fragility in Fanconi anemia patients: diagnostic implications and clinical impact

Abstract

International audienceFanconi anemia (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 DEB or MMC is the gold standard test for the diagnosis of FA. In this study we present data from 198 DEB-induced chromosome fragility tests in non-FA and in FA patients where information on genetic subtype, cell sensitivity to MMC and clinical data were available. This large series allowed us to quantify the variability and the level of overlap in ICL-sensitivity among FA patients and normal population. In this article we propose a new chromosome fragility index that provides a cut-off diagnostic level to unambiguously distinguish FA patients, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analyzed, indicating that, while both variables are correlated, 54% of FA patients do not have spontaneous fragility. Our data reveal a correlation between malformations and sensitivity to ICLs, This correlation is also statistically significant when the analysis is restricted to the patients from the FA-A complementation group and suggests that genome instability during embryo development may be related to malformations in FA. Finally, chromosome fragility does not correlate with the age of onset of hematological disease, indicating that DEB-induced chromosome breaks in T-cells has no prognostic value in FA