The genetics of Fanconi's anaemia

Fanconi's anaemia (FA) is an inherited bone marrow failure syndrome characterized by considerable clinical and cellular heterogeneity. This has also been recently demonstrated at the genetic and molecular levels following cloning of four out of the seven FA genes. Although this now enables molecular diagnosis in the majority of patients, because of the considerable molecular heterogeneity, the diepoxybutane/mitomycin-C stress test based on the increased chromosomal instability seen in FA cells, compared to normal controls, remains the front-line diagnostic test. This FA cell hallmark has led to the suggestion that FA may represent a defect in DNA repair although the precise function of the cloned FA genes remains unknown. Recent data suggest that they function in a novel cell pathway which has an important role in maintaining chromosome stability. The advances in the genetics of FA have already had some impact on diagnosis - for example, identification of patients with somatic mosaicism who have atypical clinical presentations- but to date they have had little impact on treatment. However, new treatments may now follow; indeed, for a number of reasons, FA may be a good candidate for haemopoietic gene therapy.