Introduction

From its first description as an inherited disorder, progress in our understanding of Fanconi's anemia (FA) has depended heavily on exploitation of its genetic features. This chapter summarizes our knowledge of three aspects relating to the genetic basis of FA: cellular phenotypes, genetic heterogeneity, and the identification of defective genes.

Cellular phenotypes

The cellular features of chromosome instability and sensitivity to DNA crosslinking agents were the first to be systematically described in FA. Schroeder and co-workers (Schroeder et al., 1964, 1976) were the first to suggest that spontaneous chromosomal breakage is a cellular marker for FA. However, longitudinal studies have revealed variation in the frequency of baseline breakage within the same FA patient, ranging from no breakage to high levels, thus reducing the usefulness of this feature. Cellular phenotypes are much more specific to FA when DNA-damaging agents are used, especially those that lead to the formation of crosslinks. The sensitivity of FA cells to a variety of DNA crosslinking agents has been extensively studied (Auerbach and Wolman, 1976; Poll et al., 1982; Sasaki and Tonomura, 1973) and, as a result, the hypersensitivity of FA cells to the clastogenic effect of crosslinking agents is now considered to be a unique FA cellular marker.

Based on the work of Auerbach and colleagues on the sensitivity to diepoxybutane (DEB) (Auerbach, 1993), most investigators and clinicians consider that the diagnosis of FA requires an increased cellular sensitivity to one or more DNA crosslinking agents.