LOCALIZATION OF THE FANCONI-ANEMIA COMPLEMENTATION GROUP-A GENE TO CHROMOSOME 16Q24.3

Fanconi anaemia (FA) is an autosomal recessive disorder associated wit h diverse developmental abnormalities, bone-marrow failure and predisp osition to cancer(1). FA cells show increased chromosome breakage and hypersensitivity to DNA cross-linking agents such as diepoxybutane and mitomycin C. Somatic-cell hybridisation analysis of FA cell lines has demonstrated the existence of at least five complementation groups (F A-A to FA-E)(2,3), the most common of which is FA-A(4). This genetic h eterogeneity has been a major obstacle to the positional cloning of FA genes by classical linkage analysis. The FAC gene was cloned by funct ional complementation(5), and localised to chromosome 9q22.3 (ref. 2), but this approach has thus far failed to yield the genes for the othe r complementation groups. We have established a panel of families clas sified as FA-A by complementation analysis, and used them to search fo r the FAA gene by linkage analysis. We excluded the previous assignmen t by linkage(6) of an FA gene to chromosome 20q, and obtained conclusi ve evidence for linkage of FAA to microsatellite markers on chromosome 16q24.3. Strong evidence of allelic association with the disease was detected with the marker D16S303 in the Afrikaner population of South Africa, indicating the presence of a founder effect.