SEQUENCE VARIATION IN THE FANCONI-ANEMIA GENE FAA

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy, The gene f or FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no ho mologies to any known protein that might suggest a function for FAA, W e have used single-strand conformational polymorphism analysis to scre en genomic DNA from a panel of 97 racially and ethnically diverse FA p atients from the International Fanconi Anemia Registry for mutations i n the FAA gene, A total of 85 variant bands were detected, Forty-five of the variants are probably benign polymorphisms, of which nine are c ommon and can be used for various applications, including mapping stud ies for other genes in this region of chromosome 16q. Amplification re fractory mutation system assays were developed to simplify their detec tion. Forty variants are likely to be pathogenic mutations, Seventeen of these are microdeletions/microinsertions associated with short dire ct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA repli cation, A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790 del) revealed that they are carried on about 2% and 5% of the FA allel es, respectively, 3788-3790del appears in a variety of ethnic groups a nd is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mech anism recognized as important for the generation of germ-line and soma tic mutations in a variety of cancer-related genes, including p53, APC , RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.