Identification of Alu-mediated deletions in the Fanconi anemia gene FAA

Fanconi anemia (FA) is an autosomal recessive syndrome associated with hypersensitivity to DNA cross linking agents and predisposition to neoplasia. Eight complementation groups (A-H) have been described, but the only FA genes cloned so far are FAC and FAA. We have recently identified 40 different germline mutations, including microdeletions, microinsertions, and point mutations in ge nomic DNA from 97 FA patients from the International Fanconi Anemia Registry (IFAR) by single strand conformational polymorphism (SSCP) analysis. Interestingly, only one mutant allele was identified in many of these patients. Haplotype analysis with intragenic polymorphisms, as well as cDNA analysis of some patients suggested the presence of large deletions that would not be detected by SSCP analysis. In this study, we report the occurrence of Alu mediated genomic deletions in FAA. Two different deletions of 1.2 kb and 1.9 kb were found. Both deletions include exons 16 and 17 and remove a 156-bp segment from the transcript causing a shorter in frame message. Sequence analysis revealed that introns 15 and 17 are rich in partial and complete Alu repeats. There are at least four head to-tail arranged Alu elements in intron 17 and one in intron 15, all oriented in the 3' --> 5' direction. Sequence analysis of the deletions showed that the 5' breakpoints occurred at different sites in the same Alu element in intron 15, while the 3' breakpoints were located in different Alu repeats in intron 17. Numerous Alu repeats are present in FAA, suggesting that Alu-mediated recombination might be an important mechanism for the generation of FAA mutations. Hum Mutat 12:145-152, 1998. (C) 1998 Wiley-Liss, Inc.