ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions.

In patients affected by Ataxia-Telangiectasia (A-T), mutations in the ATM gene lead to loss-of-function alleles. Nonsense, splice-site variants, small insertions or deletions (frameshifts) and missense are the most commonly found mutations. Large genomic deletions (LGDs) are rare (approximately 1%) but can lead to the same phenotype. In compound heterozygotes, deletions are not detected by most screening strategies. We analysed the ATM gene in 12 unrelated Italian A-T patients and identified all 24 mutated alleles. Twelve mutations were novel. Standardized SNP and STR haplotyping followed by DHPLC screening of genomic DNA, allowed all but three mutations to be detected (approximately 87.5%). The remaining mutations required RT-PCR analysis of ATM transcript and Southern blotting of genomic DNA. We found three LGDs: one of 8.5 and two identical of 18 kb spanning exons 32-36 and 21-29, respectively. The breakpoints of these deletions were sequenced in an attempt to understand the mechanisms of mutations; both deletions involved regions rich in repeated elements.