Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: Maximum entropy estimates of splice junction strengths

Ataxia‐telangiectasia (A‐T) is an autosomal recessive neurological disorder caused by mutations in the ATM gene. Classical splicing mutations (type I) delete entire exons during pre‐mRNA splicing. In this report, we describe nine examples of nonclassical splicing mutations in 12 A‐T patients and compare cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fall into three categories: pseudoexon insertions (type II), single nucleotide changes within the exon (type III), and intronic changes that disrupt the conserved 3′ splice sequence and lead to partial exon deletion (type IV). Four patients with a previously reported type II (pseudoexon) mutation all shared a common founder haplotype. Three patients with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five patients had type IV mutations that could have been misinterpreted as classical splicing mutations. Instead, their mutations disrupt a splice site and use another AG splice site located nearby within the exon; they lead to partial deletions at the beginning of exons. These nonclassical splicing mutations create frameshifts that result in premature termination codons. Without screening cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted. This may lead to further misinterpretation of genotype–phenotype correlations and may subsequently impact upon gene‐based therapeutic approaches. Hum Mutat 23:67–76, 2004. © 2003 Wiley‐Liss, Inc.