Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recess ive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebell ar degeneration, immunodeficiency, and cancer predisposition. In this study , 41 AT families from Denmark, Finland, Norway, and Sweden were screened fo r ATM mutations. The protein truncation test (PTT), fragment length and het eroduplex analyses of large (0.8-1.2 kb) cDNA fragments were used, In total , 67 of 82 (82%) of the disease-causing alleles were characterized. Thirty- seven unique mutations were detected of which 25 have not previously been r eported. The mutations had five different consequences for the ATM transcri pt: mutations affecting splicing (43%); frameshift mutations (32%); nonsens e mutations (16%); small in-frame deletions (5%); and one double substituti on (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands, One-third of the probands (13) were homo zygous, whereas the majority of the probands (26) were compound heterozygot e with at least one identified allele. Ten alleles were found more than onc e; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disea se-causing. Some of them even involved partial skipping of exons, leading t o subsequent truncation of the ATM protein. Hum Mutat 16:232-246, 2000. (C) 2000 Wiley-Liss, Inc.