Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients

Mutations at the ataxia-telangiectasia (A-T) locus on chromosome band 11q22 cause a distinctive autosomal recessive syndrome in homozygotes and predis pose heterozygotes to cancer, ischemic heart disease, and early mortality. PCR amplification from genomic DNA and automated sequencing of the entire c oding region (66 exons) and splice junctions detected 77 mutations (85%) in 90 A-T chromosomes. Heteroduplex analysis detected another 42 mutations at the A-T locus. Out of a total of 71 unique mutations, 50 were found only i n a single family, and 51 had not been reported previously. Most (58/71, 82 %) mutations were frameshift and nonsense mutations that are predicted to c ause truncation of the A-T protein; the less common mutation types were mis sense (9/71, 13%), splicing (3/71, 4%) and one in-frame deletion, 2546 3 (1 /71, 1%), The mean survival and height distribution of 134 A-T patients cor related significantly with the specific mutations present in the patients. Patients homozygous for a single truncating mutation, typically near the N- terminal end of the gene, or heterozygous for the in-frame deletion 2546 3, were shorter and had significantly shorter survival than those heterozygou s for a splice site or missense mutation, or heterozygous for two truncatin g mutations. Alterations of the length or amino acid composition of the A-T gene product affect the A-T clinical phenotype in different ways. Mutation analysis at the A-T locus may help estimate the prognosis of A-T patients. Am. J, Med, Genet. 92:170-177, 2000. (C) 2000 Wiley-Liss, Inc.