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

Am J Med Genet. 2000 May 29;92(3):170-7. doi: 10.1002/(sici)1096-8628(20000529)92:3<170::aid-ajmg3>;2-#.


Mutations at the ataxia-telangiectasia (A-T) locus on chromosome band 11q22 cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer, ischemic heart disease, and early mortality. PCR amplification from genomic DNA and automated sequencing of the entire coding 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 in a single family, and 51 had not been reported previously. Most (58/71, 82%) mutations were frameshift and nonsense mutations that are predicted to cause truncation of the A-T protein; the less common mutation types were missense (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 correlated 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 heterozygous for a splice site or missense mutation, or heterozygous for two truncating 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / mortality
  • Ataxia Telangiectasia / physiopathology
  • Body Height
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 11 / genetics*
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation*
  • Heteroduplex Analysis
  • Humans
  • Male
  • Phenotype
  • Point Mutation*
  • Polymerase Chain Reaction
  • RNA Splicing
  • Survival Rate