Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations

J Med Genet. 2019 May;56(5):308-316. doi: 10.1136/jmedgenet-2018-105635. Epub 2019 Feb 28.


Background: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations.

Methods: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes.

Results: This study included 35 patients who were homozygous or compound heterozygous for the ATM c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the ATM c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with ATM c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with ATM c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for ATM c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the ATM c.8147T>C mutant protein and only at a low level in some patients with ATM c.3576G>A.

Conclusion: Compared with classic A-T, the presence of ATM c.3576G>A results in a milder classic phenotype. Patients with ATM c.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.

Keywords: ataxia telangiectasia; atm gene; clinical genetics; genotype-phenotype; mutations.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Ataxia Telangiectasia / diagnosis*
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / mortality
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Genetic Association Studies*
  • Genotype*
  • Humans
  • Mutation*
  • Phenotype*
  • Prognosis
  • RNA Splice Sites
  • Sequence Deletion
  • Severity of Illness Index


  • RNA Splice Sites
  • Ataxia Telangiectasia Mutated Proteins