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Genotype–phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations
  1. Nienke J H van Os1,2,
  2. Luciana Chessa3,
  3. Corry M R Weemaes4,
  4. Marcel van Deuren5,
  5. Alice Fiévet6,7,
  6. Judith van Gaalen2,
  7. Nizar Mahlaoui8,9,10,
  8. Nel Roeleveld11,
  9. Christoph Schrader12,
  10. Detlev Schindler13,
  11. Alexander M R Taylor14,
  12. Bart P C Van de Warrenburg2,
  13. Thilo Dörk15,
  14. Michèl A A P Willemsen1
  1. 1 Department of Pediatric Neurology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
  2. 2 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
  3. 3 Department of Clinical and Molecular Medicine, Sapienza Università di Roma, Rome, Italy
  4. 4 Department of Pediatrics, Pediatric Infectious Disease and Immunology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
  5. 5 Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  6. 6 INSERM UMR 830, Institut de recherche, Institut Curie, PSL Research University, Paris, France
  7. 7 Service de Génétique, Institut Curie Hôpital, Paris, France
  8. 8 French National Reference Center for Primary Immune Deficiencies (CEREDIH), Pediatric Immuno-Haematology and Rheumatology Unit, Biostatistics Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  9. 9 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France
  10. 10 INSERM UMR 1163, Sorbonne Paris Cité, Imagine Institute, Paris Descartes University, Paris, France
  11. 11 Department of Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  12. 12 Department of Neurology, Hannover Medical School, Hannover, Germany
  13. 13 Institute of Human Genetics, University of Wurzburg, Wurzburg, Germany
  14. 14 School for Cancer Studies, University of Birmingham, Birmingham, UK
  15. 15 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  1. Correspondence to Nienke J H van Os, Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Nienke.vanOs{at}


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.

  • clinical genetics
  • ataxia telangiectasia
  • atm gene
  • genotype-phenotype
  • mutations
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  • Contributors All authors contributed to revising the work critically for important intellectual content and gave approval for the final version of the manuscript. NJHvO, CMRW and MAAPW conceptualised and designed the study and wrote the manuscript. NJHvO, LC, CMRW, MvD, JvG, CS, DS, NM, AF and TD helped with acquisition of data. NJHvO, CMRW, NR, AMRT, BPVdW and MAAPW analysed and interpreted the results.

  • Funding This study was funded by the Twan Foundation (Veenendaal, the Netherlands).

  • Disclaimer The funder had no involvement.

  • Competing interests BPCvdW receives research support from ZonMW, Hersenstichting, Radboud University Medical Center, and Bioblast Pharma.

  • Patient consent Not required.

  • Ethics approval This study was approved by the Regional Committee on Research involving Human Subjects Arnhem-Nijmegen.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Not published anonymised data are available by request from any qualified investigator for purposes of replication of procedures and results.

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