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J Med Genet. 2019 Feb 28. pii: jmedgenet-2018-105635. doi: 10.1136/jmedgenet-2018-105635. [Epub ahead of print]

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

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Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Clinical and Molecular Medicine, Sapienza Università di Roma, Rome, Italy.
Department of Pediatrics, Pediatric Infectious Disease and Immunology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
INSERM UMR 830, Institut de recherche, Institut Curie, PSL Research University, Paris, France.
Service de Génétique, Institut Curie Hôpital, Paris, France.
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.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France.
INSERM UMR 1163, Sorbonne Paris Cité, Imagine Institute, Paris Descartes University, Paris, France.
Department of Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Institute of Human Genetics, University of Wurzburg, Wurzburg, Germany.
School for Cancer Studies, University of Birmingham, Birmingham, UK.
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.



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.


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.


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.


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.


ataxia telangiectasia; atm gene; clinical genetics; genotype-phenotype; mutations

Conflict of interest statement

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

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