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

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

1 mai 2019Journal of Medical Genetics

DOI : 10.1136/jmedgenet-2018-105635

Auteurs

Nienke J H van Os, Luciana Chessa, Corry M R Weemaes, Marcel van Deuren, Alice Fiévet, Judith van Gaalen, Nizar Mahlaoui, Nel Roeleveld, Christoph Schrader, Detlev Schindler, Alexander M R Taylor, Bart P C Van de Warrenburg, Thilo Dörk, Michèl A A P Willemsen

Résumé

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.