PT  - JOURNAL ARTICLE
AU  - Nienke J H van Os
AU  - Luciana Chessa
AU  - Corry M R Weemaes
AU  - Marcel van Deuren
AU  - Alice Fiévet
AU  - Judith van Gaalen
AU  - Nizar Mahlaoui
AU  - Nel Roeleveld
AU  - Christoph Schrader
AU  - Detlev Schindler
AU  - Alexander M R Taylor
AU  - Bart P C Van de Warrenburg
AU  - Thilo Dörk
AU  - Michèl A A P Willemsen
TI  - Genotype–phenotype correlations in ataxia telangiectasia patients with <em>ATM</em> c.3576G>A and c.8147T>C mutations
AID  - 10.1136/jmedgenet-2018-105635
DP  - 2019 May 01
TA  - Journal of Medical Genetics
PG  - 308--316
VI  - 56
IP  - 5
4099  - http://jmg.bmj.com/content/56/5/308.short
4100  - http://jmg.bmj.com/content/56/5/308.full
SO  - J Med Genet2019 May 01; 56
AB  - 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.