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

• Published in: Journal of medical genetics Vol. 56; no. 5; pp. 308 - 316
• Main Authors: van Os, Nienke J H, Chessa, Luciana, Weemaes, Corry M R, van Deuren, Marcel, Fiévet, Alice, van Gaalen, Judith, Mahlaoui, Nizar, Roeleveld, Nel, Schrader, Christoph, Schindler, Detlev, Taylor, Alexander M R, Van de Warrenburg, Bart P C, Dörk, Thilo, Willemsen, Michèl A A P
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2019
• Subjects: Age; Alleles; Ataxia; Ataxia telangiectasia; Ataxia Telangiectasia - diagnosis; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia - mortality; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - genetics; Cancer; Cell cycle; Gene expression; Genetic Association Studies; Genotype; Genotype & phenotype; Genotypes; Humans; Immunodeficiency; Immunoglobulins; Kinases; Laboratories; Life span; Mutation; Neurodegenerative diseases; Patients; Phenotype; Phenotypes; Prognosis; Protein expression; Proteins; Respiratory diseases; RNA Splice Sites; Sequence Deletion; Severity of Illness Index; Tumors; Netherlands; ataxia telangiectasia; atm gene; mutations; genotype-phenotype; clinical genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2018-105635

BackgroundAtaxia 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.MethodsData 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.ResultsThis 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.ConclusionCompared 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.