Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations.
J Med Genet
; 56(5): 308-316, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30819809
ABSTRACT
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Ataxia Telangiectasia
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Alelos
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Estudos de Associação Genética
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Proteínas Mutadas de Ataxia Telangiectasia
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Genótipo
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Mutação
Tipo de estudo:
Prognostic_studies
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Systematic_reviews
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article