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Hum Mutat. 2019 May 3. doi: 10.1002/humu.23778. [Epub ahead of print]

Functional classification of ATM variants in ataxia-telangiectasia patients.

Author information

1
Institut Curie, PSL Research University, INSERM U830, Paris, France.
2
Institut Curie, Hôpital, Service de Génétique, Paris, France.
3
CHU de Toulouse, Service de Génétique Médicale, Toulouse, France.
4
Hopital des enfants de Toulouse, Unité de Neuropédiatrie, Toulouse, France.
5
CHU de Strasbourg, Service de Neurologie, Strasbourg, France.
6
CHU de Grenoble, Pole de Psychiatrie et de Neurologie, Grenoble, France.
7
CH de la côte Basque, Service de Neurologie, Bayonne, France.
8
Département des Maladies du Système Nerveux, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Paris, France.
9
Hôpitaux universitaires Pitié Salpêtrière - Charles Foix, Service de Génétique, Paris, France.
10
Hôpital Necker Enfants Malades, Service d'Immunologie, d'Hématologie et de Rhumatologie Pédiatriques, Paris, France.
11
Hôpital Necker Enfants Malades, Service d'Hématologie Adulte, Paris, France.
12
Hôpital Necker Enfants Malades, Service de Neurologie Pédiatrique, Paris, France.
13
CHU de Montpellier, Service de Neuropédiatrie, Montpellier, France.
14
CHU de Bordeaux, Service de Pédiatrie, Bordeaux, France.
15
CHU de Bordeaux, Département de Neurologie, Bordeaux, France.
16
Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc & Université Catholique de Louvain, Brussels, Belgium.
17
Hopital Armand Trousseau, Service de Neurologie Pédiatrique, Paris, France.
18
CH intercommunal de Créteil, Service de Pédiatrie, Créteil, France.
19
Hôpital Raymond Poincaré, Pôle de Pédiatrie, Garches, France.
20
Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France.
21
Hopital d'Enfants de Dijon, Service de Génétique, Dijon, France.
22
CH de Bretagne sud, Site du Scorff, Service de Pédiatrie, Lorient, France.
23
CH de Mulhouse, Service de Génétique, Mulhouse, France.
24
CHU de St Etienne, Hôpital Nord, Service de Génétique Médicale, Saint Etienne, France.
25
CHU de Nancy, Service de Neurologie, Nancy, France.
26
CHU Nancy, Hôpitaux de Brabois, Service de Pédiatrie II, Vandoeuvre, France.
27
Département de Génétique Médicale, Hopital de la Timone, Marseille, France.
28
Hopital Debrousse, Service d'Hématologie Pédiatrique, Lyon, France.
29
GH Cochin-saint-Vincent de Paul, Service d'Endocrinologie et de Neurologie Pédiatrique, Paris, France.
30
CHU de Clermont-Ferrand, Hôtel Dieu, Service de Pédiatrie B, Clermont-Ferrand, France.
31
CHU Besançon, Service de Pédiatrie, Besançon, France.
32
Unité de Génétique Clinique Pédiatrique, Hopital d'Amiens-Nord, Amiens, France.
33
CH d'Aix en Provence - du Pays d'Aix, Service de Pédiatrie, Aix en Provence, France.
34
Gynecology Research Unit, Hannover Medical School, Hannover, Germany.
35
Gustave Roussy, Service Génétique des Tumeurs, Villejuif, France.
36
Centre de ressources Biologiques, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
37
University Paris Descartes, Sorbonne Paris Cité, Paris, France.

Abstract

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

KEYWORDS:

ataxia-telangiectasia; ataxia-telangiectasia mutated (ATM); checkpoint; mutation; phenotype; splice

PMID:
31050087
DOI:
10.1002/humu.23778

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