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Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Jérôme Hadjadj 1 Nathalie Aladjidi 2, 3 Helder Fernandes 2, 3 Guy Leverger 4 Aude Magérus-Chatinet 1 Fabienne Mazerolles 1 Marie-Claude Stolzenberg 1 Sidonie Jacques 1 Capucine Picard 5, 6 Jeremie Rosain 5, 6 Cécile Fourrage 7, 8 Sylvain Hanein 5 Mohammed Zarhrate 8, 5 Marlene Pasquet 9 Wadih Chahla 10 Vincent Barlogis 11 Yves Bertrand 12, 13 Isabelle Pellier 14 Elodie Colomb Bottollier 15 Fanny Fouyssac 16 Pascale Blouin 17 Caroline Thomas 18 Nathalie Cheikh 19 Eric Dore 20 Corinne Pondarre 21 Dominique Plantaz 22 Eric Jeziorski 23 Frédéric Millot 24 Nicolas Garcelon 5, 25 Stéphane Ducassou 2, 3 Yves Perel 2, 3 Thierry Leblanc 26 Bénédicte Neven 1, 6 Alain Fischer 5, 27, 6 Frédéric Rieux-Laucat 5
1 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 CIC Bordeaux
3 CEREVANCE - Centre de Référence National des Cytopénies Auto-immunes de l'Enfant
4 Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau]
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 CHU Necker - Enfants Malades [AP-HP]
7 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
9 Hôpital des Enfants
10 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
11 Service d'hématologie pédiatrique
12 UMR AGAP - Amélioration génétique et adaptation des plantes méditerranéennes et tropicales
13 HCL - Hospices Civils de Lyon, Departement de Neurologie
14 Service d'Immuno-Hémato-Oncologie Pédiatrique
15 CHU Dijon
16 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
17 CHRU TOURS - Centre Hospitalier Régional Universitaire de Tours
18 CHU Nantes - Centre hospitalier universitaire de Nantes
19 CHRU Besançon - Centre Hospitalier Régional Universitaire [Besançon]
20 CHU Clermont-Ferrand
21 IMRB - Institut Mondor de Recherche Biomédicale
22 CHU - Centre Hospitalier Universitaire [Grenoble]
23 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
24 CHU Poitiers - Centre hospitalier universitaire de Poitiers
25 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
26 Hôpital Robert Debré
27 CDF - Collège de France
Abstract : Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
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Contributor : Frédéric Rieux-Laucat <>
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INRA | HCL | IMRB | UNAM | CDF | UPEC-UPEM | UPEC | AGROPOLIS | CIRAD | UNIV-PARIS5 | UNIV-AMU | SORBONNE-UNIVERSITE | UNIV-PARIS7 | CORDELIERS | EPHE | PSL | USPC | CNRS | MONTPELLIER-SUPAGRO | SU-SCIENCES | INRAE | UP-SANTE

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Jérôme Hadjadj, Nathalie Aladjidi, Helder Fernandes, Guy Leverger, Aude Magérus-Chatinet, et al.. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Blood, American Society of Hematology, 2019, 134 (1), pp.9-21. ⟨10.1182/blood-2018-11-887141.⟩. ⟨inserm-02439240⟩

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