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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 Abou 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, 6, 27 Frédéric Rieux-Laucat 5 
1 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
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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Submitted on : Tuesday, January 14, 2020 - 3:09:55 PM
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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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