Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Fabienne Charbit-Henrion 1, 2, 3 Marianna Parlato 1, 3 Sylvain Hanein 4 Rémi Duclaux-Loras 5, 1, 3 Jan Nowak Bernadette Begue 1, 3 Sabine Rakotobe 1, 3 Julie Bruneau 6, 7 Cécile Fourrage 8 Olivier Alibeu 4 Frédéric Rieux-Laucat 9 Eva Lévy 10 Marie-Claude Stolzenberg 9 Fabienne Mazerolles 11 Sylvain Latour 4 Christelle Lenoir 4 Alain Fischer 12, 4, 13, 6, 14, 15 Capucine Picard 6, 16 Marina Aloi Jorge Amil Dias Mongi Ben Hariz Anne Bourrier 17 Christian Breuer Anne Breton 18 Jiri Bronski Stephan Buderus Mara Cananzi Stéphanie Coopman 19 Clara Crémilleux Alain Dabadie 20 Clémentine Dumant-Forest 21 Odul Egritas Gurkan Alexandre Fabre 22 Aude Fischer Marta German Diaz Yago Gonzalez-Lama Olivier Goulet 6, 16 Graziella Guariso Neslihan Gurcan Matjaz Homan Jean-Pierre Hugot 23 Eric Jeziorski 24 Evi Karanika Alain Lachaux 25, 26 Peter Lewindon Rosa Lima Fernando Magro 27 Janos Major Georgia Malamut 28 Emmanuel Mas 29, 30 Istvan Mattyus Luisa M. Mearin Jan Melek Victor Manuel Navas-Lopez Anders Paerregaard Cecile Pelatan 31 Bénédicte Pigneur 2, 1, 3 Isabel Pinto Pais Julie Rebeuh Claudio Romano 32, 3 Nadia Siala 33 Caterina Strisciuglio Michela Tempia-Caliera Patrick Tounian 34, 35 Dan Turner Vaidotas Urbonas Stéphanie Willot 36 Frank M. Ruemmele Nadine Cerf-Bensussan 1
1 Equipe Inserm U1163 - Laboratory of Intestinal Immunity
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
9 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
Abstract : Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment. Methods: 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally. Results: Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitis and perianal lesions and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations previously missed by WES. Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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Submitted on : Friday, October 18, 2019 - 5:49:10 PM
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Fabienne Charbit-Henrion, Marianna Parlato, Sylvain Hanein, Rémi Duclaux-Loras, Jan Nowak, et al.. Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study. Journal of Crohn's and Colitis, Elsevier - Oxford University Press, 2018, ⟨10.1093/ecco-jcc/jjy068⟩. ⟨hal-02320500⟩

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