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

Fabienne Charbit-Henrion, Marianna Parlato, Sylvain Hanein, Rémi Duclaux-Loras, Jan Nowak, Bernadette Begue, Sabine Rakotobe, Julie Bruneau, Cécile Fourrage, Olivier Alibeu, Frédéric Rieux-Laucat, Eva Lévy, Marie-Claude Stolzenberg, Fabienne Mazerolles, Sylvain Latour, Christelle Lenoir, Alain Fischer, Capucine Picard, Marina Aloi, Jorge Amil DiasMongi Ben Hariz, Anne Bourrier, Christian Breuer, Anne Breton, Jiri Bronski, Stephan Buderus, Mara Cananzi, Stéphanie Coopman, Clara Crémilleux, Alain Dabadie, Clémentine Dumant-Forest, Odul Egritas Gurkan, Alexandre Fabre, Aude Fischer, Marta German Diaz, Yago Gonzalez-Lama, Olivier Goulet, Graziella Guariso, Neslihan Gurcan, Matjaz Homan, Jean-Pierre Hugot, Eric Jeziorski, Evi Karanika, Alain Lachaux, Peter Lewindon, Rosa Lima, Fernando Magro, Janos Major, Georgia Malamut, Emmanuel Mas, Istvan Mattyus, Luisa M Mearin, Jan Melek, Victor Manuel Navas-Lopez, Anders Paerregaard, Cecile Pelatan, Bénédicte Pigneur, Isabel Pinto Pais, Julie Rebeuh, Claudio Romano, Nadia Siala, Caterina Strisciuglio, Michela Tempia-Caliera, Patrick Tounian, Dan Turner, Vaidotas Urbonas, Stéphanie Willot, Frank M Ruemmele, Nadine Cerf-Bensussan

62 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftJournal of Crohn's & colitis
Vol/bind12
Udgave nummer9
Sider (fra-til)1104-1112
ISSN1873-9946
DOI
StatusUdgivet - 29 aug. 2018

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