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 Dias; Mongi Ben Hariz; Anne Bourrier; Christian Breuer; Anne Breton; 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 Ruemmele; Nadine N. Cerf-Bensussan

doi:10.1093/ecco-jcc/jjy068

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

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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, …

Journal of Crohn's and Colitis, Vol.12(9), pp.1104-1112

09/2018

DOI: https://doi.org/10.1093/ecco-jcc/jjy068

PMCID: PMC6113703

PMID: 29788237

Abstract

Genetics and molecular epidemiology

Paediatrics

TNGS

Monogenic disorders

VEO-IBD

Adolescent

Age of Onset

Male

Predictive Value of Tests

Child

Child, Preschool

Cohort Studies

Female

Hight-Throughput Nucleotide Sequencing

Humans

Infant

Inflammatory Bowel Diseases

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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Title: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study
Creators - without role: Fabienne Charbit-Henrion - Inserm
Marianna Parlato - Délégation Paris 5
Sylvain Hanein - Institut des Maladies Génétiques Imagine
Rémi Duclaux-Loras - Délégation Paris 5
Jan Nowak - Inserm
Bernadette Begue - Institut des Maladies Génétiques Imagine
Sabine Rakotobe - Inserm
Julie Bruneau - Délégation Paris 5
Cécile Fourrage - Institut des Maladies Génétiques Imagine
Olivier Alibeu - Délégation Paris 5
Frédéric Rieux-Laucat - Institut des Maladies Génétiques Imagine
Eva Lévy - Institut des Maladies Génétiques Imagine
Marie-Claude Stolzenberg - Sorbonne Paris Cité
Fabienne Mazerolles - Institut des Maladies Génétiques Imagine
Sylvain Latour - Institut des Maladies Génétiques Imagine
Christelle Lenoir - Institut des Maladies Génétiques Imagine
Alain Fischer - Inserm
Capucine Picard - Institut des Maladies Génétiques Imagine
Marina Aloi - Sapienza University of Rome
Jorge Amil Dias - Hospital de São João
Mongi Ben Hariz - Hôpital Mongi Slim
Anne Bourrier - Hôpital Saint-Antoine
Christian Breuer - University Medical Center Hamburg-Eppendorf
Anne Breton - Centre Hospitalier Universitaire de Toulouse
Stephan Buderus - St. Marien-Hospital Bonn
Mara Cananzi - University of Padua
Stéphanie Coopman - Hôpital Jeanne de Flandre
Clara Crémilleux - Centre Hospitalier Universitaire de Saint-Étienne
Alain Dabadie - Centre Hospitalier Universitaire de Rennes
Clémentine Dumant-Forest - Hôpital Charles-Nicolle
Odul Egritas Gurkan - Gazi University
Alexandre Fabre - Hôpital de la Timone
Aude Fischer - Centre Hospitalier Universitaire de La Réunion
Marta German Diaz - Hospital Universitario 12 De Octubre
Yago Gonzalez-Lama - Hospital Universitario Puerta de Hierro Majadahonda
Olivier Goulet - Université Paris Cité
Olivier Goulet - Université Paris Cité
Graziella Guariso - University of Padua
Neslihan Gurcan - Gazi University
Matjaz Homan - Ljubljana University Medical Centre
Jean-Pierre Hugot - Assistance Publique – Hôpitaux de Paris
Eric Jeziorski - Centre Hospitalier Universitaire de Montpellier
Evi Karanika - 424 General Military Hospital
Alain Lachaux - Hospices Civils de Lyon
Peter Lewindon - University of Queensland
Rosa Lima - Hospital de São João
Fernando Magro - Universidade do Porto
Janos Major - Bethesda Gyermekkórház
Georgia Malamut - Institut des Maladies Génétiques Imagine
Emmanuel Mas - Centre Hospitalier Universitaire de Toulouse
Istvan Mattyus - Semmelweis University
Luisa M. Mearin - Leiden University
Jan Melek - University Hospital Hradec Králové
Victor Manuel Navas-Lopez - Hospital Regional Universitario de Málaga
Anders Paerregaard - Copenhagen University Hospital
Cecile Pelatan - Centre Hospitalier du Mans
Bénédicte Pigneur - Institut des Maladies Génétiques Imagine
Isabel Pinto Pais
Julie Rebeuh - Hôpitaux Universitaires de Strasbourg
Claudio Romano - University of Messina
Nadia Siala - Hôpital Mongi Slim
Caterina Strisciuglio - University of Naples Federico II
Michela Tempia-Caliera - Hirslanden Clinique des Grangettes
Patrick Tounian - Hôpital Armand-Trousseau
Dan Turner - Shaare Zedek Medical Center
Vaidotas Urbonas - Vilnius University
Stéphanie Willot - Centre Hospitalier Universitaire de Tours
Frank Ruemmele - Délégation Paris 5
Nadine N. Cerf-Bensussan - Laboratory of Intestinal Immunity
Publication Details: Journal of Crohn's and Colitis, Vol.12(9), pp.1104-1112
Grant note: This work was supported by ERC-2013-AdG-339407-IMMUNOBIOTA, Investissement d’Avenir ANR-10-IAHU-01, Fondation des Maladies Rares, and Association François Aupetit. FC-H was supported by a fellowship from INSERM. JN received a fellowship from the Polish National Science Centre [2015/16/T/NZ5/00168].
Identifiers: 9936490809311
Academic Unit: Pathogenesis and Control of Chronic and Emerging Infections - PCCEI
Language: English
Resource Type: Journal article
Local Fields: hal-02320500