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 (3, 1) , Jan Nowak (3, 1, 5) , Bernadette Begue (3, 1) , Sabine Rakotobe (3, 1) , Julie Bruneau (2, 1) , Cécile Fourrage (6, 1) , Olivier Alibeu (4, 1) , Frédéric Rieux-Laucat (1, 7) , Eva Lévy (1, 7) , Marie-Claude Stolzenberg (7, 1) , Fabienne Mazerolles (7, 1) , Sylvain Latour (8, 1) , Christelle Lenoir (1, 8) , Alain Fischer (2, 9, 1, 4) , Capucine Picard (10, 2, 8) , Marina Aloi (11) , Jorge Amil Dias (12) , Mongi Ben Hariz (13) , Anne Bourrier (14) , Christian Breuer (15) , Anne Breton (16) , Stephan Buderus (17) , Mara Cananzi (18) , Stéphanie Coopman (19) , Clara Crémilleux (20) , Alain Dabadie (21) , Clémentine Dumant-Forest (22) , Odul Egritas Gurkan (23) , Alexandre Fabre (24) , Aude Fischer (25) , Marta German Diaz (26) , Yago Gonzalez-Lama (27) , Olivier Goulet (10, 2) , Olivier Goulet (10, 2) , Graziella Guariso (28) , Neslihan Gurcan (23) , Matjaz Homan (29) , Jean-Pierre Hugot (30, 31) , Eric Jeziorski (32, 33) , Evi Karanika (34) , Alain Lachaux (35, 36) , Peter Lewindon (37) , Rosa Lima (12) , Fernando Magro (38, 12) , Janos Major (39) , Georgia Malamut (40, 3) , Emmanuel Mas (41, 42) , Istvan Mattyus (43) , Luisa M. Mearin (44) , Jan Melek (45) , Victor Manuel Navas-Lopez (46) , Anders Paerregaard (47) , Cecile Pelatan (48) , Bénédicte Pigneur (2, 3) , Isabel Pinto Pais , Julie Rebeuh (49) , Claudio Romano (50) , Nadia Siala (13) , Caterina Strisciuglio (51) , Michela Tempia-Caliera , Patrick Tounian (52) , Dan Turner , Vaidotas Urbonas (53) , Stéphanie Willot (54) , Frank Ruemmele (2, 3) , Nadine N. Cerf-Bensussan (3)

1 Université Paris Descartes, Sorbonne Paris Cité
2 Hôpital Necker - Enfants Malades [AP-HP]
3 Equipe Inserm U1163 - Laboratory of Intestinal Immunity
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 PUMS - Poznan University of Medical Sciences [Poland]
6 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory
7 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
8 Equpie Inserm U1163 - Lymphocyte activation and susceptibility to EBV
9 CdF (institution) - Collège de France
10 UPD5 - Université Paris Descartes - Paris 5
11 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
12 Hospital de São João [Porto]
13 Centre Hospitalier Universitaire Mongi Slim [La Marsa]
14 CHU Saint-Antoine [AP-HP]
15 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
16 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
17 University Hospital Motol [Prague]
18 University Hospital Bonn
19 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
20 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
21 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
22 Service de pédiatrie médicale et médecine de l'adolescent [Rouen]
23 Gazi University
24 APHM - Assistance Publique - Hôpitaux de Marseille
25 CHU Saint-Pierre
26 Hospital Universitario 12 de Octubre [Madrid]
27 Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain]
28 Unipd - Università degli Studi di Padova = University of Padua
29 UMCL - University Medical Centre Ljubljana [Ljubljana, Slovenia]
30 Inflammation intestinale pathologique de l'enfant
31 AP-HP Hôpital universitaire Robert-Debré [Paris]
32 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
33 PCCEI - Pathogenesis and Control of Chronic and Emerging Infections
34 General Hospital of Thessaloniki "Ippokrateio"
35 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
36 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
37 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
38 Universidade do Porto = University of Porto
39 Pál Heim Children's Hospital = Heim Pál Gyermekkórház [Budapest]
40 HEGP - Hôpital Européen Georges Pompidou [APHP]
41 Service de Gastroentérologie et pancréatologie [CHU Toulouse]
42 Service Gastroentérologie, hépatologie nutrition, diabétologie et maladies héréditaires du métabolisme pédiatrique [CHU Toulouse]
43 Semmelweis University [Budapest]
44 Universiteit Leiden = Leiden University
45 University of Hradec Králové
46 Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain]
47 Copenhagen University Hospital
48 Centre Hospitalier Le Mans (CH Le Mans)
49 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
50 University of Messina
51 Seconda Università degli Studi di Napoli = Second University of Naples
52 CHU Trousseau [APHP]
53 Vilnius University [Vilnius]
54 CHU Trousseau [Tours]

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.

Mots clés: Genetics and molecular epidemiology; Paediatrics; TNGS; Monogenic disorders; VEO-IBD

Domaines: Hépatologie et Gastroentérologie

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, 2018, 12 (9), pp.1104-1112. ⟨10.1093/ecco-jcc/jjy068⟩. ⟨hal-02320500v2⟩