Contributors: Université Paris Descartes, Sorbonne Paris Cité; Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Laboratory of Intestinal Immunity (Equipe Inserm U1163); Imagine - Institut des maladies génétiques (IMAGINE - U1163); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM); Poznan University of Medical Sciences Poland (PUMS); The Clinical Bioinformatics laboratory (Equipe Inserm U1163); Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163); Lymphocyte activation and susceptibility to EBV (Equpie Inserm U1163); Collège de France (CdF (institution)); Université Paris Descartes - Paris 5 (UPD5); Università degli Studi di Roma "La Sapienza" = Sapienza University Rome (UNIROMA); Hospital de São João Porto; Centre Hospitalier Universitaire Mongi Slim La Marsa; CHU Saint-Antoine AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf Hamburg (UKE); Centre Hospitalier Universitaire de Toulouse (CHU Toulouse); University Hospital Motol Prague; University Hospital Bonn; Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Centre Hospitalier Universitaire de Saint-Etienne CHU Saint-Etienne (CHU ST-E); Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Ponchaillou; Service de pédiatrie médicale et médecine de l'adolescent Rouen; CHU Rouen; Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN); Normandie Université (NU); Gazi University; Assistance Publique - Hôpitaux de Marseille (APHM); CHU Saint-Pierre; Hospital Universitario 12 de Octubre Madrid; Hospital Universitario Puerta de Hierro-Majadahonda Madrid, Spain; Università degli Studi di Padova = University of Padua (Unipd); University Medical Centre Ljubljana Ljubljana, Slovenia (UMCL); Inflammation intestinale pathologique de l'enfant; Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM); AP-HP Hôpital universitaire Robert-Debré Paris; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Pathogenesis and Control of Chronic and Emerging Infections (PCCEI); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang Montpellier; General Hospital of Thessaloniki "Ippokrateio"; Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN); Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon); Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM); Hôpital Femme Mère Enfant CHU - HCL (HFME); Hospices Civils de Lyon (HCL); The University of Queensland (UQ All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations ); Universidade do Porto = University of Porto; Pál Heim Children's Hospital = Heim Pál Gyermekkórház Budapest; Hôpital Européen Georges Pompidou APHP (HEGP); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO); Service de Gastroentérologie et pancréatologie CHU Toulouse; Pôle Maladies de l'appareil digestif CHU Toulouse; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse); Service Gastroentérologie, hépatologie nutrition, diabétologie et maladies héréditaires du métabolisme pédiatrique CHU Toulouse; Pôle Enfants CHU Toulouse; Semmelweis University Budapest; Universiteit Leiden = Leiden University; University of Hradec Králové; Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga Spain; Copenhagen University Hospital; Centre Hospitalier Le Mans (CH Le Mans); Centre Hospitalier Universitaire Strasbourg (CHU Strasbourg); Les Hôpitaux Universitaires de Strasbourg (HUS); University of Messina; Seconda Università degli Studi di Napoli = Second University of Naples; CHU Trousseau APHP; Vilnius University Vilnius; CHU Trousseau Tours; Centre Hospitalier Régional Universitaire de Tours (CHRU Tours); 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 .; The authors acknowledge the use of the bioresources of the Necker Imagine DNA biobank BB-033-00065 . They are grateful to the members of the Department of Clinical Research of the Imagine Institute, headed by Elisabeth Hullier-Ammar, for their guidance with ethical procedures, and to Pauline Touche for her help with the Immunobiota protocol.; ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010); European Project: 339407,EC:FP7:ERC,ERC-2013-ADG,IMMUNOBIOTA(2014)
نبذة مختصرة : International audience ; 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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