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 to adapt treatment. METHODS: A total of 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.

Bioinformatics Platform Imagine Institute Paris France

Centro Hospitalar Gaia Espinho Department of Paediatrics Vila Nova de Gaia Portugal

Collège de France Médecine expérimentale Paris France

Department of Gastroenterology and Hepatology Lady Cilento Children's Hospital and the Faculty of Medicine and Biomedical Sciences TUniversity of Queensland Brisbane Australia

Department of Gastroenterology Hepatology and Nutrition University Children's Hospital Ljubljana Slovenia

Department of Gastroenterology Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris Paris France

Department of Gastroenterology Hôpital St Antoine Assistance Publique Hôpitaux de Paris Paris France

Department of Paediatric Gastroenterology and Metabolic Diseases Poznan University of Medical Sciences Poznan Poland

Department of Paediatric Gastroenterology Hepatology and Nutrition Centre de Nutrition parentérale à domicile Hôpital Femme Mère Enfant CHU de Lyon HCL GH Est Bron France

Department of Paediatric Gastroenterology Vilnius University Clinic for Children's Diseases Vilnius Lithuania

Department of Paediatric Nutrition and Gastroenterology Hôpital Armand Trousseau Assistance Publique Hôpitaux de Paris Paris France

Department of Paediatrics Assistance publique Hôpitaux de Marseille Hôpital de la Timone Marseille France

Department of Paediatrics Centre Hospitalier du Mans Le Mans France

Department of Paediatrics Centre hospitalier régional universitaire Hôpital Clocheville Tours France

Department of Paediatrics Centre Hospitalo Universitaire Charles Nicolle Rouen France

Department of Paediatrics Centre Hospitalo Universitaire de St Etienne St Etienne France

Department of Paediatrics Centre Hospitalo Universitaire de Strasbourg Strasbourg France

Department of Paediatrics Centre Hospitalo Universitaire Sud Réunion St Pierre France

Department of Paediatrics Centro Hospitalar São João Porto Portugal

Department of Paediatrics FMH Pédiatrie et FA Gastroentérologie et hépatologie Clinique des Grangettes Geneva Switzerland

Department of Paediatrics Gastroenterology Hepatology Nutrition and Diabetes Centre Hospitalier Universitaire de Toulouse Toulouse France

Department of Paediatrics Hopital La Marsa Tunisia

Department of Paediatrics Hôpital Mongi Slim La Marsa Tunisia

Department of Paediatrics Hospital of Messina University of Messina Messina Italy

Department of Paediatrics Infectious diseases and Immunology Centre Hospitalo Universitaire de Montpellier Montpellier France

Department of Paediatrics Universitätsklinikum Hamburg Hamburg Germany

Department of Paediatrics University General Hospital of Thessaloniki Thessaloniki Greece

Department of Woman Child and General and Specialized Surgery 2nd University of Naples Naples Italy

Departments of Paediatric Digestive and Respiratory Diseases Hôpital Robert Debré Assistance Publique Hôpitaux de Paris Paris France

Division of Gastroenterology Hepatology and Nutrition Department of Paediatrics Jeanne De Flandre Children's Hospital Lille University Faculty of Medicine Lille France

Gastroenterology Department Hospital de São João Institute of Pharmacology and Therapeutics Faculty of Medicine and MedInUP Centre for Drug Discovery and Innovative Medicines University of Porto Porto Portugal

GENIUS Group [GENetically ImmUne mediated enteropathieS] from the European Society for Paediatric Gastroenterology Hepatology and Nutrition [ESPGHAN]

Genomic Platform Imagine Institute Paris France

Hospital Regional Universitario de Málaga Departamento de Pediatría Malaga Spain

Hvidovre University Hospital Department of Paediatrics Copenhagen Denmark

Inflammatory Bowel Disease Unit Hospital Universitario Puerta de Hierro Majadahonda Madrid Spain

INSERM UMR 1163 and Imagine Institute Paris France

INSERM UMR 1163 Translational Genetic and Imagine Institute Paris France

INSERM UMR1163 Immunogenetics of Paediatric Autoimmunity and Imagine Institute Paris France

INSERM UMR1163 Laboratory of Intestinal Immunity and Imagine Institute Paris France

INSERM UMR1163 Lymphocyte activation and EBV susceptibility and Imagine Institute Paris France

Investigation Centre for Immunodeficiency Hôpital Necker Enfants Malades Assistance Publique Hôpitaux de Paris and Imagine Institute Paris France

Leiden University Medical Centre Department of Paediatrics Leiden The Netherlands

MRE Bethesda Gyermekkórháza; Department of Pediatrics Budapest Hungary

Paediatric Gastroenterology Hepatology and Nutrition Gazi University Ankara Turkey

Paediatric Gastroenterology Hepatology and Nutrition Unit Hôpital Necker Enfants Malades Assistance Publique Hôpitaux de Paris Paris France

Pathology Department Hôpital Necker Enfants Malades Assistance Publique Hôpitaux de Paris Paris France

Sapienza University of Rome Paediatric Gastroenterology and Liver Unit Department of Pediatrics Rome Italy

Semmelweis University; Department of Paediatrics Budapest Hungary

Service de médecine de l'enfant et de l'adolescent Hôpital Sud Centre Hospitalo Universitaire de Rennes Rennes France

Shaare Zedek Medical Centre Jerusalem Israel

St Marien Hospital Bonn Germany

Unit of Paediatric Hepatology Department of Woman and Child Health University Hospital of Padova Padova Italy

Unit of Paediatric Nutrition Hospital Universitario 12 de Octubre Madrid Spain

Université Paris Descartes Sorbonne Paris Cité Paris France

University Hospital Hradec Kralove Czech Republic

University Hospital Motol Prague Czech Republic

University of Padua Italy

Erratum v

J Crohns Colitis. 2021 Mar 5;15(3):517-518. doi: 10.1093/ecco-jcc/jjaa164. PubMed

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