1Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany; 2Center for Chronic Immunodeficiency (CCI), DZIF Satellite Center, Medical Center, Faculty of Medicine, Germany; 3Paediatric Gastroenterology, Klinikum Nürnberg, Nuremberg, Germany; 4Laboratory of Applied Molecular Biology and Immunology, University of Abou-Bekr Belkaïd, Tlemcen, Algeria; 5Department of Pediatrics, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; 6Clinic of Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey; 7Department of Gastroenterology and Clinical Nutrition, Birmingham Children's Hospital, Birmingham, United Kingdom; 8Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 9Department of Immunology, Royal Free Hospital, London, United Kingdom; 10Primary Immunodeficiencies Unit, Hospital Dona Estefania, Pediatric University Hospital, and CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal; 11Department of Pediatric Gasteroentrology and Hepatology, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 12Helios Kliniken, Childrens Hospital, Krefeld, Germany; 13Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt; 14Paediatric Gastroenterology/Hepatology, University of Freiburg, Freiburg, Germany; 15Institute of Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany; 16Department of Pediatrics, University Medical Center Dresden, Technische Universität Dresden, Dresden, Germany; 17Department of Medicine II, University Hospital and Medical Faculty, University Freiburg, Freiburg, Germany; 18Department of Paediatrics, Centre for Diagnosis and Treatment of Primary Immunodeficiencies, Jessenius Faculty of Medicine, Commenius University in Bratislava, Martin, Slovakia; 19Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey; 20Department of Allergy and Clinical Immunology, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 21Pediatric Immunology Division, Uludag University Medical Faculty, Department of Pediatrics, Bursa, Turkey; 22Dr. von Hauner Children's Hospital, Department of Pediatrics, Ludwig-Maximilians-Universität Munich, Munich, Germany; 23Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; 24Center for Pediatrics, Department of Pediatric Hematology and Oncology, University Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; 25Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital, Dublin, Ireland; 26Department of Immunology, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 27Department of Paediatric Gastroenterology, St. George's Healthcare NHS Trust and University of London, London, United Kingdom; 28Department of Gastroenterology and Clinical Nutrition, Marmara University Medical Faculty, Istanbul, Turkey; 29Service of Clinical Laboratory, Division of Immunology, San Pedro De Alcántara Hospital, Cáceres, Spain; 30Bone Marrow Failure Group, Division of Pediatric Hematology and Oncology, University of Freiburg, Germany; 31Children's Hospital, University of Bonn, Germany; 32University College London Institute of Immunity and Transplantation, Royal Free Campus, London, United Kingdom; 33Department of Paediatrics, St. George's Hospital, University of London, London, United Kingdom; 34Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium; 35Pediatric Pneumology and Immunology, Department of Immunology, Charité University Medicine Labor Berlin Charité Vivantes GmbH, Berlin, Germany; 36Department of Medicine I, University Medical Center Dresden, Technische Universität Dresden, Dresden, Germany; 37Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany; and 38Institute of Laboratory Medicine, Brandenburg Hospital, Brandenburg Medical School, Brandenburg/Havel, Germany.
In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients.
We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients.
Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients.
Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.