Jochen Kammermeier1, Suzanne Drury2, Chela T James3, Robert Dziubak4, Louise Ocaka3, Mamoun Elawad4, Philip Beales5, Nicholas Lench2, Holm H Uhlig6, Chiara Bacchelli5, Neil Shah7. 1. Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK Experimental & Personalised Medicine Section, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK. 2. North East Thames Regional Genetics Service, Hospital for Children, London, UK. 3. Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK. 4. Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK. 5. Experimental & Personalised Medicine Section, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK. 6. Translational Gastroenterology Unit, University of Oxford, Oxford, UK Department of Pediatrics, University of Oxford, Oxford, UK. 7. Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK Katholic University Leuven, Leuven, Belgium.
Abstract
BACKGROUND: Multiple monogenetic conditions with partially overlapping phenotypes can present with inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important. DESIGN: We have introduced targeted next-generation sequencing (NGS) technology as a prospective screening tool in children with very early onset IBD (VEOIBD). We evaluated the coverage of 40 VEOIBD genes in two separate cohorts undergoing targeted gene panel sequencing (TGPS) (n=25) and whole exome sequencing (WES) (n=20). RESULTS: TGPS revealed causative mutations in four genes (IL10RA, EPCAM, TTC37 and SKIV2L) discovered unexpected phenotypes and directly influenced clinical decision making by supporting as well as avoiding haematopoietic stem cell transplantation. TGPS resulted in significantly higher median coverage when compared with WES, fewer coverage deficiencies and improved variant detection across established VEOIBD genes. CONCLUSIONS: Excluding or confirming known VEOIBD genotypes should be considered early in the disease course in all cases of therapy-refractory VEOIBD, as it can have a direct impact on patient management. To combine both described NGS technologies would compensate for the limitations of WES for disease-specific application while offering the opportunity for novel gene discovery in the research setting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: Multiple monogenetic conditions with partially overlapping phenotypes can present with inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important. DESIGN: We have introduced targeted next-generation sequencing (NGS) technology as a prospective screening tool in children with very early onset IBD (VEOIBD). We evaluated the coverage of 40 VEOIBD genes in two separate cohorts undergoing targeted gene panel sequencing (TGPS) (n=25) and whole exome sequencing (WES) (n=20). RESULTS: TGPS revealed causative mutations in four genes (IL10RA, EPCAM, TTC37 and SKIV2L) discovered unexpected phenotypes and directly influenced clinical decision making by supporting as well as avoiding haematopoietic stem cell transplantation. TGPS resulted in significantly higher median coverage when compared with WES, fewer coverage deficiencies and improved variant detection across established VEOIBD genes. CONCLUSIONS: Excluding or confirming known VEOIBD genotypes should be considered early in the disease course in all cases of therapy-refractory VEOIBD, as it can have a direct impact on patient management. To combine both described NGS technologies would compensate for the limitations of WES for disease-specific application while offering the opportunity for novel gene discovery in the research setting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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