title: Targeted gene panel sequencing in children with very early onset inflammatory bowel disease--evaluation and prospective analysis.
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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Jochen
authors.identifier: http://orcid.org/0000-0002-6046-8727
authors.initials: J
authors.lastname: Kammermeier
authors.affiliation: North East Thames Regional Genetics Service, Hospital for Children, London, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Drury
authors.affiliation: Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Chela T
authors.initials: CT
authors.lastname: James
authors.affiliation: Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Dziubak
authors.affiliation: Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Mamoun
authors.initials: M
authors.lastname: Elawad
authors.affiliation: Experimental & Personalised Medicine Section, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Beales
authors.affiliation: North East Thames Regional Genetics Service, Hospital for Children, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lench
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, UK Department of Pediatrics, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Experimental & Personalised Medicine Section, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK Katholic University Leuven, Leuven, Belgium.
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
mesh_terms: D017668:Age of Onset; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D011446:Prospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: Gastroenterology; Genetic screening/counselling; Genetics; Inflammatory bowel disease; Molecular genetics