title: Identification of Variants in Genes Associated with Single-gene Inflammatory Bowel Disease by Whole-exome Sequencing.
abstract: Most cases of inflammatory bowel disease (IBD) are caused by complex host-environment interaction. There are a number of conditions associated with a single-gene mutation, most cases are very early onset (aged < 6 yr), present with a unique form of disease and often have atypical features.
  
  
  
  Whole-exome data for 147 pediatric patients with IBD were interrogated for a panel of 51 genes associated with monogenic IBD. Observed variation was categorized according to the American College of Medical Genetics (ACMG) guidelines to identify rare, novel, and known variants that might contribute to IBD.
  
  
  
  Five hundred seventy-four variants were identified across 51 genes. These were categorized in line with ACMG guidance to remove benign variants and to identify "pathogenic" and "likely pathogenic" variants. In 6 patients, we observed 6 pathogenic variants of which CYBA(c.287+2T>C), COL7A1(c.6501+1G>C), LIG4(p.R814X), and XIAP(p.T470S) were known causative mutations, and FERMT1(p.R271Q) and SKIV2L(c.354+5G>A) were novel. In the 3 patients with XIAP, SKIV2L, and FERMT1 variants, individuals' disease features resembled the monogenic phenotype. This was despite apparent heterozygous carriage of pathogenic variation for the latter 2 genes. The XIAP variant was observed in a hemizygous male.
  
  
  
  Whole-exome sequencing allows for identification of known and de novo potentially causative mutations in genes associated with monogenic IBD. Although these are rare conditions, it is vital to identify causative mutations early to improve prognosis. We postulate that in a subset of IBD, heterozygous mutations (in genes believed to manifest IBD through autosomal recessive inheritance) may contribute to clinical presentation.
authors.affiliation: *Human Genetics and Genomic Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom; †Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, United Kingdom; and ‡NIHR Nutrition Biomedical Research Centre, Southampton Centre for Biomedical Research, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: James J
authors.initials: JJ
authors.lastname: Ashton
authors.forename: Gaia
authors.initials: G
authors.lastname: Andreoletti
authors.forename: Tracy
authors.initials: T
authors.lastname: Coelho
authors.forename: Rachel
authors.initials: R
authors.lastname: Haggarty
authors.forename: Akshay
authors.initials: A
authors.lastname: Batra
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Afzal
authors.forename: R Mark
authors.initials: RM
authors.lastname: Beattie
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
mesh_terms: D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics*; D024143:Collagen Type VII / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D000072481:DNA Ligase ATP / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D000073359:Exome Sequencing; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
chemical_list: C569053:COL7A1 protein, human; D024143:Collagen Type VII; C475301:FERMT1 protein, human; C000607893:LIG4 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019255:NADPH Oxidases; C086986:CYBA protein, human; D004265:DNA Helicases; C114718:SKIV2L protein, human; D000072481:DNA Ligase ATP