title: Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.
abstract: OBJECTIVE
  Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD.
  
  
  METHODS
  WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay.
  
  
  RESULTS
  We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD.
  
  
  CONCLUSIONS
  Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.
authors.affiliation: *Department of Pediatrics †Department of Human Genetics, Emory University School of Medicine, Atlanta, GA ‡Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN §Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: David T
authors.initials: DT
authors.lastname: Okou
authors.forename: Kajari
authors.initials: K
authors.lastname: Mondal
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Kobrynski
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mulle
authors.forename: Dhanya
authors.initials: D
authors.lastname: Ramachandran
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.forename: Phyllis
authors.initials: P
authors.lastname: Svingen
authors.forename: Viren
authors.initials: V
authors.lastname: Patel
authors.forename: Promita
authors.initials: P
authors.lastname: Bose
authors.forename: Jon P
authors.initials: JP
authors.lastname: Waters
authors.forename: Sampath
authors.initials: S
authors.lastname: Prahalad
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zwick
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
mesh_terms: D004485:Eczema / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D005838:Genotype; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics; D017422:Sequence Analysis, DNA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors