Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease

David T. Okou, Kajari Mondal, William Alvis Faubion, Lisa J. Kobrynski, Lee A. Denson, Jennifer G. Mulle, Dhanya Ramachandran, Yuning Xiong, Phyllis Svingen, Viren Patel, Promita Bose, Jon P. Waters, Sampath Prahalad, David J. Cutler, Michael E. Zwick, Subra Kugathasan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)561-568
Number of pages8
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume58
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Exome
Inflammatory Bowel Diseases
Mutation
Mothers
Forkhead Transcription Factors
Phenotype
Aptitude
Regulatory T-Lymphocytes
Nuclear Family
Autoimmunity
Fathers
Glycine
Cysteine
Vertebrates
Exons
Staining and Labeling
T-Lymphocytes
Genes

Keywords

  • atypical
  • enteropathy
  • exome
  • immune dysregulation
  • inflammatory bowel disease
  • polyendocrinopathy
  • X-linked

ASJC Scopus subject areas

  • Gastroenterology
  • Pediatrics, Perinatology, and Child Health

Cite this

Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. / Okou, David T.; Mondal, Kajari; Faubion, William Alvis; Kobrynski, Lisa J.; Denson, Lee A.; Mulle, Jennifer G.; Ramachandran, Dhanya; Xiong, Yuning; Svingen, Phyllis; Patel, Viren; Bose, Promita; Waters, Jon P.; Prahalad, Sampath; Cutler, David J.; Zwick, Michael E.; Kugathasan, Subra.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 58, No. 5, 2014, p. 561-568.

Research output: Contribution to journalArticle

Okou, DT, Mondal, K, Faubion, WA, Kobrynski, LJ, Denson, LA, Mulle, JG, Ramachandran, D, Xiong, Y, Svingen, P, Patel, V, Bose, P, Waters, JP, Prahalad, S, Cutler, DJ, Zwick, ME & Kugathasan, S 2014, 'Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease', Journal of Pediatric Gastroenterology and Nutrition, vol. 58, no. 5, pp. 561-568. https://doi.org/10.1097/MPG.0000000000000302
Okou, David T. ; Mondal, Kajari ; Faubion, William Alvis ; Kobrynski, Lisa J. ; Denson, Lee A. ; Mulle, Jennifer G. ; Ramachandran, Dhanya ; Xiong, Yuning ; Svingen, Phyllis ; Patel, Viren ; Bose, Promita ; Waters, Jon P. ; Prahalad, Sampath ; Cutler, David J. ; Zwick, Michael E. ; Kugathasan, Subra. / Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. In: Journal of Pediatric Gastroenterology and Nutrition. 2014 ; Vol. 58, No. 5. pp. 561-568.
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abstract = "Objectives: 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.",
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AU - Okou, David T.

AU - Mondal, Kajari

AU - Faubion, William Alvis

AU - Kobrynski, Lisa J.

AU - Denson, Lee A.

AU - Mulle, Jennifer G.

AU - Ramachandran, Dhanya

AU - Xiong, Yuning

AU - Svingen, Phyllis

AU - Patel, Viren

AU - Bose, Promita

AU - Waters, Jon P.

AU - Prahalad, Sampath

AU - Cutler, David J.

AU - Zwick, Michael E.

AU - Kugathasan, Subra

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N2 - Objectives: 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.

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