Exome Sequencing Identifies a Novel FOXP3 Mutation in a 2-Generation Family With Inflammatory Bowel Disease
David T. Okou
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorKajari Mondal
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorWilliam A. Faubion
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorLisa J. Kobrynski
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorLee A. Denson
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorJennifer G. Mulle
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorDhanya Ramachandran
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorYuning Xiong
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorPhyllis Svingen
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorViren Patel
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorPromita Bose
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorJon P. Waters
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorSampath Prahalad
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorDavid J. Cutler
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorMichael E. Zwick
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorCorresponding Author
Subra Kugathasan
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Address correspondence and reprint requests to Subra Kugathasan, MD, Emory University School of Medicine, Division of Pediatric Gastroenterology, Emory Children's Center, 1760 Haygood Drive, Room W427, Atlanta, GA 30322 (e-mail: [email protected]).Search for more papers by this authorDavid T. Okou
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorKajari Mondal
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorWilliam A. Faubion
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorLisa J. Kobrynski
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorLee A. Denson
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorJennifer G. Mulle
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorDhanya Ramachandran
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorYuning Xiong
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorPhyllis Svingen
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Search for more papers by this authorViren Patel
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorPromita Bose
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorJon P. Waters
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorSampath Prahalad
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorDavid J. Cutler
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorMichael E. Zwick
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorCorresponding Author
Subra Kugathasan
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Address correspondence and reprint requests to Subra Kugathasan, MD, Emory University School of Medicine, Division of Pediatric Gastroenterology, Emory Children's Center, 1760 Haygood Drive, Room W427, Atlanta, GA 30322 (e-mail: [email protected]).Search for more papers by this authorDrs Okou and Mondal contributed equally to the article.
This work was supported by National Institutes of Health grants DK087694 (S.K.), AI089714 (W.A.F.), and DK078683 (L.A.D.).
The authors report no conflicts of interest.
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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