Exome Sequencing Identifies a Novel FOXP3 Mutation in a 2-Generation Family With Inflammatory Bowel Disease

• Authors: David Okou, Emory University; Kajari Mondal, Emory University; Willam A. Faubion, Mayo Clinic; Lisa Kobrynski, Emory University; Lee A. Denson, Children's Hospital Medical Center; Jennifer Mulle, Emory University; Dhanya Ramachandran, Emory University; Yuning Xiong, Mayo Clinic; Phyllis Svingen, Mayo Clinic; Viren Patel, Emory University; Promita Bose, Emory University; Jon P. Waters, Emory University; Sampath Prahalad, Emory University; David Cutler, Emory University; Michael Zwick, Emory University; Subra Kugathasan, Emory University
• Journal Title: Journal of Pediatric Gastroenterology and Nutrition
• Volume: Volume 58, Number 5
• Publisher: Lippincott, Williams & Wilkins | 2014-05-01, Pages 561-568
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/MPG.0000000000000302
• Subjects: Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics; inflammatory bowel disease; immune dysregulation; X-linked; enteropathy; polyendocrinopathy; atypical; exome; X-LINKED SYNDROME; REGULATORY T-CELLS; IMMUNE DYSREGULATION; IPEX SYNDROME; SUPPRESSIVE FUNCTION; POLYENDOCRINOPATHY; ENTEROPATHY; IMMUNODYSREGULATION; DIMERIZATION; EXPRESSION

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.