Novel loss-of-function intronic mutation in ELF4 is associated with intestinal autoinflammation

Monogenic errors of immunity can present with inflammatory bowel disease (IBD)-like enteropathy. We describe an adolescent with IBD- and Behçet's-like phenotype, resulting from an intronic, loss of function mutation (c.248-7G > A) in ELF4, an X-linked transcription factor executing multiple biological functions. The mutation causes abnormal splicing and decreased mRNA expression and impairs ELF4 protein expression in the blood and colon. Functionally, the mutation results in loss of ELF4 transcriptional activity, and transcriptionally induces auto-inflammatory responses in the patient's peripheral blood mononuclear cells, which promote secretion of the pro-inflammatory cytokine interleukin-6 upon lipopolysaccharide stimulation. Single-cell transcriptional profiling of inflamed colonic biopsy specimens from the patient delineates a comprehensive landscape of mucosal innate and adaptive immune dysregulation. This analysis not only uncovers inflammatory signatures reminiscent of Crohn's disease but also demonstrates heightened angiogenic chemokine responses and enhanced chemotactic activity in innate immune cells. These results demonstrate that a new ELF4 loss-of-function intronic mutation predisposes to an intestinal autoinflammatory disorder.