RELA Haploinsufficiency Manifesting as an Atypical Phenotype of Crohn's Disease

Mutations in RELA, a key component of NF-κB signaling, are associated with dysregulated immune responses and inflammatory disorders. While immunodeficiency phenotypes associated with RELA haploinsufficiency have been reported, gastrointestinal manifestations remain poorly described. This study aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn's-like phenotype driven by RELA haploinsufficiency.

Whole-exome sequencing was performed, and results were confirmed by Sanger sequencing. Protein modeling, Western blotting, immunofluorescence, and nuclear extract-based NF-κB activation assays were conducted to assess the functional impact of the identified variant. Immune profiling was performed using mass cytometry time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) and compared to controls.

We studied a 17-year-old male diagnosed with pan-enteric Crohn's disease (CD), perianal fistulas, chronic mucocutaneous candidiasis, and chronic lymphopenia. Sequencing identified a heterozygous missense variant in RELA (c.587T>C, p.V196A) that potentially impairs RelA (p65) protein stability, confirmed by reduced activity and diminished protein expression. CyTOF analysis revealed decreased circulating T regulatory cells (Tregs), absence of mucosal Tregs, high apoptotic rates, and elevated IFN-γ induced levels, while scRNA-seq demonstrated a robust type I/II interferon signature in multiple immune subsets. Dysregulated mucosal-associated invariant T (MAIT) and cytotoxic CD4+ T cells exhibited upregulation of IL23R and ADAM12, further linking RELA dysfunction to enhanced pro-inflammatory T cell response and tissue inflammation.

This study links RELA haploinsufficiency with CD-like features, Th1/Th17 polarization, and interferon-driven inflammation, emphasizing the importance of genetic evaluation in patients with atypical or refractory IBD.