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. We aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn’s-like phenotype driven by RELA haploinsufficiency. We report a case of RELA haploinsufficiency in a 17-year-old male presenting with a Crohn’s-like phenotype, including pan-enteric inflammation, perianal disease, chronic mucocutaneous candidiasis, and lymphopenia. Whole exome sequencing revealed a heterozygous RELA missense variant (p.V196A), which might impaired RelA protein stability and function. Functional assays showed reduced NF-κB activity and protein expression. Immune profiling by CyTOF and scRNA-seq demonstrated Treg deficiency, high IFN-γ levels, a strong interferon signature, and aberrant activation of MAIT and cytotoxic CD4+ T cells with upregulation of IL23R and ADAM12. Whole exome sequencing was performed and results confirmed by Sanger sequencing. Protein modeling, Western blot, immunofluorescence, and nuclear extract-based NF-κB activation assays were conducted to assess the functional impact of the identified mutation. Immune profiling was performed using mass cytometry time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) and compared to controls.