Novel mutation and expanding phenotype in IRF2BP2 deficiency

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Inborn errors of immunity (IEI) present with infections or immune dysregulation, with common variable immunodeficiency (CVID) comprising ~50% of cases.
• Monogenic causes for CVID are rarely identified, with IRF2BP2 being a known gene associated with CVID phenotypes, previously reported in only two families.

Observation:

• A 33-year-old male patient presented with recurrent infections, colitis, and rheumatoid arthritis.
• Whole-exome sequencing identified a novel de novo nonsense variant (c.1618C>T; p.(Q540*)) in the IRF2BP2 gene.

Findings:

• The IRF2BP2 variant resulted in severe B cell differentiation defects, impaired plasmablast formation, and IgG deficiency.
• The patient exhibited impaired T cell homeostasis, including altered cytokine production and CTLA4 expression on Tregs, alongside an elevated type I interferon signature.

Implications:

• This loss-of-function variant in IRF2BP2 significantly impacts B cell development and immune regulation.
• The findings expand the understanding of IRF2BP2's role in CVID pathogenesis and suggest its association with inflammatory conditions like colitis and rheumatoid arthritis.