To characterize the clinical and molecular spectrum of N-terminal IκBα gain-of-function (GOF) disease and identify shared immunologic phenotypes among patients with novel NFKBIA variants.
Key Findings:
Clinical severity varied from recurrent infections in adolescence to severe multisystem disease in infancy.
All patients exhibited ectodermal abnormalities and a consistent lymphocyte phenotype with expanded naïve T-cell and B-cell compartments.
Delayed TNF-α-induced IκBα degradation was observed in patient PBMCs.
All four mutant proteins suppressed TNF-α-induced NF-κB reporter activity more strongly than wild-type IκBα.
Interpretation:
The study broadens the understanding of N-terminal IκBα GOF disease.
Limitations:
The study involved a small cohort of patients, limiting generalizability.
Clinical data were heterogeneous and may not cover all aspects of the disease.
Conclusion:
The findings support defective regulated IκBα degradation and impaired lymphocyte maturation as features of N-terminal IκBα GOF disease.
