RelB deficiency causes combined immunodeficiency

Background: Combined immunodeficiency (CID) presents in infancy with severe microbial infections due to either the depletion or dysfunction of lymphocytes. Several mutated genes have been implicated in causing this condition. These encoded proteins are involved in gene recombination, signal transduction from receptors to transcription factors, or they are critical for lymphocyte development. There remain 20%–30% of patients with similar phenotypes but with no known genetic aberration. The objective of this study was to define the molecular basis of CID in a group of patients. Genotyping was performed using linkage panel chips, and the results were analyzed for parametric linkage. Whole genome sequencing was also performed. In vitro mitogen stimulation, flow cytometry, real time PCR, Western blotting, and cytokine ELISA were used to assess immunological status and signal transduction pathways. We identified a homozygous mutation in the gene for the NFκB transcription factor RelB in 3 patients who suffered ...