Submission Details

The IRF4 gene encodes the transcription factor interferon regulatory factor 4. IRF4 is a member of the human interferon (IFN) regulatory factor (IRF) family. IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription cofactors as a transcription factor, it can bind to the canonical IFN-stimulated response elements (ISREs) as a homodimer; and/or to erythroblast transformation-specific IRF composite elements (EICEs) and activating protein 1 (AP1)–IRF composite elements (AICE1 or AICE2) as a heterodimer requiring PU.1 or SPIB, or AP-1 family members. It is a predominantly hematopoietic TF that is necessary for B and T cell development, differentiation and function, as well as dendritic cells and macrophages. It plays an essential role in IgM, IgG, and IgA secretion, antibody responses, the generation of germinal center B cells, and is required for Ig class-switch recombination and plasma cell differentiation. IRF4 Autosomal Dominant primary immunodeficiency (MONDO: N/A) has a wide range of phenotypes: combined immunodeficiency, age of onset early childhood, recurrent respiratory infections/pneumonia, recurrent viral infections/opportunistic pathogens, recurrent diarrhea, decreased circulating antibody levels and abnormal B/T cell subset distribution. A total of four variants, including nonsense and missense, have been reported in 15 patients in 4 publications only (PMID: 36662884, 36917008, 29537367, 29408330). The missense variants, but not the non-sense variant, were found in an autosomal dominant trait, and the disease mechanism is suggested to be loss of function. Only one patient has a bi-allelic genetic condition associated with IRF4 deficiency, the genetic mechanism underlying the defect consisted of a maternal uniparental isodisomy (UPID). This patient was recorded but not scored. Experimental evidence includes: impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation in patient B cells, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production, gain-of-function hypermorph activity by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, indicating hypomorphic activity, and neomorphic function by binding to noncanonical DNA sites to alter the gene expression profile. Additionally, the IRF4 knockout mouse recapitulates most of the cellular phenotypes, and results in the impairment of mature B and T lymphocytes. In summary, there is strong evidence to support this gene-disease relationship. Clinical data included in the curation span the time period from 2018 until present, therefore the classification is definitive.