Comprehensive overview of IE-IRFs
| Gene | Inheritance (mechanism) | OMIM | Known variants (# patients, # kindreds) | Effect on protein | Effect on gene expression | Cytokine defects | Major clinical features | Pathogen susceptibility | Effect on lymphoid cells | Effect on myeloid cells | Other effects | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IRF1 | AR (LOF) | 620668 | p.R129* (1, 1) | Elevated level but truncated | Reduced activity for ISRE5 and IRFE3. Impaired gene expression for leukocyte activation, cytokine signaling | Impaired IFN-γ response. Mild impairment of IFN-α/β response | Early-onset severe MSMD | Weakly virulent mycobacteria and H. capsulatum | Severe reduction of NK cells and ILC precursors. Reduced naïve CD8+ T cells and RTE CD4+ T cells. Elevated memory CD8+, TFH, effector T, and IgA+ memory B cells. Impaired Th1 response | Reduced cDC1, cDC2, and pDCs | Impaired control of mycobacteria in IRF1-deficient phagocytes | Rosain et al. (2023) |
| p.Q35* (1, 1) | Produced but lacking the first 84 amino acids of the DBD | |||||||||||
| IRF3 | AD (HI) | 616532 | p.R285Q (1, 1) | Impaired phosphorylation and dimerization | Impaired IFNB promoter activity | Impaired type I/III IFN, CXCL10, and TNF-α | Healthy until HSE (ages 15 and 34). Incomplete penetrance | HSV-1 | Not reported | Not reported | Reduced fibroblast IFN-β. Reduced interaction with innate adaptor proteins | Andersen et al. (2015); Mørk et al. (2015) |
| p.A277T (1, 1) | Not reported | |||||||||||
| N/A | c.1576C>T (p.P447S) (1, 1) | Reduced in PBMCs, normal in vitro | Impaired ISG expression. Failed IRF7 upregulation | Impaired type I/III IFN, IL-6, and TNF-α | Severe respiratory viral infections | IAV & SARS-CoV-2 | Not reported | Not reported | | Thomsen et al. (2019b); Zhang et al. (2020) | ||
| p.E49del (1, 1) p.N146K (1, 1) | Not reported | |||||||||||
| IRF4 | AR (UPD) | 621097 | p.V405GfsTer127 (1, 1) | Reduced level | Increased expression of genes associated with proinflammatory macrophage polarization | Impaired IFN-γ production | Intrauterine growth retardation, dermatitis, fevers, tachycardia, generalized adenopathy, hypoglycemia, and failure to thrive. HSCT at 2 years, died at day +2 | Rotavirus, C. albicans, HSV, and respiratory infections with unknown cause | Reduced B cells, TFH, Th17, Tregs, and memory T cells with a severe reduction of memory B and effector memory CD8+ T cells. Elevated RTE CD4+ T cells. Agammaglobulinemia. Elevated Th1:Th2 ratio | Hypereosinophilia, and hemophagocytosis. Severely reduced CD1a+ DCs and elevated pDCs | Abnormal lymph node architecture | Bravo García-Morato et al. (2018) |
| AD (MM) | p.T95R (7, 6) | Normal protein level, impaired localization | Impaired expression of genes associated with plasma cell differentiation. Neomorphic upregulation of CXCL13 | Impaired IL-12 and IFN-γ production. Reduced polyfunctional cells producing both IFN-γ and TNF-α | High susceptibility to opportunistic infection. Hypogammaglobulinemia. Early onset (<1 year). HSCT (2/7). Chronic diarrhea | P. jirovecii, CMV, EBV, vaccine strain BCG, M. bovis, Escherichia coli, enterovirus, Streptococcus pneumoniae, PIV, rhinovirus, Streptococcus mitis, Aspergillus fumigatus, and Klebsiella pneumoniae | Reduced CD19+ B, memory B cells, Th17, and TFH. Elevated naïve and transitional B cells. Impaired B cell maturation, isotype switching, plasma cell maturation, and agammaglobulinemia | None reported | Multimorphic: hypomorphic binding to canonical sites, neomorphic binding to novel targets, and hypermorphic binding to ISRE | Fornes et al. (2023) | ||
| p.F359L (3, 1) | Normal level, and localization. DN effect on ISRE | Impaired ISRE binding but increased expression from AICE and EICE. Low expression of genes associated with plasma cell differentiation | Neomorphic binding to proteins for positive regulation of type I IFN production | High susceptibility to opportunistic infection. Hypogammaglobulinemia. Premature hair graying | CMV, G. lamblia, HSV, molluscum contagiosum, VZV, C. albicans, and onychomycosis | Childhood panhypogammaglobulinemia. Reduced plasmablasts, naïve CD4+ & CD8+ T cells. Elevated terminal effector CD4+ and CD8+ T cells | None reported | Altered binding with IRF4-associated proteins (↓ PC4, ↑ JUNB, novel binding ETV6) | Thouenon et al. (2023) | |||
| AD (HI) | p.R98W (4, 1) | Elevated level. Normal nuclear localization | Impaired expression from ISRE and AICE. Decreased expression of STAT1 and CD80 | Impaired expression of IFNG, LTA, and IL2RA | WD (2 classic WD, 2 with joint symptoms). Incomplete penetrance | Tw | None reported | None reported | | Guérin et al. (2018) | ||
| IRF6 | AD (VWS) | 119300 | Missense, nonsense, or splicing variants in the DBD and IAD | Primarily hypomorphic effect | | | Lip pits with or without CLP | No known infection susceptibility | None reported | None reported | | Kondo et al. (2002); Peyrard-Janvid et al. (2005) |
| | AD (PPS) | 119500 | Missense, nonsense, or splicing variants in the DBD and IAD, with a high prevalence of missense variants near R84 in the DBD | Primarily dominant negative | p.S424L variant significantly reduced transcriptional activity. Loss of contact between DBD and DNA in p.R84C and p.R84H variants | | CLP, lip pits, popliteal webbing, syndactyly, hypodontia, and deformities of the limbs and genitals | No known infection susceptibility | None reported | None reported | A single case of AR IRF6 variants has been linked to PPS | Kondo et al. (2002); Peyrard-Janvid et al. (2005); Matsuzawa et al. (2010); Leslie et al. (2015) |
| IRF7 | AR (LOF) | 616345 | p.F410V/p.Q421* (1, 1) | Reduced level, impaired localization | Impaired expression of many ISGs, but normal upregulation of a subset of ISGs. Failed IRF7 upregulation | Impaired type I/II/III IFN. Normal IL-6 and TNF-α | Severe viral infections with one to three major episodes | Severe IAV and SARS-CoV-2. RSV, TBE virus and adenovirus | Increased memory T cells to SARS-CoV-2 infection or vaccination. Increased CD4+ T cells to IAV. Intact B cell responses | Normal pDC counts but impaired type I/III IFN production | Fibroblasts: impaired IFN-β and poor control of viral replication. Pulmonary epithelial cells: poor IRF7 and IFN-β production | Ciancanelli et al. (2015); Zhang et al. (2020); Campbell et al. (2022) |
| p.A280GfsX12 (2, 1) p.W91* (1, 1) p.P364AfsX38 (1, 1) p.D117N/p.M371V (1, 1) | Reduced level | |||||||||||
| p.E28Q/A62T (1, 1) | Normal level | |||||||||||
| AD (likely LOF) | N/A | p.Q185* (1, 1) | Reduced level | Impaired response to IFN-β pretreatment but normal ISG (IFIT1) and TNFA expression | Impaired type I/II/III IFN | Severe SARS-CoV-2 (4/5) and influenza (1/5) | Severe IAV and SARS-CoV-2 | Not reported | Not reported | Defective control of viral replication in monocyte-derived macrophages | Thomsen et al. (2019a); Zhang et al. (2020) | |
| p.E331V (isoform B, canonical p.E360V, 1, 1) | Normal level | |||||||||||
| p.R7fs (1, 1) p.P246fs (1, 1) p.R369Q (1, 1) p.F95S (1, 1) | Not reported | |||||||||||
| IRF8 | AR (LOF) | 226990 | p.K108E (1, 1) | Normal amount but altered structure/folding | Nearly inactive for IL12B and NOS2 promoters | Reduced IFN-γ, TNF-α, IL-17, IL-6, and IL-10. Impaired IL-12 response to IFN-γ pretreatment, absent at baseline | MSMD. HSCT curative | Weakly virulent mycobacteria and C. albicans | Reduced NK cells but elevated CD56bright population. Normal T and B cells | Severely reduced monocytes and DCs, reduced tissue macrophages. Elevated CD34+ progenitors. >98% granulocytes with cultivation of stem cells | | Hambleton et al. (2011); Salem et al. (2014); Mace et al. (2017) |
| p.R83C/R291Q (1, 1) | Normal level but impaired nuclear localization | Reduced expression of IRF4 and IRF1. Impaired regulation of IRF1-driven ISRE activity. Failed expression from EICE. Altered gene expression pattern, including genes crucial to immune development, and function | Absent IL-12, reduced IFN-γ, IL-6, IL-10, and TNF-α levels. Elevated IL-10 in one case | Fatal in infancy (2/3). Recurrent viral infection, intracerebral calcification, disseminated BCGosis. Developmental delay, facial dysmorphism, and short stature (1/3). HSCT (1/3) | Influenza, rhinovirus, non-SARS-CoV-2 coronavirus, CMV, mycoplasma, and Acinetobacter baumannii | Reduced Th1, Th17, CD3+, CD8+ T cells, CD8+ memory T cells, memory B cells. Reduced NK cell terminal differentiation with impaired B cell class switching and somatic hypermutation. One case with only mild CD4+ lymphopenia with no other T cell defects | Increased dysfunctional granulocytes. Reduced or absent monocytes, pDCs, and cDC1s | | Bigley et al. (2018); Dang et al. (2021); Rosain et al. (2022) | |||
| p.R111*/p.R111* (1,1) p.R111*/c.55del (1, 1) | Reduced level of truncated protein and impaired localization | |||||||||||
| AD (DN) | 614893 | p.T80A (2, 2) | Normal level | Low activity for IL12B and NOS2 promoters. Impaired expression of genes vital for pDC function and development | Reduced IL-12 in vitro but normal in BCG-stimulated blood. Normal IFN-γ but impaired IFN-α production | MSMD (1/3), EBV viremia (1/3), and HPV-positive tumor (1/3) | Weakly virulent mycobacteria, EBV, and HPV | Elevated central and effector memory T cells. Impaired Th1 response. Decreased memory B cells, but increased IgG and normal IgA levels | Reduced pDCs, cDC1 DCs. Mild neutrophilia and monocytosis | | Hambleton et al. (2011); Ham et al. (2025) | |
| p.∗427Lext∗42 (2, 1) | Impaired localization. DN effect on IRF8 and IRF1 | |||||||||||
| IRF9 | AR (LOF) | 618648 | c.991G>A (IRF9-Δex7, p.D331N) (1, 1) | Transcripts missing exon 7, none with D331N. Formation of ISGF3 lost | Impaired ISRE activity and reduced expression of a wide range of canonical ISGs. Failed upregulation of IRF7 | Impaired type I IFN production. Some IFN-α2 in blood | Repeated severe viral infections | IAV/IBV, SARS-CoV-2, adenovirus, PIV, MMR-strain virus, RSV, VZV, dengue fever, Zika virus, and enterovirus | Reduced B cells, CD4+ T cells, and transient decrease in NK cells. Hypogammaglobulinemia | None reported | Fibroblasts: poor IFN-α2 response and impaired control of IAV and VSV. Prolonged IFNAR signaling and IFN-γ–like transcriptional profile | (Hernandez et al., 2018; Bravo García-Morato et al., 2019); Lévy et al. (2021b); Gothe et al. (2022) |
| p. E166Lfs*80 (IRF9-Δex5) (2, 1) | No detectible protein |
| Gene | Inheritance (mechanism) | OMIM | Known variants (# patients, # kindreds) | Effect on protein | Effect on gene expression | Cytokine defects | Major clinical features | Pathogen susceptibility | Effect on lymphoid cells | Effect on myeloid cells | Other effects | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AR (LOF) | 620668 | p.R129* (1, 1) | Elevated level but truncated | Reduced activity for ISRE5 and IRFE3. Impaired gene expression for leukocyte activation, cytokine signaling | Impaired IFN-γ response. Mild impairment of IFN-α/β response | Early-onset severe MSMD | Weakly virulent mycobacteria and | Severe reduction of NK cells and ILC precursors. Reduced naïve CD8+ T cells and RTE CD4+ T cells. Elevated memory CD8+, TFH, effector T, and IgA+ memory B cells. Impaired Th1 response | Reduced cDC1, cDC2, and pDCs | Impaired control of mycobacteria in IRF1-deficient phagocytes | ||
| p.Q35* (1, 1) | Produced but lacking the first 84 amino acids of the DBD | |||||||||||
| AD (HI) | 616532 | p.R285Q (1, 1) | Impaired phosphorylation and dimerization | Impaired | Impaired type I/III IFN, CXCL10, and TNF-α | Healthy until HSE (ages 15 and 34). Incomplete penetrance | HSV-1 | Not reported | Not reported | Reduced fibroblast IFN-β. Reduced interaction with innate adaptor proteins | ||
| p.A277T (1, 1) | Not reported | |||||||||||
| N/A | c.1576C>T (p.P447S) (1, 1) | Reduced in PBMCs, normal | Impaired ISG expression. Failed IRF7 upregulation | Impaired type I/III IFN, IL-6, and TNF-α | Severe respiratory viral infections | IAV & SARS-CoV-2 | Not reported | Not reported | | |||
| p.E49del (1, 1) | Not reported | |||||||||||
| AR (UPD) | 621097 | p.V405GfsTer127 (1, 1) | Reduced level | Increased expression of genes associated with proinflammatory macrophage polarization | Impaired IFN-γ production | Intrauterine growth retardation, dermatitis, fevers, tachycardia, generalized adenopathy, hypoglycemia, and failure to thrive. HSCT at 2 years, died at day +2 | Rotavirus, | Reduced B cells, TFH, Th17, Tregs, and memory T cells with a severe reduction of memory B and effector memory CD8+ T cells. Elevated RTE CD4+ T cells. Agammaglobulinemia. Elevated Th1:Th2 ratio | Hypereosinophilia, and hemophagocytosis. Severely reduced CD1a+ DCs and elevated pDCs | Abnormal lymph node architecture | ||
| AD (MM) | p.T95R (7, 6) | Normal protein level, impaired localization | Impaired expression of genes associated with plasma cell differentiation. Neomorphic upregulation of CXCL13 | Impaired IL-12 and IFN-γ production. Reduced polyfunctional cells producing both IFN-γ and TNF-α | High susceptibility to opportunistic infection. Hypogammaglobulinemia. Early onset (<1 year). HSCT (2/7). Chronic diarrhea | P. jirovecii, CMV, EBV, vaccine strain BCG, | Reduced CD19+ B, memory B cells, Th17, and TFH. Elevated naïve and transitional B cells. Impaired B cell maturation, isotype switching, plasma cell maturation, and agammaglobulinemia | None reported | Multimorphic: hypomorphic binding to canonical sites, neomorphic binding to novel targets, and hypermorphic binding to ISRE | |||
| p.F359L (3, 1) | Normal level, and localization. DN effect on ISRE | Impaired ISRE binding but increased expression from AICE and EICE. Low expression of genes associated with plasma cell differentiation | Neomorphic binding to proteins for positive regulation of type I IFN production | High susceptibility to opportunistic infection. Hypogammaglobulinemia. Premature hair graying | CMV, | Childhood panhypogammaglobulinemia. Reduced plasmablasts, naïve CD4+ & CD8+ T cells. Elevated terminal effector CD4+ and CD8+ T cells | None reported | Altered binding with IRF4-associated proteins (↓ PC4, ↑ JUNB, novel binding ETV6) | ||||
| AD (HI) | p.R98W (4, 1) | Elevated level. Normal nuclear localization | Impaired expression from ISRE and AICE. Decreased expression of STAT1 and CD80 | Impaired expression of IFNG, LTA, and IL2RA | WD (2 classic WD, 2 with joint symptoms). Incomplete penetrance | Tw | None reported | None reported | | |||
| AD (VWS) | 119300 | Missense, nonsense, or splicing variants in the DBD and IAD | Primarily hypomorphic effect | | | Lip pits with or without CLP | No known infection susceptibility | None reported | None reported | | ||
| | AD (PPS) | 119500 | Missense, nonsense, or splicing variants in the DBD and IAD, with a high prevalence of missense variants near R84 in the DBD | Primarily dominant negative | p.S424L variant significantly reduced transcriptional activity. Loss of contact between DBD and DNA in p.R84C and p.R84H variants | | CLP, lip pits, popliteal webbing, syndactyly, hypodontia, and deformities of the limbs and genitals | No known infection susceptibility | None reported | None reported | A single case of AR IRF6 variants has been linked to PPS | |
| AR (LOF) | 616345 | p.F410V/p.Q421* (1, 1) | Reduced level, impaired localization | Impaired expression of many ISGs, but normal upregulation of a subset of ISGs. Failed IRF7 upregulation | Impaired type I/II/III IFN. Normal IL-6 and TNF-α | Severe viral infections with one to three major episodes | Severe IAV and SARS-CoV-2. RSV, TBE virus and adenovirus | Increased memory T cells to SARS-CoV-2 infection or vaccination. Increased CD4+ T cells to IAV. Intact B cell responses | Normal pDC counts but impaired type I/III IFN production | Fibroblasts: impaired IFN-β and poor control of viral replication. Pulmonary epithelial cells: poor IRF7 and IFN-β production | ||
| p.A280GfsX12 (2, 1) | Reduced level | |||||||||||
| p.E28Q/A62T (1, 1) | Normal level | |||||||||||
| AD (likely LOF) | N/A | p.Q185* (1, 1) | Reduced level | Impaired response to IFN-β pretreatment but normal ISG (IFIT1) and TNFA expression | Impaired type I/II/III IFN | Severe SARS-CoV-2 (4/5) and influenza (1/5) | Severe IAV and SARS-CoV-2 | Not reported | Not reported | Defective control of viral replication in monocyte-derived macrophages | ||
| p.E331V (isoform B, canonical p.E360V, | Normal level | |||||||||||
| p.R7fs (1, 1) | Not reported | |||||||||||
| AR (LOF) | 226990 | p.K108E (1, 1) | Normal amount but altered structure/folding | Nearly inactive for | Reduced IFN-γ, TNF-α, IL-17, IL-6, and IL-10. Impaired IL-12 response to IFN-γ pretreatment, absent at baseline | MSMD. HSCT curative | Weakly virulent mycobacteria and | Reduced NK cells but elevated CD56bright population. Normal T and B cells | Severely reduced monocytes and DCs, reduced tissue macrophages. Elevated CD34+ progenitors. >98% granulocytes with cultivation of stem cells | | ||
| p.R83C/R291Q (1, 1) | Normal level but impaired nuclear localization | Reduced expression of IRF4 and IRF1. Impaired regulation of IRF1-driven ISRE activity. Failed expression from EICE. Altered gene expression pattern, including genes crucial to immune development, and function | Absent IL-12, reduced IFN-γ, IL-6, IL-10, and TNF-α levels. Elevated IL-10 in one case | Fatal in infancy (2/3). Recurrent viral infection, intracerebral calcification, disseminated BCGosis. Developmental delay, facial dysmorphism, and short stature (1/3). HSCT (1/3) | Influenza, rhinovirus, non-SARS-CoV-2 coronavirus, CMV, mycoplasma, and | Reduced Th1, Th17, CD3+, CD8+ T cells, CD8+ memory T cells, memory B cells. Reduced NK cell terminal differentiation with impaired B cell class switching and somatic hypermutation. One case with only mild CD4+ lymphopenia with no other T cell defects | Increased dysfunctional granulocytes. Reduced or absent monocytes, pDCs, and cDC1s | | ||||
| p.R111*/p.R111* (1,1) | Reduced level of truncated protein and impaired localization | |||||||||||
| AD (DN) | 614893 | p.T80A (2, 2) | Normal level | Low activity for | Reduced IL-12 | MSMD (1/3), EBV viremia (1/3), and HPV-positive tumor (1/3) | Weakly virulent mycobacteria, EBV, and HPV | Elevated central and effector memory T cells. Impaired Th1 response. Decreased memory B cells, but increased IgG and normal IgA levels | Reduced pDCs, cDC1 DCs. Mild neutrophilia and monocytosis | | ||
| p.∗427Lext∗42 (2, 1) | Impaired localization. DN effect on IRF8 and IRF1 | |||||||||||
| AR (LOF) | 618648 | c.991G>A (IRF9-Δex7, p.D331N) (1, 1) | Transcripts missing exon 7, none with D331N. Formation of ISGF3 lost | Impaired ISRE activity and reduced expression of a wide range of canonical ISGs. Failed upregulation of IRF7 | Impaired type I IFN production. Some IFN-α2 in blood | Repeated severe viral infections | IAV/IBV, SARS-CoV-2, adenovirus, PIV, MMR-strain virus, RSV, VZV, dengue fever, Zika virus, and enterovirus | Reduced B cells, CD4+ T cells, and transient decrease in NK cells. Hypogammaglobulinemia | None reported | Fibroblasts: poor IFN-α2 response and impaired control of IAV and VSV. Prolonged IFNAR signaling and IFN-γ–like transcriptional profile | ||
| p. E166Lfs*80 (IRF9-Δex5) (2, 1) | No detectible protein |
HI, haploinsufficiency; DN, dominant negative; MM, multimorphic; ILC, innate lymphoid cell; RTE, recent thymic emigrant.
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