Version June 2024
| Disease | Genetic defect | Inheritance | OMIM | T cells | B cells | Functional defects | Associated features |
| Type 1 interferonopathies | |||||||
| AD STING-associated vasculopathy, infantile onset (SAVI) | Stimulator of interferon response cGAMP interactor 1 (STING1) | AD | 612374 | Not assessed | Not assessed | STING activates both the NFkB and IRF3 transcription pathways to induce expression of IFN | Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL |
| AR STING-associated vasculopathy, infantile onset (SAVI) | Stimulator of interferon response cGAMP interactor 1 (STING1) | AR GOF | 615934 | Not assessed | Not assessed | STING activates both the NFkB and IRF3 transcription pathways to induce expression of IFN | Failure to thrive, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoantibodies, increased inflammatory markers, IFN gene signature; phenocopy of SAVI due to AD GOF STING1 |
| ADA2 deficiency | Adenosine deaminase 2 (ADA2) | AR | 607575 | Not assessed | Not assessed | ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors | Childhood-onset polyarteritis nodosa, early-onset recurrent ischemic stroke and fever, some patients develop hypogammaglobulinemia |
| TREX1 deficiency, AGS1 | Three-prime repair exonuclease 1 (TREX1) | AR and AD | 606609 | Not assessed | Not assessed | Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production | Classical AGS, SLE, FCL |
| RNASEH2B deficiency, AGS2 | Ribonuclease H2 subunit B (RNASEH2B) | AR | 610326 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS, spastic paraparesis |
| RNASEH2C deficiency, AGS3 | Ribonuclease H2 subunit C (RNASEH2C) | AR | 610330 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS |
| RNASEH2A deficiency, AGS4 | Ribonuclease H2 subunit A (RNASEH2A) | AR | 606034 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS |
| SAMHD1 deficiency, AGS5 | SAM and HD domain-containing deoxynucleoside triphosphate (SAMHD1) | AR | 606754 | Not assessed | Not assessed | Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production | Classical AGS, FCL |
| ADAR1 deficiency, AGS6 | Adenosine deaminase RNA specific (ADAR) | AR | 146920 | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production | Classical AGS, BSN, spastic paraparesis |
| AGS7 | Interferon induced with helicase C domain 1 (IFIH1) | AD GOF | 615846 | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type 1 IFN signaling through the MAVS adaptor molecule | Classical AGS, SLE, spastic paraparesis, SMS |
| DNAse II deficiency | Deoxyribonuclease 2, lysosomal (DNASE2 | AR | 126350 | Not assessed | Not assessed | DNAse II degrades and eliminates DNA; loss of DNAse II activity induces type I IFN signaling | AGS |
| LSM11 deficiency | LSM11, U7 small nuclear RNA associated (LSM11) | AR | 619486 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| RNU7-1 deficiency | RNA, U7 small nuclear 1 (RNU7-1) | AR | 619487 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| Pediatric SLE due to DNASE1L3 deficiency | Deoxyribonuclease 1-like 3 (DNASE1L3) | AR | 614420 | DNASE1L3 is an endonuclease that degrades extracellular DNA; DNASE1L3 deficiency decreased clearance of apoptotic cells | Very-early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticaria vasculitis syndrome | ||
| Spondyloenchondrodysplasia with immune dysregulation (SPENCD) | Acid phosphatase 5, tartrate resistant (ACP5) | AR | 171640 | Not assessed | Not assessed | Upregulation of IFN through a mechanism possibly relating to pDCs | Short stature, spastic paraparesis, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections |
| X-linked reticulate pigmentary disorder | DNA polymerase alpha 1, catalytic subunit (POLA1) | XL | 301220 | Not assessed | Not assessed | POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased production of type I IFN | Hyperpigmentation, characteristic facies, lung and GI involvement |
| USP18 deficiency | Ubiquitin-specific peptidase 18 (USP18) | AR | 607057 | Not assessed | Not assessed | Defective negative regulation of ISG15 leading to increased IFN | TORCH-like syndrome |
| OAS1 deficiency | 2'-5'-oligoadenylate synthetase 1 (OAS1) | AD GOF | 164350 | Low | Increased IFN from recognition of RNA | Pulmonary alveolar proteinosis, skin rash | |
| CDC42 deficiency | Cell division cycle 42 (CDC42) | AD | 616737 | Normal/decreased | Normal/decreased | Increased serum levels of IL-1, IL-18, IFN-gamma, ferritin, sCD25, CRP, etc; mutation affects actin function; decreased NK cell cytotoxicity | Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GI tract/upper respiratory tract infections; neurodevelopmental delay, failure to thrive |
| STAT2 R148 LOF/regulation | Signal transducer and activator of transcription 2 (STAT2) | AR | 616636 | Increased | Normal | Patient cells hypersensitive to IFN-alpha; GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses | Severe fatal early-onset autoinflammation, elevated serum IFN-alpha, IL-6, TNF-alpha; phenocopy of USP18 deficiency |
| ATAD3A deficiency | ATPase family AAA domain-containing 3A (ATAD3A) | AD and AR | 617183 | Not assessed | Not assessed | Increased ISG expression; increased serum type 1 IFNs | Predominantly neurologic defects (developmental delay, spasticity) |
| Disease | Genetic defect | Inheritance | OMIM | Affected cells | Functional defects | Associated features | |
| Defects affecting the inflammasome | |||||||
| Familial Mediterranean fever | MEFV innate immunity regulator, pyrin (MEFV) | AR LOF | 249100 | Mature granulocytes, cytokine-activated monocytes | Increased inflammasome-mediated induction of IL-1-beta | Recurrent fever, serositis and inflammation responsive to colchicine, predisposes to vasculitis and IBD | |
| AD | 134610 | Mature granulocytes, cytokine-activated monocytes | Usually M694del variant | Recurrent fever, serositis and inflammation responsive to colchicine, predisposes to vasculitis and IBD | |||
| Mevalonate kinase deficiency (hyper-IgD syndrome) | Mevalonate kinase (MVK) | AR | 260920 | Somatic and hematopoietic | Affecting cholesterol synthesis, pathogenesis of disease unclear | Periodic fever and leukocytosis with high IgD levels | |
| Muckle-Wells syndrome | NLR family pyrin domain containing 3 (NLRP3) | AD GOF | 191900 | PMNs, monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis | |
| Familial cold autoinflammatory syndrome 1 | NLR family pyrin domain containing 3 (NLRP3) | AD GOF | 120100 | PMNs, monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Nonpruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure | |
| Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | NLR family pyrin domain containing 3 (NLRP3) | AD GOF | 607115 | PMNs, chondrocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Neonatal-onset rash, chronic meningitis, arthropathy with fever and inflammation | |
| Familial cold autoinflammatory syndrome 2 | NLR family pyrin domain containing 12 (NLRP12) | AD GOF | 611762 | PMNs, monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Nonpruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure | |
| NLRC4-MAS | NLR family CARD domain containing 4 (NLRC4) | AD GOF | 616050 | PMNs, monocytes, macrophages | GOF mutation in NLRC4 results in elevated secretion of IL-1-beta and IL-18 as well as macrophage activation | Severe enterocolitis and MAS | |
| Familial cold autoinflammatory syndrome 4 | NLR family CARD domain containing 4 (NLRC4) | AD GOF | 616115 | PMNs, monocytes, macrophages | GOF mutation in NLRC4 results in elevated secretion of IL-1-beta and IL-18 as well as macrophage activation | Severe enterocolitis and MAS | |
| PLC-gamma-2-associated antibody deficiency and immune dysregulation (PLAID) | Phospholipase C gamma 2 (PLCG2) | AD GOF | 614878 | B cells, NK cells, mast cells | Mutations activate IL-1 pathways | Cold urticaria, hypogammaglobulinemia, impaired humoral immunity, autoinflammation | |
| Familial cold autoinflammatory syndrome 3 or APLAID (c2120A>C) | Phospholipase C gamma 2 (PLCG2) | AD GOF | 614468 | B cells, NK cells, mast cells | Mutations activate IL-1 pathways | Cold urticaria, hypogammaglobulinemia, impaired humoral immunity, autoinflammation | |
| NLRP1 deficiency | NLR family pyrin domain containing 1 (NLRP1) | AR | 617388 | Leukocytes | Systemic elevation of IL-18 and caspase 1, suggesting involvement of NLRP1 inflammasome | Dyskeratosis, autoimmunity and arthritis | |
| NLRP1 GOF | NLR family pyrin domain containing 1 (NLRP1) | AD GOF | 615225 | Keratinocytes | Increased IL-1-beta | Palmoplantar carcinoma, corneal scarring, recurrent respiratory papillomatosis | |
| RIPK1 deficiency | Receptor-interacting serine/threonine kinase 1 (RIPK1) | AD | 618852 | Increased inflammatory markers and proinflammatory cytokines/gene signature | Autoinflammatory disorder: regular/prolonged fevers, lymphadenopathy, splenomegaly/hepatomegaly, ulcers, arthralgia, GI features | ||
| Noninflammasome-related conditions | |||||||
| TNF receptor-associated periodic syndrome (TRAPS) | TNF receptor superfamily member 1A (TNFRSF1A) | AD | 142680 | PMNs, monocytes | Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF | Recurrent fever, serositis, rash, and ocular or joint inflammation | |
| Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia and hypercalprotectinemia | Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) | AD | 604416 | Hematopoietic tissues, upregulated in activated T cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | |
| Blau syndrome | Nucleotide-binding oligomerization domain-containing 2 (NOD2) | AD | 186580 | Monocytes | Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NFkB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn colitis | |
| ADAM17 deficiency | ADAM metallopeptidase domain 17 (ADAM17) | AR | 614328 | Leukocytes, epithelial cells | Defective TNF-alpha production | Early-onset diarrhea and skin lesions | |
| Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) | Lipin 2 (LPIN2) | AR | 609628 | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | |
| Deficiency of the IL-1 receptor antagonist (DIRA) | Interleukin 1 receptor antagonist (IL1RN) | AR | 612852 | PMNs, monocytes | Mutations in IL1RN allow unopposed action of IL-1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis | |
| Deficiency of IL-36 receptor antagonist (DITRA) | Interleukin 36 receptor antagonist (IL36RN) | AR | 614204 | Keratinocytes, leukocytes | Mutations in IL36RN lead to increased IL-8 production | Pustular psoriasis | |
| SLC29A3 mutation | Solute carrier family 29 member 3 (SLC29A3) | AR | 602782 | Leukocytes, bone cells | Hyperpigmentation, hypertrichosis, histiocytosis-lymphadenopathy plus syndrome | ||
| CARD14-mediated psoriasis (CAMPS) | Caspase recruitment domain family member 14 (CARD14) | AD | 602723 | Mainly keratinocytes | Mutations in CARD14 activate the NFkB pathway and production of Il-8 | Psoriasis | |
| Cherubism | SH3 domain binding protein 2 (SH3BP2) | AD | 118400 | Stroma cells, bone cells | Hyperactive macrophage and increased NFkB | Bone degeneration in jaws | |
| Chronic atypical neutrophilic dermatitis with lipodystrophy (CANDLE) | Proteasome 20S subunit beta 8 (PSMB8)* | AR and AD | 256040 | Keratinocytes, B cell adipose cells | Mutations cause increased IFN signaling through an undefined mechanism | Contractures, panniculitis, ICC, fevers | |
| Proteasome assembly chaperone 2 (PSMG2) | AR | 609702 | Lymphocytes | Mutations cause increased IFN signaling through an undefined mechanism | Panniculitis, lipodystrophy, autoimmune hemolytic anemia | ||
| COPA defect | COPI coat complex subunit alpha (COPA) | AD | 601924 | PMNs and tissue-specific cells | Defective intracellular transport via the coat protein complex I (COPI) | Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production | |
| Otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) | OTU deubiquitinase with linear linkage specificity (OTULIN) | AR | 615712 | Leukocytes | Increased LUBAC induction of NFkB activation leading to high proinflammatory cytokine levels | Fever, diarrhea, dermatitis | |
| A20 deficiency | TNF-alpha-induced protein 3 (TNFAIP3) | AD | 616744 | Lymphocytes | Defective inhibition of NFkB signaling pathway | Arthralgia, mucosal ulcers, ocular inflammation | |
| AP1S3 deficiency | Adaptor-related protein complex 1 subunit sigma 3 (AP1S3) | AR | 615781 | Keratinocytes | Disrupted TLR3 translocation | Pustular psoriasis | |
| ALPI deficiency | Alkaline phosphatase, intestinal (ALPI) | AR | 171740 | Intestinal epithelial cells | Deficient inhibition of LPS in intestine | IBD | |
| TRIM22 deficiency | Tripartite motif containing 22 (TRIM22) | AR | 606559 | Macrophages, intestinal epithelial cells | Granulomatous colitis | IBD | |
| T cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency) | Hepatitis A virus cellular receptor 2 (HAVCR2) | AR | 618398 | Leukocytes | Increased inflammasome activity due to defective checkpoint signaling | Panniculitis, HLH, polyclonal cutaneous T cell infiltrates or T cell lymphoma | |
| C2orf69 deficiency | Chromosome 2 open reading frame 69 (C2orf69) | AR | 619423 | Early-onset severe autoinflammation disorder, often fatal; global developmental delay with recurrent seizures, muscle weakness, liver dysfunction | |||
| NCKAP1L deficiency | NCK-associated protein 1-like (NCKAP1L) | AR | 618982 | Lymphocytes | Hyperinflammation and cytokine overproduction (increased Th1), decreased T cell proliferation, cytoskeletal defects | Recurrent upper respiratory tract infection, skin rashes/abscesses/atopy, ulcers, lymphoproliferation/lymphadenopathy, hyperinflammation, anti-dsDNA antibodies, fever, failure to thrive | |
| SYK GOF | Spleen-associated tyrosine kinase (SYK) | AD GOF | 619381 | Lymphocytes | Increased SYK phosphorylation, enhanced downstream signaling | Recurrent infections, multiorgan inflammation/inflammatory disease (gut, skin, CNS, lung, liver), B cell lymphoma (2 patients) | |
| HCK GOF | HCK proto-oncogene, Src family tyrosine kinase (HCK) | AD GOF | Increased kinase activity of HCK mutant in vitro, increased production of inflammatory cytokines (IL-1-beta, IL-8, IL-8, TNF-alpha), ROS | Cutaneous vasculitis, inflammatory leukocyte infiltration of the lungs (pulmonary fibrosis) and skin, anemia, hepatosplenomegaly | |||
| PSMB9 GOF | Proteasome 20S subunit beta 9 (PSMB9) | AD GOF | 617591 | Mild pancytopenia, leukocytes | Elevated levels of inflammatory cytokines (IL-6, IL-18, IP-10, IFN-alpha), liver enzymes in blood and CSF (IFN-alpha), hyperactivation of IFN-alpha, pSTAT1, reduced proteasome activities | Severe autoinflammatory phenotype (neonatal-onset fever, skin rash, myositis, severe pulmonary hypertension, basal ganglia calcification), periodic inflammatory exacerbation, immunodeficiency; partial phenocopy of PRAAS | |
| IKBKG (NEMO exon 5 deletion) | Inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG) | XL | Leukocytes | Mutant NEMO lacked exon 5, failed to bind TBK1 and stabilized IKKi, increasing type 1 IFN production | Fever, skin, rash, systemic autoinflammation, infections, CNS involvement, panniculitis, uveitis, hepatosplenomegaly, ectodermal dysplasia | ||
| TBK1 deficiency | TANK-binding kinase 1 (TBK1) | AR | Leukocytes | Autoinflammation driven by TNF-induced RIPK1-dependent cell death | Chronic systemic autoinflammation (polyarthritis, vasculitis, rash), delayed neurocognitive development | ||
IUIS: International Union of Immunological Societies; AD: autosomal dominant; NFkB: nuclear factor kappa B; IRF: interferon regulatory factor; IFN: interferon; ICC: intracranial calcification; FCL: familial chilblain lupus; AR: autosomal recessive; GOF: gain of function; AGS: Aicardi-Goutières syndrome; ssDNA: single-stranded deoxyribonucleic acid; SLE: systemic lupus erythematosus; RNA: ribonucleic acid; dNTP: deoxynucleoside triphosphate; dsRNA: double-stranded RNA; BSN: bilateral striatal necrosis; MAVS: mitochondrial antiviral-signaling protein; SMS: Singleton-Merten syndrome; dsDNA: double-stranded DNA; ANCA: antineutrophil cytoplasmic antibody; pDC: plasmacytoid dendritic cell; XL: X linked; GI: gastrointestinal; ISG: interferon-stimulated gene; TORCH: toxoplasmosis, other (syphilis), rubella, cytomegalovirus, herpes simplex virus; IL: interleukin; CRP: C-reactive protein; NK: natural killer; HLH: hemophagocytic lymphohistiocytosis; LOF: loss of function; TNF: tumor necrosis factor; IBD: inflammatory bowel disease; IgD: immunoglobulin D; PMN: polymorphonuclear neutrophil; SNHL: sensorineural hearing loss; MAS: macrophage activation syndrome; CARD15: caspase recruitment domain family, member 15; Th17: T helper type 17; LUBAC: linear ubiquitin chain assembly complex; TLR: toll-like receptor; LPS: lipopolysaccharide; TIM3: T cell immunoglobulin mucin family member 3; Th1: T helper type 1; CNS: central nervous system; ROS: reactive oxygen species; IP-10: IFN-gamma inducible protein 10kDa; CSF: cerebrospinal fluid; NEMO: NFkB essential modulator; TBK1: TANK-binding kinase 1; IKKi: I-kappa-B kinase epsilon; RIPK1: receptor-interacting serine/threonine kinase 1.
* Variants in proteasome 20S subunit beta 4 (PSMB4), proteasome 20S subunit beta 9 (PSMB9), proteasome 20S subunit alpha 3 (PSMA3), and proteasome maturation protein (POMP) have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8), PSMB4/PSMB8), and AD monogenic (POMP) models.[1]
From: Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42:1473. Copyright © 2022 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0.
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