Classifications of IEIs
Explore the foundational categories of Inborn Errors of Immunity (IEI). Our classification follows the IUIS expert committee standards, providing a detailed framework for understanding the diverse clinical presentations and underlying genetic causes of these rare disorders.
1. Immunodeficiencies Affecting Cellular and Humoral Immunity
Description
These inborn errors impair both T-cell and B-cell function, leading to increased susceptibility to a wide range of infections. The severity ranges from severe combined immune deficiency (SCID), typically presenting in infancy, to less profound combined immunodeficiency (CID) with later or milder onset.
Pathophysiology / Cause
Disruptions in genes essential for T-cell and B-cell development, survival, or function. Defects may affect cytokine receptor signaling (e.g., common gamma chain), V(D)J recombination, DNA repair, or T-cell receptor complex components. Some hypomorphic mutations result in "leaky" SCID or Omenn syndrome.
Key Conditions
T-B+ SCID: IL2RG deficiency (X-linked SCID), JAK3 deficiency, IL7Rα deficiency.
T-B- SCID: RAG1/2 deficiency, DCLRE1C (Artemis) deficiency, ADA deficiency, DNA ligase IV deficiency.
Combined Immunodeficiency (CID): CD40 ligand deficiency, DOCK8 deficiency (elevated IgE, eosinophilia, viral susceptibility), MHC class II deficiency, ICOS deficiency, ZAP-70 deficiency.
Recent Additions
IRF4, NFATC1, PRIM1, FOXI3, POLD3, NUDCD3, PSMB10.
2. Combined Immunodeficiencies with Syndromic Features
Description
These disorders combine immunodeficiency with non-immunological congenital anomalies affecting multiple organ systems, including skeletal, neurologic, dermatologic, or cardiac structures.
Pathophysiology / Cause
Genetic defects often involve DNA repair mechanisms, cytoskeletal regulation, cytokine signaling, or thymic development. Some conditions result from telomere maintenance defects or transcription factor abnormalities.
Key Conditions
Immunodeficiency with congenital thrombocytopenia: Wiskott-Aldrich syndrome (WAS LOF, small platelets), WIPF1 deficiency, ARPC1B deficiency.
DNA repair defects: Ataxia-telangiectasia (ATM), Nijmegen breakage syndrome (NBN), Bloom syndrome (BLM), ICF syndromes (DNMT3B, ZBTB24).
Thymic defects with congenital anomalies: 22q11.2 deletion syndrome, CHARGE syndrome (CHD7), FOXN1 deficiency (alopecia, nail dystrophy).
Hyper-IgE syndromes: STAT3 deficiency (Job syndrome), IL6ST deficiency, ZNF341 deficiency.
Other: PGM3 deficiency (severe eczema, skeletal anomalies), STAT6 gain-of-function (severe allergic disease).
Recent Additions
Dominant negative IKZF2 (ICHAD syndrome), GINS4 deficiency, STAT6 gain-of-function, SLC19A1 deficiency, SGPL1 deficiency, PTCR, FLT3L deficiency, ITPR3 deficiency, RECQL4-associated disease.
3. Predominantly Antibody Deficiencies
Description
These disorders are defined by defective antibody production, leading to recurrent sinopulmonary infections, particularly with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.
Pathophysiology / Cause
Genetic lesions disrupt B-cell development, class-switch recombination, somatic hypermutation, or plasma cell function. Some defects affect B-cell receptor signaling or survival.
Key Conditions
Agammaglobulinemia: BTK deficiency (X-linked agammaglobulinemia), μ heavy chain deficiency, IGHM.
CVID phenotype: PIK3CD gain-of-function (APDS1), PIK3R1 loss-of-function (APDS2), NFKB1 deficiency, NFKB2 deficiency, IKAROS deficiency.
Hyper-IgM syndromes: AID deficiency (AICDA), UNG deficiency, CD40 ligand deficiency.
Isotype or functional deficiencies: Selective IgA deficiency, specific antibody deficiency with normal immunoglobulins, IgG subclass deficiency.
Recent Additions
PAX5 deficiency, KARS1 deficiency.
4. Diseases of Immune Dysregulation
Description
These inborn errors present predominantly with autoimmunity, lymphoproliferation, hemophagocytic lymphohistiocytosis (HLH), or susceptibility to Epstein-Barr virus (EBV), often without prominent susceptibility to routine infections.
Pathophysiology / Cause
Defects in lymphocyte cytotoxicity, regulatory T-cell function, apoptosis pathways, or cytokine signaling. Hyperinflammatory states may result from uncontrolled inflammasome activation or impaired immune checkpoint function.
Key Conditions
Familial HLH syndromes: Perforin deficiency (PRF1), UNC13D deficiency, STX11 deficiency, STXBP2 deficiency.
Regulatory T-cell defects: IPEX syndrome (FOXP3), CD25 deficiency (IL2RA), CTLA4 haploinsufficiency, LRBA deficiency.
Autoimmunity: APECED (AIRE), STAT3 gain-of-function, SOCS1 haploinsufficiency, PD-1 deficiency (PDCD1), PD-L1 deficiency (CD274).
Autoimmune lymphoproliferative syndrome (ALPS): FAS, FASLG, CASP10 mutations.
Susceptibility to EBV: SAP deficiency (SH2D1A, XLP1), XIAP deficiency (XLP2), CD27 deficiency, CD70 deficiency, MAGT1 deficiency (XMEN syndrome).
Recent Additions
CD274 (PD-L1) deficiency, TLR7 gain-of-function (monogenic lupus), UNC93B1 gain-of-function (lupus), TRAF3 haploinsufficiency, CBLB deficiency, PLCG1 gain-of-function, SH2B3 deficiency, ARPC5 deficiency, NFATC2 deficiency, DOCK11 deficiency, RHBDF2 deficiency, LACC1 deficiency (arthritis), ERN1 deficiency (IRE1α), NBEAL2 deficiency, IL27RA deficiency, TNFSF9 deficiency (CD137L), DPP9 deficiency, GIMAP6 deficiency.
5. Congenital Defects of Phagocyte Number or Function
Description
These disorders affect neutrophils, monocytes, and other phagocytes, resulting in increased susceptibility to bacterial and fungal infections, often with atypical or severe presentations.
Pathophysiology / Cause
Defects in myeloid differentiation, chemotaxis, respiratory burst activity, or granule formation. Genetic lesions may impair adhesion, migration, or intracellular killing.
Key Conditions
Congenital neutropenia: ELANE deficiency, HAX1 deficiency (Kostmann disease), G6PC3 deficiency, VPS45 deficiency.
Defects of motility: Leukocyte adhesion deficiency (LAD type I, ITGB2), WDR1 deficiency, cystic fibrosis (CFTR), CCR2 deficiency.
Defects of respiratory burst: Chronic granulomatous disease (CGD) due to CYBB (X-linked), CYBA, NCF1, NCF2, NCF4.
Other non-lymphoid defects: Pulmonary alveolar proteinosis (CSF2RA, CSF2RB deficiencies).
Recent Additions
DBF4 deficiency, SRP19 deficiency, SRPRA deficiency, CCR2 deficiency (pulmonary alveolar proteinosis and recurrent infections).
6. Defects in Intrinsic and Innate Immunity
Description
These inborn errors impair innate immune responses to specific pathogen classes, including mycobacteria, viruses, and fungi, without necessarily causing global immunodeficiency.
Pathophysiology / Cause
Disruptions in pattern recognition receptor signaling, interferon production and response, or cytokine pathways essential for controlling particular microorganisms.
Key Conditions
MSMD: IFN-γ receptor deficiency (IFNGR1, IFNGR2), IL-12p40 deficiency (IL12B), IL-12RB1 deficiency, STAT1 deficiency (LOF), IRF8 deficiency, TYK2 deficiency.
Predisposition to severe viral infections: STAT1/STAT2 deficiencies, IRF9 deficiency, MDA5 deficiency (IFIH1), OAS1/2 and RNASEL deficiencies.
HSE susceptibility: TLR3 deficiency, UNC93B1 deficiency, TRAF3 deficiency, TBK1 deficiency, IRF3 deficiency.
CMC: IL-17RA deficiency, IL-17F deficiency, STAT1 gain-of-function, ACT1 deficiency (TRAF3IP2).
TLR signaling pathway deficiencies: IRAK4 deficiency, MyD88 deficiency.
Recent Additions
IRF1 deficiency, MCTS1 deficiency, OAS1 deficiency, OAS2 deficiency, RNASEL deficiency, RIPK3 deficiency, MD2 deficiency (LY96), TLR4 deficiency, GTF3A deficiency, IKBKE deficiency.
7. Autoinflammatory Diseases
Description
These disorders are characterized by unprovoked recurrent episodes of systemic inflammation, often without high-titer autoantibodies or antigen-specific T cells. Fever, rash, arthritis, and serositis are common.
Pathophysiology / Cause
Dysregulation of the innate immune system, particularly involving inflammasome activation, type I interferon overproduction (interferonopathies), or NF-κB pathway dysregulation.
Key Conditions
Type I interferonopathies: TREX1 deficiency (Aicardi-Goutières syndrome), STING-associated vasculopathy (SAVI), USP18 deficiency, DNASE2 deficiency.
Inflammasome defects: Familial Mediterranean fever (MEFV), mevalonate kinase deficiency (MVK), cryopyrin-associated periodic syndromes (NLRP3 GOF), NLRC4 GOF (MAS), NLRP1 deficiency/GOF.
Non-inflammasome related: TRAPS, Blau syndrome (NOD2), DIRA (IL1RN deficiency), HA20 (TNFAIP3 haploinsufficiency), OTULIN deficiency.
Recent Additions
STAT4 gain-of-function, PMVK deficiency, ALPK1 gain-of-function (ROSAH syndrome), LYN gain-of-function, SHARPIN deficiency, LSM11 deficiency, RNU7-1 deficiency, two new OTULIN-associated disorders, RELA dominant-negative mutation.
8. Complement Deficiencies
Description
These defects impair the complement system, leading to increased susceptibility to encapsulated bacterial infections, particularly Neisseria meningitidis, and immune complex diseases such as systemic lupus erythematosus (SLE).
Pathophysiology / Cause
Genetic lesions affecting classical, alternative, or lectin pathway components, as well as regulatory proteins. Loss of hemolytic activity (CH50, AH50) is a common laboratory finding.
Key Conditions
Classical pathway: C1q deficiency (C1QA, C1QB, C1QC), C1r deficiency, C1s deficiency, C4 deficiency, C2 deficiency, C3 deficiency.
Alternative pathway: Factor B deficiency, Factor D deficiency, properdin deficiency (X-linked), Factor I deficiency, Factor H deficiency.
Lectin pathway: MASP2 deficiency, ficolin-3 deficiency.
Regulatory defects: C1 inhibitor deficiency (hereditary angioedema), CD55 deficiency (CHAPEL disease), CD59 deficiency.
Terminal pathway: C5, C6, C7, C8α/β/γ, C9 deficiencies.
Recent Additions
No new disorders were added to this table in the 2024 update.
9. Bone Marrow Failure
Description
These inborn errors present with impaired production of one or more hematopoietic lineages, often accompanied by immunodeficiency, congenital anomalies, and increased risk of malignancy.
Pathophysiology / Cause
Defects in DNA repair, telomere maintenance, ribosome biogenesis, or hematopoietic stem cell survival. Chromosomal breakage and telomere shortening are frequent mechanisms.
Key Conditions
Fanconi anemia: Multiple complementation groups (FANCA, FANCC, BRCA2/FANCD1, etc.).
Dyskeratosis congenita: DKC1 (X-linked), TERT, TERC, TINF2, etc.
Other syndromes: Coats plus syndrome (CTC1, STN1), MECOM deficiency, SRP72 deficiency, ERCC6L2 deficiency.
Recent Additions
SNM1B/DCLRE1B (Apollo) deficiency, DUT deficiency, RAD50 deficiency.
10. Phenocopies of Inborn Errors of Immunity
Description
These disorders clinically mimic genetic IEIs but are not caused by inherited germline mutations. Instead, they arise from somatic mutations (acquired) or autoantibodies that disrupt immune function.
Pathophysiology / Cause
Somatic mutations: Post-zygotic genetic alterations restricted to certain cell lineages, leading to clonal expansion or dysregulation.
Autoantibodies: Neutralizing antibodies against specific cytokines or complement proteins, phenocopying genetic deficiencies of those pathways.
Key Conditions
Somatic Mutations
ALPS due to somatic FAS mutations, RALD (somatic KRAS/NRAS), VEXAS syndrome (somatic UBA1), Cryopyrinopathy (somatic NLRP3), Somatic JAK1 GOF, Somatic TLR8 GOF.
Autoantibodies
Autoantibodies to IL-17A/F (CMC), IFN-γ (Adult-onset immunodeficiency), type I IFNs (severe viral reactions), GM-CSF (PAP), IL-27 (infectious mononucleosis phenocopy), C1 inhibitor deficiency.
Recent Additions
Somatic variant in JAK1, autoantibodies against IL-27.
Note: The classification system is updated regularly by the IUIS expert committee to include newly discovered genetic variants. For professional diagnostic use, please refer to the latest IUIS report.