Immune Dysregulation IEIs (IUIS Table 4)

name: Immune Dysregulation IEIs
display_name: Immune Dysregulation IEIs (IUIS Table 4)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 4 — diseases of immune dysregulation. These inborn errors of
  immunity feature uncontrolled lymphocyte activation, impaired immune
  checkpoints, or hyperinflammatory cytokine storms rather than isolated
  humoral or cellular deficiency. Clinical overlap includes
  lymphoproliferation, autoimmunity, hemophagocytic syndromes, and
  endocrinopathy.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the shared immune-dysregulation phenotype recognized by IUIS
  Table 4. Members are kept as separate Disease entries because the causal
  gene and dominant pathway differ (cytotoxic granule exocytosis in HLH,
  FAS-mediated apoptosis in ALPS, AIRE-driven tolerance failure in APS-1,
  CTLA4/LRBA checkpoint recycling defects). No MONDO mapping: IUIS Table 4 has no
  equivalent MONDO grouping class (candidates such as lymphoproliferative
  syndrome or ALPS subsume only a subset of members). Criteria are NECESSARY
  and aspirational until IEI mechanism modules and iuis_category backfill are
  complete across the knowledge base.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 4 (immune dysregulation) if it is an IEI
    with dominant immune dysregulation — lymphoproliferation, autoimmunity,
    or hyperinflammation — rather than isolated antibody or T-cell deficiency.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:immune dysregulation"
    description: >-
      Assigned to IUIS Table 4 (immune dysregulation) on the member Disease
      entry via classifications.iuis_category. Stated in the keyed
      `<slot>:<value>` form so the audit reads the structured classifications
      block.
members:
- member: Hemophagocytic Lymphohistiocytosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic or X-linked defects in the cytotoxic granule exocytosis
      pathway (PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A, XIAP)
      impair CTL/NK killing, causing IFN-gamma-driven cytokine storm and
      hemophagocytosis.
    gene:
      preferred_term: PRF1
      term:
        id: hgnc:9360
        label: PRF1
- member: FAS-related Autoimmune Lymphoproliferative Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FAS (TNFRSF6) pathway defects impair activation-induced lymphocyte
      apoptosis, causing chronic lymphoproliferation, autoimmunity, and
      increased lymphoma risk (canonical ALPS).
    gene:
      preferred_term: FAS
      term:
        id: hgnc:11920
        label: FAS
- member: Autoimmune Polyendocrine Syndrome Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic AIRE loss impairs thymic negative selection, causing
      multi-organ autoimmunity with chronic mucocutaneous candidiasis and
      endocrine failure (APECED/IPEX-like regulatory failure).
    gene:
      preferred_term: AIRE
      term:
        id: hgnc:360
        label: AIRE
- member: LRBA Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic LRBA loss destabilizes intracellular CTLA-4 recycling,
      combining hypogammaglobulinemia with lymphoproliferation, enteropathy,
      and autoimmunity.
    gene:
      preferred_term: LRBA
      term:
        id: hgnc:1742
        label: LRBA
- member: CTLA4 Haploinsufficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous CTLA4 loss reduces inhibitory checkpoint signaling,
      causing lymphoproliferation, hypogammaglobulinemia, and multi-organ
      autoimmunity (CHAI disease).
    gene:
      preferred_term: CTLA4
      term:
        id: hgnc:2505
        label: CTLA4
- member: DEF6 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The third route to CTLA-4 insufficiency in this grouping, and the one
      furthest from the receptor itself. Biallelic loss of the guanine
      nucleotide exchange factor DEF6 leaves RAB11-dependent vesicular delivery
      of CTLA-4 to the T-cell surface unable to proceed, so regulatory T cells
      hold a normal CTLA-4 protein pool they cannot mobilise. Where CTLA4
      haploinsufficiency removes half the protein and LRBA deficiency fails to
      recycle it away from lysosomal degradation, this lesion blocks the
      outbound trafficking step. All three converge on too little surface
      CTLA-4 and all three respond to abatacept, which is why the trafficking
      machinery and the receptor sit in one grouping.
    gene:
      preferred_term: DEF6
      term:
        id: hgnc:2760
        label: DEF6
- member: CD27-related lymphoproliferative and immune disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic CD27 or CD70 defects impair germinal-center B-cell
      homeostasis and EBV control, causing lymphoproliferation and
      Hodgkin-like lymphoma susceptibility.
    gene:
      preferred_term: CD27
      term:
        id: hgnc:11922
        label: CD27
- member: Autoimmune Lymphoproliferative Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The ALPS concept itself, curated as a thin root over the Fas-pathway
      subtypes (ALPS-FAS, ALPS-sFAS, ALPS-FASLG, ALPS-CASP10, ALPS-U) that the
      2009 NIH revision retained. It is listed alongside, not instead of, the
      gene-specific `FAS-related Autoimmune Lymphoproliferative Syndrome`
      entry: this entry carries the genotype classification axis and the shared
      apoptosis-defect chain, that one carries the FAS-specific
      pathophysiology, diagnostics and management. IUIS likewise enumerates
      FAS, FASLG and CASP10 as separate Table 4 gene entries under one clinical
      syndrome.
    gene:
      preferred_term: FAS
      term:
        id: hgnc:11920
        label: FAS
- member: IPEX Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss-of-function FOXP3 variants abolish the master transcription factor
      of CD4+CD25+ regulatory T cells, so dominant peripheral tolerance fails
      outright. Where the checkpoint members (CTLA4, LRBA) attenuate Treg
      function, IPEX removes the Treg compartment itself — the X-linked
      prototype of monogenic autoimmunity, presenting in infant boys with
      autoimmune enteropathy, endocrinopathy and dermatitis.
    gene:
      preferred_term: FOXP3
      term:
        id: hgnc:6106
        label: FOXP3
- member: Chediak-Higashi Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic LYST loss disrupts the biogenesis and fusion of lysosomes and
      lysosome-related organelles, giving pathognomonic giant leukocyte
      granules. It reaches the HLH phenotype shared with the familial
      hemophagocytic members by a different route — organelle biogenesis
      rather than granule exocytosis — and pays for it outside the immune
      system too, with partial oculocutaneous albinism from the same
      LRO defect in melanocytes.
    gene:
      preferred_term: LYST
      term:
        id: hgnc:1968
        label: LYST
- member: Immunodeficiency 60
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Autosomal dominant haploinsufficiency for the transcriptional repressor
      BACH2 impairs regulatory T-cell differentiation, placing it with the
      Tregopathy members rather than the cytotoxic-granule or apoptosis
      members. What distinguishes it inside that subcategory is that the same
      lesion also hits the B-cell arm: BACH2 is a lineage specification factor
      for both compartments, so a single dosage defect yields lymphocytic
      colitis and progressive T-cell lymphopenia alongside impaired memory
      B-cell development and sinopulmonary infection. IUIS places it in Table
      4 on that basis, although ClinGen curated the gene through its Antibody
      Deficiencies expert panel and rates the relationship Moderate.
    gene:
      preferred_term: BACH2
      term:
        id: hgnc:14078
        label: BACH2
- member: Griscelli Syndrome Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic RAB27A loss removes the small GTPase that docks cytotoxic
      granules for regulated exocytosis in CTL and NK cells, so lymphocyte
      killing fails and patients present with hemophagocytic
      lymphohistiocytosis. The same RAB27A loss untethers melanosomes in
      melanocytes, giving the silvery-grey hair and partial albinism that
      distinguish GS2 from the non-pigmentary FHL members. Unlike
      Chediak-Higashi, organelle biogenesis is intact — only the transport
      step is lost.
    gene:
      preferred_term: RAB27A
      term:
        id: hgnc:9766
        label: RAB27A
- member: Hermansky-Pudlak Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Only the AP-3 subtypes — HPS-2 (AP3B1) and HPS-10 (AP3D1) — are IUIS
      Table 4 members: the AP-3 adaptor complex sorts cargo into
      lysosome-related organelles including cytotoxic granules, so its loss
      adds neutropenia and impaired CTL/NK cytotoxicity with HLH risk to the
      oculocutaneous albinism and bleeding diathesis shared by all HPS
      subtypes. The BLOC-complex subtypes (HPS-1/3/4/5/6/7/8/9/11) share the
      pigmentary and platelet phenotype but are not inborn errors of
      immunity.
    gene:
      preferred_term: AP3B1
      term:
        id: hgnc:566
        label: AP3B1
- member: Interleukin-10 Receptor Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of either IL-10 receptor chain (IL10RA or IL10RB)
      abolishes the IL-10 anti-inflammatory brake on myeloid cells, producing
      severe infantile-onset enterocolitis with perianal fistulas that is
      refractory to conventional immunosuppression. It anchors the "immune
      dysregulation with colitis" arm of Table 4: the lesion is loss of a
      restraining cytokine circuit in the gut rather than lymphoproliferation
      or a cytotoxicity defect, and it is curable by allogeneic HSCT.
    gene:
      preferred_term: IL10RA
      term:
        id: hgnc:5964
        label: IL10RA
- member: FADD-Related Immunodeficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic FADD loss disables the adaptor that nucleates the FAS
      death-inducing signalling complex, so patients carry the ALPS biomarker
      profile (impaired Fas-dependent apoptosis, expanded double-negative T
      cells) and IUIS files it in the ALPS section. It differs from the other
      ALPS members in its Fas-independent features — recurrent febrile
      encephalopathic crises, hepatopathy, cardiac malformations and
      functional hyposplenism with invasive bacterial infection — without the
      florid lymphoproliferation of ALPS-FAS.
    gene:
      preferred_term: FADD
      term:
        id: hgnc:3573
        label: FADD
- member: SOCS1 Haploinsufficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous SOCS1 loss removes half the dose of the negative-feedback
      brake on JAK-STAT signalling, so lymphocytes over-respond to ordinary
      cytokine levels (increased STAT activation to IFN-gamma, IL-2 and
      IL-4). The result is early-onset multisystemic autoimmunity with
      cytopenias and incomplete penetrance — a dosage-sensitive restraint
      defect rather than a receptor or cytotoxicity lesion, and one of the
      seven new Table 4 genes in the 2022 update.
    gene:
      preferred_term: SOCS1
      term:
        id: hgnc:19383
        label: SOCS1
- member: Autoinflammation, immune dysregulation, and eosinophilia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous germline JAK1 gain-of-function variants (the row IUIS
      names "JAK1 GOF") drive hyperactive baseline and cytokine-induced STAT
      phosphorylation, producing severe early-onset atopy, eosinophilia,
      eosinophilic enteritis and autoimmunity. It is the constitutively
      active kinase counterpart of SOCS1 haploinsufficiency's lost brake on
      the same pathway, and it is directly treatable with JAK inhibitors.
    gene:
      preferred_term: JAK1
      term:
        id: hgnc:6190
        label: JAK1
- member: Congenital Disorder of Glycosylation, Type ICC
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked MAGT1 loss (XMEN disease) impairs magnesium transport and
      N-linked glycosylation, decreasing NKG2D expression on NK and CD8+ T
      cells and crippling their control of Epstein-Barr virus. It sits in the
      EBV-susceptibility arm of Table 4: chronic EBV viremia with
      EBV-driven lymphoma risk rather than autoimmunity or
      lymphoproliferation from an apoptosis defect.
    gene:
      preferred_term: MAGT1
      term:
        id: hgnc:28880
        label: MAGT1
- member: Kindler Epidermolysis Bullosa
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic FERMT1 loss removes kindlin-1 from focal adhesions of basal
      keratinocytes, causing a mechanobullous dermatosis with congenital
      blistering, photosensitivity and progressive poikiloderma. It is the
      outlier of the Treg-defect section: IUIS records intracellular
      accumulation of IgG, IgM, IgA and C3 in colloid bodies beneath the
      basement membrane as the functional defect, and the entry's Table 4
      membership follows the committee's placement rather than a strong
      immunological phenotype.
    gene:
      preferred_term: FERMT1
      term:
        id: hgnc:15889
        label: FERMT1
- member: Lysinuric protein intolerance
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SLC7A7 loss disables the y+LAT1 cationic amino acid
      transporter, and IUIS places the disease in the FHL section for its
      macrophage phenotype: a hyper-inflammatory response of macrophages with
      normal NK cell function, plus pulmonary alveolar proteinosis and
      bleeding tendency. It reaches immune dysregulation through a metabolic
      transport lesion rather than a cytotoxicity, checkpoint or apoptosis
      defect, which distinguishes it from every other FHL-section member.
    gene:
      preferred_term: SLC7A7
      term:
        id: hgnc:11065
        label: SLC7A7
- member: X-linked Lymphoproliferative Disease Due To SH2D1A Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of the SAP adaptor switches SLAM-family receptors from activating to
      inhibitory signalling, so 2B4 on NK cells and EBV-specific CD8 cytotoxicity
      both fail and iNKT cells never develop. The EBV-susceptibility arm of the
      table in its purest form: the trigger is a specific pathogen rather than a
      constitutive lesion, and the consequences — fulminant infectious
      mononucleosis with HLH, dysgammaglobulinemia, and B-cell lymphoma — follow
      from the inability to control it. Distinguished from its XIAP sibling by
      the lymphoma risk.
    gene:
      preferred_term: SH2D1A
      term:
        id: hgnc:10820
        label: SH2D1A
- member: X-linked Lymphoproliferative Disease Due To XIAP Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      XIAP loss removes both a caspase brake and the ubiquitin scaffold NOD2
      signalling depends on, so lymphocytes die on activation while NOD2 responses
      in gut epithelium and monocytes fail. The result is HLH that does not
      require EBV, refractory Crohn-like colitis, and inflammasome dysregulation
      with elevated IL-18. The key negative separates it from the SAP sibling
      sharing its clinical name: lymphoma is not part of this disease.
    gene:
      preferred_term: XIAP
      term:
        id: hgnc:592
        label: XIAP
notes: >-
  Intentionally unmapped to MONDO: no single MONDO class covers IUIS Table 4.
  Run `uv run python scripts/grouping_mondo_gaps.py --grouping "Inborn"` for
  umbrella IEI descendant coverage and curation gaps.

  Expanded 2026-08-20 with Autoimmune Lymphoproliferative Syndrome, IPEX
  Syndrome and Chediak-Higashi Syndrome, all three of which already carried
  `classifications.iuis_category: immune dysregulation` but were not listed
  here. STAT6 Gain-of-Function Disease was reclassified from Table 4 to Table 2
  in the same pass (the IUIS 2024 update places it there, PMID:41608114) and is
  now listed under Combined Immunodeficiency with Syndromic Features IEIs. It
  was never listed in this file's `members:`, so nothing was removed here — what
  changed is the entry's `iuis_category`, and therefore which sub-grouping's
  criterion it satisfies.

  Expanded 2026-08-29 with the nine existing KB entries backfilled with
  `iuis_category: immune dysregulation` in the same pass: Griscelli Syndrome
  Type 2, Hermansky-Pudlak Syndrome (AP-3 subtypes only — see that member's
  differentiator), Interleukin-10 Receptor Deficiency, FADD-Related
  Immunodeficiency, SOCS1 Haploinsufficiency, AIIDE (the IUIS "JAK1 GOF" row),
  Congenital Disorder of Glycosylation Type ICC (the IUIS "XMEN" row), Kindler
  Epidermolysis Bullosa and Lysinuric protein intolerance. The same campaign
  added the two new XLP entries (SH2D1A and XIAP, IUIS Table 4 section 7), and
  Immunodeficiency 60 (BACH2) arrived independently on main. A review pass on
  the same campaign PR added DEF6 Deficiency, which had carried
  `iuis_category: immune dysregulation` on main since before this work and was
  never listed here — a state `just check-groupings` cannot report, because it
  evaluates only the members a grouping already names. Membership now stands at
  22 entries spanning 24 of the 52 Table 4 gene rows (two more rows are carried
  as subtypes of the HLH and ALPS entries); the remaining rows have no KB entry
  yet.
discussions:
- discussion_id: alps_umbrella_and_gene_entry_both_listed
  kind: KNOWLEDGE_GAP
  prompt: >-
    This grouping lists both the ALPS concept and the FAS-specific ALPS entry as
    separate members. Is a grouping the right place to express that
    relationship, or does it double-count one disease?
  rationale: >-
    `Autoimmune Lymphoproliferative Syndrome` is curated as a thin root carrying
    the genotype classification axis over the 2009 NIH Fas-pathway subtypes,
    while `FAS-related Autoimmune Lymphoproliferative Syndrome` carries the
    FAS-specific pathophysiology, diagnostics and management in depth. Both are
    genuine Table 4 entities under IUIS, which itself enumerates FAS, FASLG and
    CASP10 as separate gene entries beneath one clinical syndrome, so listing
    both is defensible. But dismech's Grouping class is documented as a union
    over already-distinct entries, and these two are not distinct in the usual
    sense — one subsumes the other. A consumer counting members of this grouping
    will count ALPS twice, and a consumer following `differentiating_mechanisms`
    will find the FAS gene named on both. The KB has no parent/child member
    relation to express "member A contains member B", so the containment is
    currently only stated in prose. Whether the fix is a new member relation, a
    nested GROUPING member, or dropping one of the two entries is unresolved.
  proposed_experiments:
  - experiment_id: survey_umbrella_plus_subtype_member_pairs
    name: Survey the KB for grouping members that subsume other members
    description: >-
      Across all kb/groupings/, find member pairs where one member's
      `has_subtypes` or MONDO descendants include the other member, and count
      how often the pattern occurs. If ALPS is the only instance it is a local
      curation call; if the pattern recurs, it argues for a first-class
      "subsumes" relation on `members[]` so containment is machine-readable
      rather than restated per grouping.