Combined Immunodeficiencies IEIs (IUIS Table 1)

name: Combined Immunodeficiencies IEIs
display_name: Combined Immunodeficiencies IEIs (IUIS Table 1)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 1 — immunodeficiencies affecting both cellular and humoral
  immunity. These combined immunodeficiencies (CID) and severe combined
  immunodeficiencies (SCID) feature impaired T-cell development or function
  with secondary B-cell/antibody defects, predisposing to early-onset
  opportunistic and bacterial infections.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 1 combined cellular-and-humoral immunodeficiency
  phenotype. Members differ in the causal gene and whether T-cell deficiency
  is severe (SCID-equivalent) or moderate (CID). Kept as separate Disease
  entries because gene, inheritance, and syndromic features differ. Syndromic
  forms with prominent non-immune features are grouped under the sibling
  Combined Immunodeficiency with Syndromic Features IEIs grouping.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015131
      label: combined immunodeficiency
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      IUIS Table 1 aligns closely with MONDO combined immunodeficiency
      (MONDO:0015131), but MONDO does not nest that class under inborn error
      of immunity (MONDO:0003778) — both are immune-system-disorder siblings.
      broadMatch because this is an IUIS-guided partial union: Activated
      PI3K-delta syndrome is classified under IUIS combined immunodeficiency
      but sits outside MONDO:0015131's is-a subtree. See
      `grouping_mondo_gaps.py --audit`.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        2/3 listed members are is-a descendants of MONDO:0015131. Activated
        PI3K-delta syndrome is an IUIS Table 1 member, but MONDO:0018338
        lies outside this subtree; this discrepancy is recorded rather than
        used to determine IUIS-table membership.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 1 if it is an IEI with combined cellular
    and humoral immunodeficiency without syndromic features being the primary
    organizing axis.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:combined immunodeficiency"
    description: >-
      Assigned to IUIS Table 1 (combined immunodeficiency) on the member
      Disease entry via classifications.iuis_category. Stated in the keyed
      `<slot>:<value>` form so the audit reads the structured
      classifications block rather than a free-text `parents:`/`categories:`
      tag that happens to use the same words.
members:
- member: STK4 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic STK4 (MST1) loss impairs naive T-cell survival via FOXO1 and
      IL-7R/BCL2, with defective lymphocyte adhesion and chemotaxis; combined
      T- and B-cell lymphopenia with autoimmunity and EBV-driven
      lymphoproliferation.
    gene:
      preferred_term: STK4
      term:
        id: hgnc:11408
        label: STK4
- member: Cernunnos-XLF deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic NHEJ1 (Cernunnos/XLF) deficiency impairs nonhomologous
      end-joining, causing microcephaly, growth retardation, and combined
      T-/B-cell immunodeficiency with radiosensitivity.
    gene:
      preferred_term: NHEJ1
      term:
        id: hgnc:25737
        label: NHEJ1
- member: Activated PI3K-delta syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous gain-of-function PIK3CD or PIK3R1 variants hyperactivate
      PI3K-delta-AKT-mTOR signaling, causing lymphoproliferation,
      bronchiectasis, and herpesvirus susceptibility with immune dysregulation
      (APDS).
    gene:
      preferred_term: PIK3CD
      term:
        id: hgnc:8977
        label: PIK3CD
- member: Severe Combined Immunodeficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The severe end of IUIS Table 1: profound failure of T-lymphocyte
      development that abrogates adaptive immunity from birth, reached by
      three mechanistically distinct routes — defective common-gamma-chain
      cytokine receptor signaling (IL2RG, JAK3, IL7R), failed V(D)J
      recombination or DNA double-strand-break repair (RAG1, RAG2,
      DCLRE1C/Artemis), and purine-salvage metabolite toxicity (ADA). Unlike
      the gene-specific Table 1 members alongside it, this entry is curated as
      the SCID concept itself, with the causal genes carried as subtypes.
    gene:
      preferred_term: IL2RG
      term:
        id: hgnc:6010
        label: IL2RG
- member: Immunodeficiency 131
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A recurrent heterozygous IRF4 p.Thr95Arg substitution in the DNA-binding
      domain acts simultaneously as hypomorph, hypermorph and neomorph
      (multimorphic), altering IRF4's DNA-binding specificity rather than
      merely reducing its output. The result is agammaglobulinemia with
      impaired B-cell maturation and class switching plus reduced TH17/TFH
      populations, and susceptibility to Pneumocystis jirovecii pneumonia —
      an autosomal dominant combined immunodeficiency, and one of the seven
      Table 1 entities newly recognized in the IUIS 2024 update.
    gene:
      preferred_term: IRF4
      term:
        id: hgnc:6119
        label: IRF4
notes: >-
  Expanded 2026-08-20 with Severe Combined Immunodeficiency and Immunodeficiency
  131 (IRF4), both of which already carried
  `classifications.iuis_category: combined immunodeficiency` but were not listed
  here. Note the two member shapes now sitting side by side: three gene-specific
  entities (STK4, NHEJ1, PIK3CD/PIK3R1) and one concept-level entity (SCID)
  whose causal genes are carried as `has_subtypes` rather than as separate
  Disease entries. IUIS Table 1 enumerates 73 mutant genes, so neither shape is
  wrong, but a consumer counting members of this grouping is not counting IUIS
  entities.