Complement Deficiency IEIs (IUIS Table 8)

name: Complement Deficiency IEIs
display_name: Complement Deficiency IEIs (IUIS Table 8)
creation_date: "2026-08-20T00:00:00Z"
description: >-
  IUIS Table 8 — complement deficiencies. These inborn errors of immunity
  disable a component or regulator of the complement cascade, an innate humoral
  effector system that operates without cells. The infection phenotype is
  strikingly pathway-specific: terminal-component defects impair membrane
  attack complex assembly and admit Neisseria almost exclusively, while early
  classical-pathway defects impair immune-complex clearance and present as
  lupus-like autoimmunity.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 8 lesion in the complement system. Complement is
  kept as its own table, and its own grouping, rather than being folded into
  innate immunity (Table 6): it is a soluble cascade rather than a cellular
  program, its deficiencies are inherited as clean autosomal recessive
  enzymopathies of individual components, and the position of the defect within
  the cascade — early classical, alternative, lectin, terminal, or regulatory —
  predicts the clinical phenotype directly. Members are kept as separate Disease
  entries because that cascade position differs.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0003832
      label: complement deficiency
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      IUIS Table 8 aligns with MONDO complement deficiency (MONDO:0003832).
      broadMatch rather than exactMatch because MONDO's class is not restricted
      to germline monogenic inborn errors, whereas IUIS Table 8 is; the MONDO
      term is therefore wider than this grouping.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The listed member is an is-a descendant of MONDO:0003832, verified
        2026-08-20 with `runoak -i sqlite:obo:mondo descendants -p i
        MONDO:0003832` (immunodeficiency due to a late component of complement
        deficiency, MONDO:0015700).
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 8 if it is an inborn error of immunity
    caused by deficiency of a complement component or complement regulatory
    protein.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:complement deficiency"
    description: >-
      Assigned to IUIS Table 8 (complement deficiencies) via
      classifications.iuis_category on the member Disease entry. Stated in the
      keyed `<slot>:<value>` form so the audit reads the structured
      classifications block.
members:
- member: Late Complement Component Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of any terminal component (C5, C6, C7, C8, C9) prevents
      assembly of the membrane attack complex C5b-9 and so abolishes direct
      serum bactericidal activity. Because Neisseria are killed principally by
      MAC lysis rather than by opsonophagocytosis, the deficiency produces an
      almost pathognomonic susceptibility to recurrent invasive meningococcal
      and disseminated gonococcal disease with otherwise unremarkable immunity —
      the terminal-pathway arm of Table 8.
    gene:
      preferred_term: C5
      term:
        id: hgnc:1331
        label: C5
notes: >-
  Created 2026-08-20 to give the IUIS Table 8 disorders a place in the Inborn
  Errors of Immunity tree; the member already carried
  `classifications.iuis_category: complement deficiency` but was unreachable
  from the umbrella grouping. Single-member for now: the early classical-pathway
  (C1q/C1r/C1s/C2/C4), alternative-pathway, lectin-pathway and regulatory
  (C1-inhibitor, factor H/I, CD55/CD59) arms of Table 8 are not yet curated in
  kb/disorders/ — see the `complement_table8_pathway_coverage` discussion.
discussions:
- discussion_id: complement_table8_pathway_coverage
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does a single terminal-pathway member support the phenotype claim this
    grouping makes about complement deficiency as a class?
  rationale: >-
    The clinically important property of Table 8 is that the position of the
    defect within the cascade predicts the phenotype — terminal defects give
    neisserial infection, early classical defects give lupus-like autoimmunity
    and immune-complex disease, regulatory defects give hereditary angioedema
    or atypical haemolytic uraemic syndrome. With only the terminal arm curated,
    the grouping states that contrast in prose but cannot demonstrate it across
    members, and a SUFFICIENT criterion cannot be written because the criteria
    would have to enumerate phenotypes the KB does not yet carry. This is a
    coverage gap in kb/disorders/ rather than an open scientific question, but
    it bounds what this grouping can currently audit.
  proposed_experiments:
  - experiment_id: curate_early_and_regulatory_complement_defects
    name: Curate early-classical and regulatory complement deficiency entries
    description: >-
      Curate at least one early classical-pathway deficiency (C1q, C1r/C1s, C2
      or C4, presenting as SLE-like immune-complex disease) and one regulatory
      defect, assign each `classifications.iuis_category: complement
      deficiency`, and add them here. With three cascade positions represented,
      the pathway-position-predicts-phenotype claim becomes auditable as a
      structured contrast between members rather than an assertion in the
      grouping rationale.