Congenital Phagocyte Defect IEIs (IUIS Table 5)

name: Congenital Phagocyte Defect IEIs
display_name: Congenital Phagocyte Defect IEIs (IUIS Table 5)
creation_date: "2026-08-20T00:00:00Z"
description: >-
  IUIS Table 5 — congenital defects of phagocyte number or function. These
  inborn errors of immunity impair the neutrophil/monocyte/macrophage
  compartment, either quantitatively (congenital neutropenia) or qualitatively
  (defective respiratory burst, adhesion, or chemotaxis). The characteristic
  clinical signature is recurrent deep bacterial and fungal infection —
  classically staphylococcal, Burkholderia, Nocardia, Serratia and Aspergillus
  — with abscess and granuloma formation rather than the viral and
  opportunistic susceptibility of T-cell disease.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 5 phagocyte-compartment lesion. Members are kept as
  separate Disease entries because the defect sits at a different point in
  phagocyte biology — CGD abolishes the NOX2 respiratory burst in a phagocyte
  that is present in normal numbers, whereas G6PC3 deficiency depletes the
  neutrophil itself through a metabolite-repair failure. Grouping them records
  that "phagocyte defect" is a compartment, not a mechanism: number and function
  are separate axes within the table and members may sit on either. No MONDO
  mapping: the Orphanet-derived grouping term for this table, MONDO:0015133
  (quantitative and/or qualitative congenital phagocyte defect), is obsolete,
  and MONDO:0005910 (phagocyte bactericidal dysfunction) covers only the
  functional axis, so it would silently exclude the neutropenia members.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 5 if it is an inborn error of immunity
    whose primary lesion is in the number or the function of phagocytes
    (neutrophils, monocytes, macrophages, eosinophils).
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:phagocyte defect"
    description: >-
      Assigned to IUIS Table 5 (congenital defects of phagocyte number or
      function) 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: Severe Congenital Neutropenia 1, Autosomal Dominant
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous ELANE missense variants produce a misfolded neutrophil
      elastase that triggers the unfolded protein response in granulocytic
      precursors, killing them at the promyelocyte stage. The defect of
      phagocyte *number* rather than function, and the archetype of the
      table's neutropenia arm: marrow arrest rather than a mature cell that
      cannot act. Uniquely among the members here it carries a defined
      leukemic route — somatic CSF3R truncation under long-term G-CSF — and
      the same gene's other allelic disease, cyclic neutropenia, is merged
      into this IUIS row.
    gene:
      preferred_term: ELANE
      term:
        id: hgnc:3309
        label: ELANE
- member: Chronic Granulomatous Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defects in the phagocyte NADPH oxidase (NOX2) complex abolish the
      respiratory burst, so phagocytes are present in normal numbers but cannot
      kill ingested catalase-positive bacteria and fungi. The functional axis of
      Table 5, and the member whose second phenotype — sterile granuloma and
      inflammatory bowel disease — comes from failed resolution of inflammation
      rather than from infection.
    gene:
      preferred_term: CYBB
      term:
        id: hgnc:2578
        label: CYBB
- member: G6PC3 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic G6PC3 loss is a metabolite-repair failure: unhydrolyzed
      1,5-anhydroglucitol-6-phosphate accumulates in granulocytes, inhibits
      hexokinase and stalls early glycolysis, causing neutrophil dysfunction and
      neutropenia. The quantitative axis of Table 5, and the member that shows a
      housekeeping enzymopathy reaching the immune system through a
      cell-type-specific metabolic vulnerability.
    gene:
      preferred_term: G6PC3
      term:
        id: hgnc:24861
        label: G6PC3
- member: Shwachman-Diamond syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A ribosomopathy reaching the phagocyte compartment through translation
      rather than through any immune-specific pathway: loss of SBDS uncouples
      EFL1 GTP hydrolysis from eIF6 release, blocking 80S assembly, and the
      granulopoietic compartment is one of the three tissues that tolerates the
      resulting global translation deficit least well. The member that shows
      Table 5 admitting a bone-marrow-failure syndrome on the strength of its
      neutropenia, and the only member covering several Table 5 rows at once
      (SBDS, DNAJC21 and SRP54; the EFL1 row is carried by the sibling entry
      below).
    gene:
      preferred_term: SBDS
      term:
        id: hgnc:19440
        label: SBDS
- member: EFL1-related Shwachman-Diamond syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The EFL1-defined molecular subtype of Shwachman-Diamond syndrome,
      curated separately because the lesion is in the GTPase partner rather
      than in SBDS itself: biallelic EFL1 variants impair EIF6 eviction during
      late 60S maturation directly, reaching the same node from the other side
      of the same complex. Scope note — this member and the Shwachman-Diamond
      syndrome member deliberately split the four Table 5 rows printed under
      the Shwachman-Diamond label; this entry claims the EFL1 row only.
    gene:
      preferred_term: EFL1
      term:
        id: hgnc:25789
        label: EFL1
- member: Papillon-Lefevre Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic cathepsin C loss leaves the three neutrophil serine proteases
      never activated and, in mature neutrophils, absent altogether. The member
      that bounds what a Table 5 assignment claims: patients are not broadly
      immunocompromised, their neutrophils kill bacteria in vitro about as well
      as controls, and the IUIS affected-function cell is narrow (chemotaxis
      only). The disease is a tissue-selective failure of oxygen-independent
      defence in the anaerobic periodontal pocket rather than a systemic
      phagocyte failure.
    gene:
      preferred_term: CTSC
      term:
        id: hgnc:2528
        label: CTSC
- member: Leukocyte Adhesion Deficiency 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic ITGB2 loss prevents assembly of the beta-2 integrin
      heterodimers (LFA-1, Mac-1, p150,95), so neutrophils cannot convert
      rolling into firm adhesion and never transmigrate. The adhesion arm of
      the table, and the sibling of LAD2's trafficking lesion: both produce
      tissue neutropenia alongside blood neutrophilia, but here the receptor
      itself is absent rather than its ligand unfucosylated. Severity tracks
      residual CD18 expression, and the periodontal disease is driven by a
      dysregulated IL-23/IL-17 axis rather than by unpoliced infection.
    gene:
      preferred_term: ITGB2
      term:
        id: hgnc:6155
        label: ITGB2
- member: Leukocyte Adhesion Deficiency Type II
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A Golgi GDP-fucose transporter failure starves the fucosyltransferases of
      their donor substrate, so neutrophils lose sialyl-Lewis X and cannot roll
      along activated endothelium. The trafficking arm of the table: neutrophils
      are made in normal or excess numbers and never reach tissue, which is why
      the blood count is high while the infection risk is that of a phagocyte
      deficiency. Distinct from every other member in that its causal lesion is
      a general glycosylation defect whose other branches (Bombay blood
      phenotype, growth failure) are immunologically inert.
    gene:
      preferred_term: SLC35C1
      term:
        id: hgnc:20197
        label: SLC35C1
- member: Neutrophil Immunodeficiency Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The dominant-negative RAC2 p.Asp57Asn allele disables a single
      haematopoietic Rho-GTPase branch point that controls two effector arms at
      once — NOX2 assembly and chemoattractant-driven actin polymerization — so
      one allele breaks both killing and getting there. The member that sits on
      both axes of the table simultaneously, and the one where the IUIS
      classification itself splits on OMIM number rather than disease name: this
      is the AD LOF arm (MIM 608203, Table 5), not the AD GOF arm (Table 1) or
      the AR arm (Table 3), which share MIM 602049.
    gene:
      preferred_term: RAC2
      term:
        id: hgnc:9802
        label: RAC2
- member: Hereditary Pulmonary Alveolar Proteinosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of a GM-CSF receptor subunit prevents alveolar macrophage
      maturation, so surfactant and cholesterol are never cleared and
      proteinaceous material fills the alveoli. The member that makes the point
      that "phagocyte" in this table is a compartment and not a cell type: the
      failing phagocyte is the tissue macrophage, the lesion is in a cytokine
      receptor rather than in a killing or motility machine, and the clinical
      presentation is respiratory rather than infectious. Covers both Table 5
      rows of the pulmonary alveolar proteinosis pair, CSF2RA and CSF2RB.
    gene:
      preferred_term: CSF2RA
      term:
        id: hgnc:2435
        label: CSF2RA
  - description: >-
      The autosomal recessive CSF2RB arm of the same receptor lesion, printed in
      the source table with the transposed gene symbol "CSFR2B".
    gene:
      preferred_term: CSF2RB
      term:
        id: hgnc:2436
        label: CSF2RB
- member: deafness-lymphedema-leukemia syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      GATA2 haploinsufficiency depletes the monocyte and dendritic-cell
      compartments from the stem-cell end rather than disabling a mature
      phagocyte, giving multilineage cytopenias with mycobacterial, HPV and
      fungal susceptibility on a background of MDS/AML predisposition. The
      member whose phagocyte defect is a transcription-factor dosage problem,
      and the one where the phagocyte lesion is inseparable from a malignancy
      risk. Scope note — IUIS names this row generically as "GATA2 deficiency";
      this entry is the Emberger presentation (lymphedema is named in the row's
      own associated-features cell), and MonoMAC/DCML deficiency
      (MONDO:0013607) will share the same row when curated.
    gene:
      preferred_term: GATA2
      term:
        id: hgnc:4171
        label: GATA2
- member: Barth syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defective tafazzin-mediated cardiolipin remodeling destabilizes the
      mitochondrial inner membrane, and the neutrophil is one of the tissues
      that fails. The member that reaches Table 5 through bioenergetics: the
      IUIS affected-function cell reads "mitochondrial function", not a
      phagocyte-specific process. Scope note — neutropenia is one feature of a
      cardiomyopathy-led mitochondrial disorder, and the entry binds the
      current HGNC symbol TAFAZZIN where the source prints the legacy TAZ.
    gene:
      preferred_term: TAFAZZIN
      term:
        id: hgnc:11577
        label: TAFAZZIN
- member: Cohen Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of the VPS13B bulk lipid-transport protein impairs Golgi membrane
      expansion and Golgi-dependent glycosylation and secretion, and a
      mild-to-moderate neutropenia is present in almost all affected
      individuals. The member with the weakest mechanistic link between the
      causal lesion and the phagocyte phenotype — the route from VPS13B loss to
      the neutropenia is not established — held here on the strength of the IUIS
      row (affected function: myeloid differentiation) rather than on a curated
      mechanism. Scope note — otherwise curated as an intellectual-disability
      syndrome.
    gene:
      preferred_term: VPS13B
      term:
        id: hgnc:2183
        label: VPS13B
- member: Glycogen Storage Disease Type I
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of the SLC37A4 glucose-6-phosphate transporter leaves neutrophils
      unable to maintain energy homeostasis, and accumulating
      1,5-anhydroglucitol-6-phosphate drives ER stress and apoptosis — the same
      metabolite-repair logic as the G6PC3 member, reached through the
      transporter rather than the catalytic subunit, which makes the two the
      clearest mechanistic pair in the grouping. Scope note — only the GSD Ib
      subtype is the IUIS Table 5 row; this is a combined Ia+Ib entry and the Ia
      subtype explicitly has no neutropenia. iuis_category is single-valued and
      cannot be scoped to a subtype, so the restriction lives in that entry's
      notes.
    gene:
      preferred_term: SLC37A4
      term:
        id: hgnc:4061
        label: SLC37A4
notes: >-
  Created 2026-08-20 to give the IUIS Table 5 disorders a place in the Inborn
  Errors of Immunity tree; both members already carried
  `classifications.iuis_category: phagocyte defect` but were unreachable from
  the umbrella grouping. Intentionally unmapped to MONDO — see
  grouping_rationale. Audit with
  `uv run python scripts/grouping_mondo_gaps.py --grouping "Inborn"`.

  Expanded 2026-09-01 from 2 to 14 members in the IUIS Table 5 pass: ten
  existing entries gained `classifications.iuis_category: phagocyte defect`,
  and two Table 5 diseases were newly curated in the same campaign — severe
  congenital neutropenia 1 (ELANE) and leukocyte adhesion deficiency 1
  (ITGB2). Membership is kept in step with that tag by hand: the NECESSARY
  HAS_CLASSIFICATION criterion means an entry carrying the tag but missing from
  `members` leaves the grouping silently under-reporting the table, which is
  what the 2-member state was.

  Coverage is deliberately partial and should not be read as the whole of
  Table 5. The table has 42 gene rows; the 14 members here cover 22 of them
  (CGD accounts for six, Shwachman-Diamond plus its EFL1 sibling for four,
  hereditary PAP for two, and SCN1 for the ELANE row into which IUIS merged
  cyclic neutropenia). Twenty rows have no KB entry at all — among them
  FERMT3 (LAD3), HAX1 (Kostmann), CEBPE (specific granule deficiency), and
  CXCR2, the table's only new 2022 IEI. Several are already in `stubs/`.

  Two rows were reviewed and deliberately left unassigned rather than
  overlooked. Cystic fibrosis is genuinely a Table 5 row (CFTR, affected cells
  "M only", affected function chemotaxis), but `iuis_category` is single-valued,
  so tagging the KB's multisystem CF entry would assert that CF *is* a phagocyte
  inborn error of immunity; that is a policy call for a maintainer, not a
  curation call. G6PD deficiency class I is likewise a Table 5 row, but the KB's
  G6PD entry is scoped to the common erythrocyte enzymopathy and carries no
  neutrophil or respiratory-burst content, so the tag would point at material
  the entry does not contain. Myeloperoxidase deficiency is NOT a Table 5 row
  and must not be given the tag — MPO is absent from the entire IUIS 2022
  paper, having been dropped from the older phagocyte tables.