Combined Immunodeficiency with Syndromic Features IEIs (IUIS Table 2)

name: Combined Immunodeficiency with Syndromic Features IEIs
display_name: Combined Immunodeficiency with Syndromic Features IEIs (IUIS Table 2)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 2 — combined immunodeficiencies with associated or syndromic
  features. These IEIs combine T- and/or B-cell immunodeficiency with
  prominent developmental, craniofacial, ectodermal, hematologic, or
  multi-organ syndromic findings that are part of the recognized clinical
  spectrum.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 2 pattern: combined immunodeficiency plus
  syndromic features beyond infection susceptibility alone. Members are kept
  as separate Disease entries because the primary genetic lesion and
  extravascular phenotype differ (22q11.2 deletion vs DNMT3B/ICF vs SP110
  VODI vs NEMO/IKBKG ectodermal dysplasia). No MONDO mapping: IUIS Table 2
  has no MONDO grouping class (MONDO:0015133 is an obsolete phagocyte-defect
  orphan; ectodermal dysplasia and immune deficiency subsume only EDA-ID
  members). Criteria are NECESSARY and aspirational pending iuis_category
  backfill.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 2 if it is an IEI with combined
    immunodeficiency and prominent associated syndromic features (craniofacial,
    cardiac, ectodermal, or hematologic) that define the clinical entity.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:combined immunodeficiency with syndromic features"
    description: >-
      Assigned to IUIS Table 2 (combined immunodeficiency with syndromic
      features) 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: 22q11.2 Deletion Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Hemizygous 22q11.2 deletion (TBX1 haploinsufficiency and contiguous
      genes) causes DiGeorge spectrum disease with thymic hypoplasia, T-cell
      deficiency, conotruncal heart defects, and hypocalcemia.
    gene:
      preferred_term: TBX1
      term:
        id: hgnc:11592
        label: TBX1
- member: Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DNMT3B, ZBTB24, or CDCA7 defects cause DNA hypomethylation with
      centromeric instability, facial dysmorphism, and progressive combined
      immunodeficiency (ICF syndrome).
    gene:
      preferred_term: DNMT3B
      term:
        id: hgnc:2979
        label: DNMT3B
- member: Hepatic veno-occlusive disease-immunodeficiency syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SP110 loss causes hepatic veno-occlusive disease with
      combined immunodeficiency and failure to control intracellular
      pathogens (VODI syndrome).
    gene:
      preferred_term: SP110
      term:
        id: hgnc:5401
        label: SP110
- member: IKBKG ectodermal dysplasia with immunodeficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked NEMO (IKBKG) hypomorphic variants impair NF-kappaB signaling,
      causing ectodermal dysplasia with combined immunodeficiency and
      susceptibility to mycobacterial and pyogenic infections.
    gene:
      preferred_term: IKBKG
      term:
        id: hgnc:5961
        label: IKBKG
- member: Ectodermal Dysplasia and Immunodeficiency 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Autosomal recessive IKBA (NFKBIA) loss impairs NF-kappaB inhibitor
      function, causing ectodermal dysplasia with combined immunodeficiency
      (EDA-ID2) overlapping NEMO disease.
    gene:
      preferred_term: NFKBIA
      term:
        id: hgnc:7797
        label: NFKBIA
- member: Autosomal Dominant Hyper-IgE Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous dominant-negative STAT3 poisons the obligate STAT3 dimer,
      collapsing transcriptional output across the IL-6/IL-11/IL-21/IL-23
      network. The immune arm (Th17 failure, cold staphylococcal abscesses,
      pneumatoceles, extreme IgE) is inseparable from a non-immune
      connective-tissue, skeletal, dental and vascular syndrome — the defining
      Table 2 pattern, and the anchor of the hyper-IgE subtable.
    gene:
      preferred_term: STAT3
      term:
        id: hgnc:11364
        label: STAT3
- member: Cartilage-hair hypoplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic variants in RMRP, a non-coding RNA rather than a protein,
      disable the RNase MRP endoribonuclease. One RNA-folding lesion reaches
      four organ systems at once (pre-rRNA processing, cyclin B2 mRNA cleavage,
      TERT partnering, small-RNA silencing), giving the immuno-osseous Table 2
      pattern: metaphyseal chondrodysplasia and hypoplastic hair alongside
      combined immunodeficiency, anemia and a marked lymphoma excess.
    gene:
      preferred_term: RMRP
      term:
        id: hgnc:10031
        label: RMRP
- member: Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Hypomorphic biallelic EXTL3 alleles yield structurally aberrant heparan
      sulfate — longer chains, abnormal sulfation — rather than its absence.
      Because HS proteoglycans tune morphogen and cytokine signaling as
      co-receptors, one glycosyltransferase lesion is transduced in opposite
      directions by tissue, coupling spondyloepimetaphyseal dysplasia and
      neurodevelopmental disease to a T-cell-deficient combined
      immunodeficiency.
    gene:
      preferred_term: EXTL3
      term:
        id: hgnc:3518
        label: EXTL3
- member: Vici Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of EPG5 blocks the late autophagosome-lysosome fusion step of
      macroautophagy. The immunodeficiency is one arm of a cardinal pentad
      (callosal agenesis, cataracts, oculocutaneous hypopigmentation,
      cardiomyopathy, combined immunodeficiency) — the only Table 2 member
      here whose syndromic breadth follows from a defect in a general
      catabolic pathway rather than a lymphocyte- or skeleton-specific one.
    gene:
      preferred_term: EPG5
      term:
        id: hgnc:29331
        label: EPG5
- member: STAT6 Gain-of-Function Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous gain-of-function STAT6 amplifies IL-4/IL-13 type-2 signaling,
      producing early-onset severe allergic dysregulation with extreme IgE — a
      hyper-IgE-like syndromic presentation that IUIS groups with
      dominant-negative STAT3 rather than with the Table 4 dysregulation
      disorders. The only member here whose defining lesion is excess rather
      than loss of cytokine signal transduction, and one of the ten Table 2
      entities newly recognized in the IUIS 2024 update.
    gene:
      preferred_term: STAT6
      term:
        id: hgnc:11368
        label: STAT6
notes: >-
  Intentionally unmapped to MONDO. Audit with
  `uv run python scripts/grouping_mondo_gaps.py --grouping "Inborn"`.

  STAT6 Gain-of-Function Disease was reclassified from IUIS Table 4 to Table 2
  on 2026-08-20 and newly listed here: the IUIS 2024 update lists STAT6 (AD GOF)
  under combined immunodeficiencies with syndromic features, Table 2 subtable 1
  (PMID:41608114). Its allergic/type-2 phenotype had previously been read as a
  Table 4 signal. It had never been listed as a member of the Immune
  Dysregulation IEIs grouping — only its `iuis_category` carried the Table 4
  assignment — so this is a first listing, not a transfer between member lists.