Predominantly Antibody Deficiencies IEIs (IUIS Table 3)

name: Predominantly Antibody Deficiencies IEIs
display_name: Predominantly Antibody Deficiencies IEIs (IUIS Table 3)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 3 — predominantly antibody deficiencies. These inborn errors of
  immunity feature impaired B-cell differentiation, class-switch recombination,
  or immunoglobulin secretion, resulting in hypogammaglobulinemia and
  recurrent sinopulmonary and enteric bacterial infections. Cellular immunity
  is relatively preserved compared with combined immunodeficiencies.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 3 humoral-deficiency phenotype. Members are kept
  as separate Disease entries because monogenic causes (when known), antibody
  class affected, and inheritance differ. CVID is retained as a distinct entry
  because it is clinically an umbrella diagnosis with heterogeneous genetic
  etiologies rather than a single-gene disorder — see the
  `cvid_umbrella_cuts_across_the_iuis_tables` discussion for why that makes
  CVID membership here weaker than the other members'. Additional Table 3
  members should be added as they are curated in kb/disorders/: XLA and
  autosomal agammaglobulinemia were added 2026-08-20, while selective IgA
  deficiency and the hyper-IgM syndromes remain uncurated. MONDO maps the
  obsolete Orphanet grouping
  MONDO:0015132 (predominantly antibody production) without an is-a parent;
  broader terms such as B cell deficiency (MONDO:0002211) are not yet used as
  grouping anchors here.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 3 if it is an IEI with predominantly
    antibody/humoral deficiency and relatively preserved cellular immunity.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:predominantly antibody deficiency"
    description: >-
      Assigned to IUIS Table 3 (predominantly antibody deficiency) 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: Common Variable Immunodeficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterogeneous defects in B-cell differentiation and class-switch
      recombination produce hypogammaglobulinemia with recurrent bacterial
      infections, autoimmunity, and lymphoproliferation; the most common
      symptomatic primary antibody deficiency.
    biological_processes:
    - preferred_term: Immunoglobulin production
      term:
        id: GO:0002377
        label: immunoglobulin production
      modifier: DECREASED
- member: X-linked Agammaglobulinemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of BTK, the Tec-family kinase transducing pre-BCR and BCR signals,
      arrests B-lineage maturation at the pre-B stage in marrow. The
      prototypical Table 3 entity and the only X-linked member here: affected
      males have a near-absence of circulating B cells and plasma cells with
      panhypogammaglobulinemia, against largely intact T-cell immunity.
    gene:
      preferred_term: BTK
      term:
        id: hgnc:1133
        label: BTK
- member: Autosomal Agammaglobulinemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The autosomal 10-15% of congenital agammaglobulinemia — the same pre-B
      developmental block as XLA reached without touching BTK, by biallelic
      loss of pre-BCR structural components (IGHM, IGLL1) or of its proximal
      signalling module (CD79A, CD79B, BLNK). Mechanistically it is the
      demonstration that the Table 3 phenotype tracks pre-BCR assembly and
      signalling rather than any one gene.
    gene:
      preferred_term: IGHM
      term:
        id: hgnc:5541
        label: IGHM
- member: Immunodeficiency 93 and Hypertrophic Cardiomyopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of FNIP1, the folliculin-interacting protein, gives
      profoundly decreased or absent circulating B cells with
      hypogammaglobulinemia — Table 3 by its humoral phenotype — but uniquely
      among the members here couples it to hypertrophic cardiomyopathy, a
      non-immune manifestation of the same metabolic-regulator defect.
    gene:
      preferred_term: FNIP1
      term:
        id: hgnc:29418
        label: FNIP1
discussions:
- discussion_id: cvid_umbrella_cuts_across_the_iuis_tables
  kind: KNOWLEDGE_GAP
  prompt: >-
    Common variable immunodeficiency is listed here as one member, but a
    substantial share of CVID patients turn out to carry a monogenic defect
    that IUIS classifies in a different table. Is CVID a Table 3 disease, a
    clinical presentation that several IEIs converge on, or both?
  rationale: >-
    The nine IUIS-table sub-groupings under Inborn Errors of Immunity partition
    disease entities cleanly, because each entity carries exactly one
    `iuis_category`. CVID breaks that cleanliness at the level of the patient
    rather than the entity: it is a diagnosis of exclusion made on
    hypogammaglobulinemia and poor vaccine responses, and genetic workup
    reassigns a fraction of those patients to entities this tree already lists
    elsewhere — a PIK3R1 gain-of-function patient is Activated PI3K-delta
    syndrome (Table 1, a member of the Combined Immunodeficiencies IEIs
    sub-grouping), while LRBA and CTLA4 patients are Table 4 members, both
    curated with hypogammaglobulinemia in their own differentiating mechanisms.
    The same person can therefore satisfy this grouping's NECESSARY criterion
    today and a sibling grouping's tomorrow, with no change in their biology.
    What is genuinely unknown is the size of the residue: reported monogenic
    yield ranges from 2% to 30% across cohorts, so it is not settled whether
    CVID names a real disease with an undiscovered cause, a heterogeneous
    collection of rare monogenic disorders, or a polygenic entity. Until that
    resolves, this grouping should be read as listing the clinical CVID
    concept, not as a claim that CVID patients are disjoint from the other
    sub-groupings' members.
  evidence:
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common variable immunodeficiency (CVID) represents an "umbrella" diagnosis
      due to its clinical and immunological heterogeneity.
    explanation: >-
      States the premise this gap turns on: CVID is an umbrella over
      heterogeneous entities rather than a single disease, which is why it does
      not partition cleanly against the other IUIS tables.
  - reference: PMID:40079712
    reference_title: "Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      allowing the identification of monogenic genetic variants from 2% to 30%
      of CVID patients in different cohorts
    explanation: >-
      Quantifies the unresolved residue: the fraction of CVID reassignable to a
      monogenic entity in another IUIS table varies more than tenfold between
      cohorts, so the size of the overlap with the sibling sub-groupings is
      itself unknown.
  proposed_experiments:
  - experiment_id: cvid_reassignment_crosswalk
    name: Crosswalk CVID monogenic causes to their IUIS table assignments
    description: >-
      For each gene reported as a monogenic cause of a CVID phenotype, record
      the IUIS table the resulting entity is assigned to, and mark which of
      those entities already exist as kb/disorders/ entries in a sibling
      sub-grouping. The output is a machine-readable statement of where the CVID
      umbrella overlaps this tree's partition, which is what a consumer needs in
      order to interpret a CVID membership assertion correctly.