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, and Activated PI3K-delta
  syndrome was moved here 2026-08-29 from the Combined Immunodeficiencies IEIs
  grouping after its Table 1 assignment was found to contradict the IUIS 2022
  tables (both APDS rows sit in Table 3 section 2). The same campaign added
  Selective IgA Deficiency and Hyper-IgM Syndrome Type 2 (AID deficiency) as
  new entries and classified Immunodeficiency 14B and Immunodeficiency 61;
  membership was synced to that full classified set on 2026-08-30. 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
- member: Activated PI3K-delta syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member here driven by pathway hyperactivation rather than a
      loss: heterozygous gain-of-function PIK3CD (APDS1) or loss-of-function
      PIK3R1 (APDS2) variants both hyperactivate PI3K-delta-AKT-mTOR
      signaling, skewing B cells toward transitional forms with reduced
      switched memory B cells and a hyper-IgM pattern, alongside
      lymphoproliferation and herpesvirus susceptibility. IUIS 2022 places
      both forms in Table 3 section 2 (CVID phenotype); the T-cell
      senescence in the same patients is why older sources read APDS as a
      combined immunodeficiency.
    gene:
      preferred_term: PIK3CD
      term:
        id: hgnc:8977
        label: PIK3CD
- member: Selective IgA Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The most common primary antibody deficiency and the only member with no
      monogenic cause: a polygenic, HLA-associated failure of terminal IgA
      plasma-cell differentiation with normal IgG and IgM and normal B-cell
      counts. The majority of affected individuals are asymptomatic — the
      opposite pole of Table 3 from the agammaglobulinemias — with
      mucosal-infection, celiac, autoimmune, and anti-IgA transfusion-reaction
      risks in the symptomatic minority.
- member: Hyper-IgM Syndrome Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic AICDA loss abolishes class-switch recombination and somatic
      hypermutation B-cell-intrinsically: an IgM-only repertoire with massive
      germinal-center hyperplasia. Unlike the CD40LG/CD40 hyper-IgM defects
      that IUIS places in Table 1, T-cell licensing of macrophages is intact,
      so there is no opportunistic-infection susceptibility — the contrast
      that keeps this entity among the antibody deficiencies.
    gene:
      preferred_term: AICDA
      term:
        id: hgnc:13203
        label: AICDA
- member: Immunodeficiency 14B, Autosomal Recessive
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic PIK3CD loss-of-function — the recessive mirror image of APDS1
      on the same gene: absent p110-delta catalytic activity impairs B-cell
      antibody responses, producing severe bacterial infections with
      autoimmune complications. IUIS 2022 lists it in Table 3 section 1
      alongside the agammaglobulinemias.
    gene:
      preferred_term: PIK3CD
      term:
        id: hgnc:8977
        label: PIK3CD
- member: Immunodeficiency 61
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked SH3KBP1 (CIN85) deficiency impairs B-cell receptor signal
      amplification, with reduced antibody responses despite preserved B-cell
      development. IUIS 2022 places it in Table 3 section 2 (CVID phenotype)
      despite the entry's agammaglobulinemia-flavored synonyms.
    gene:
      preferred_term: SH3KBP1
      term:
        id: hgnc:13867
        label: SH3KBP1
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 a monogenic entity — sometimes
    in a different table (LRBA and CTLA4 patients are Table 4 members, both
    curated with hypogammaglobulinemia in their own differentiating
    mechanisms), and sometimes within this one (a PIK3CD or PIK3R1 patient is
    Activated PI3K-delta syndrome, itself a Table 3 section 2 member of this
    grouping, so that reassignment exchanges the CVID umbrella for a monogenic
    sibling without leaving Table 3).
    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.