Disorders of GPI Anchor Biosynthesis (GPIBD)

name: Disorders of GPI Anchor Biosynthesis
display_name: Disorders of GPI Anchor Biosynthesis (GPIBD)
creation_date: "2026-08-14T00:00:00Z"
description: >-
  The disorders of glycosylphosphatidylinositol (GPI) anchor biosynthesis are a
  group of inborn (and, in one acquired case, somatic) errors of the pathway that
  builds the GPI anchor and attaches it to nascent proteins in the endoplasmic
  reticulum and Golgi. More than 150 human proteins reach the cell surface as
  GPI-anchored proteins; a defect anywhere along the ~30-step PIG/PGAP assembly
  and remodeling pathway therefore reduces or alters cell-surface GPI-anchored
  protein display broadly rather than affecting a single client. The shared
  consequence of the inherited (germline, biallelic) forms is a multisystem
  disorder — classically developmental and epileptic encephalopathy with
  intellectual disability, hypotonia, seizures, and dysmorphism, often with
  hyperphosphatasia (elevated alkaline phosphatase, a biochemical hallmark of the
  Mabry/HPMRS arm that occurs across both assembly-step defects — HPMRS1/PIGV,
  HPMRS2/PIGO — and post-attachment remodeling defects, because the GPI-anchored
  alkaline phosphatase is shed into serum). The single acquired member,
  paroxysmal nocturnal hemoglobinuria, results from a somatic PIGA mutation in a
  hematopoietic stem cell clone rather than germline inheritance; MONDO
  nonetheless classifies it directly under the mapped GPI-anchor-biosynthesis
  parent, so its membership sits squarely within the group.
grouping_basis:
- SHARED_PATHWAY
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on the shared GPI-anchor biosynthetic pathway: each member disrupts a
  distinct step of GPI anchor assembly, transfer, or remodeling, and each
  member's disorder entry annotates one of the component processes of GPI
  anchored protein biosynthesis (GO:0180046): GPI anchor biosynthetic process
  (GO:0006506), attachment of GPI anchor to protein (GO:0016255), or GPI anchor
  remodelling (GO:0120574). Members are kept as separate Disease entries because they act at
  different steps and present differently — de-N-acetylation of the first GlcNAc
  intermediate (PIGL, CHIME syndrome), the committed first transfer step of GPI
  synthesis (PIGA, paroxysmal nocturnal hemoglobinuria), and the
  mannosyltransferase / ethanolamine-phosphate-transferase and post-attachment
  remodeling steps (PIGV, PIGO, PGAP2, PGAP3, and others in Mabry syndrome), and
  the transamidase step that attaches the completed anchor to protein (GPAA1,
  glycosylphosphatidylinositol biosynthesis defect 15). The
  primary criterion is NECESSARY (every member is a GPI-anchor-biosynthesis
  defect); this grouping is a pathway-based classification and does not attempt
  to recapitulate the full MONDO GPIBD subtype series. The NECESSARY-only
  criterion (GO:0180046) is intentionally not defining: dolichol-phosphate-mannose
  donor lesions such as DPM2- and MPDU1-congenital disorder of
  glycosylation also annotate GPI anchor biosynthetic process and would satisfy
  it, but are deliberately excluded here because their primary lesion is in the
  shared Dol-P-Man supply that also cripples N- and O-glycosylation, placing them
  in the broader glycosylation grouping rather than in a pathway-specific GPI
  group. Intended future members
  and curation gaps include the numbered inherited GPI-deficiency series
  (glycosylphosphatidylinositol biosynthesis defects, GPIBD1..N), e.g.
  GPIBD18/PIGS (MONDO:0029140, DEE95); these can be added once their own Disease
  entries exist, since grouping membership is a foreign key to a curated entry.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024321
      label: disorder of GPI anchor biosynthesis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO "disorder of GPI anchor
      biosynthesis" class (itself an is-a child of disorder of glycosylation).
      exactMatch records the intended conceptual alignment; MONDO descendants
      without DisMech entries (the numbered GPIBD series) are curation gaps
      rather than a reason to downgrade the mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Six members are is-a descendants of MONDO:0024321 in MONDO:
        Mabry syndrome (MONDO:0016596), CHIME syndrome (MONDO:0010221),
        paroxysmal nocturnal hemoglobinuria (MONDO:0100244), developmental and
        epileptic encephalopathy 55 (MONDO:0033364), developmental and
        epileptic encephalopathy 77 (MONDO:0032808), and
        glycosylphosphatidylinositol biosynthesis defect 15 (MONDO:0060627). MONDO:0024321 is
        logically defined by disruption of GPI anchor biosynthetic process
        (RO:0004021 some GO:0006506), and inheritance mode is not part of that
        definition, so the ACQUIRED somatic-PIGA clone in PNH classifies under
        the parent without exception — its membership needs no special pleading.
        The remaining two members (multiple congenital
        anomalies-hypotonia-seizures syndrome, MONDO:0100247; developmental and
        epileptic encephalopathy 38, MONDO:0014868) are not is-a descendants of
        MONDO:0024321 in the current MONDO release, yet each disrupts GPI anchor
        biosynthetic process and satisfies the NECESSARY criterion;
        their absence under MONDO:0024321 is an upstream MONDO classification gap
        rather than a reason to exclude them. The GPIBD15 lesion (GPAA1) is in
        the attachment step (GO:0016255) rather than in GPI anchor biosynthetic
        process itself, so MONDO's logical definition is read broadly there. Additional MONDO GPIBD descendants
        without DisMech entries should be surfaced as curation gaps from this
        mapping.
membership_criteria:
- description: >-
    A member is caused by a defect in the biosynthesis, transfer, or remodeling
    of the glycosylphosphatidylinositol (GPI) anchor, and accordingly perturbs
    GPI anchored protein biosynthesis — the shared, machine-checkable biological
    process across the group. In GO its component processes are GPI anchor
    biosynthesis, attachment of the anchor to protein, and anchor
    remodelling, which are the three kinds of defect this grouping admits.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_BIOLOGICAL_PROCESS
    description: Involves GPI anchored protein biosynthesis.
    biological_processes:
    - preferred_term: GPI anchored protein biosynthesis
      term:
        id: GO:0180046
        label: GPI anchored protein biosynthesis
members:
- member: Mabry Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mabry syndrome (hyperphosphatasia with mental retardation syndrome, HPMRS)
      is caused by biallelic defects in the
      mannosyltransferase/ethanolamine-phosphate-transferase steps of GPI
      assembly (PIGV, PIGO) and in the
      post-attachment fatty-acid remodeling steps (PGAP2, PGAP3). In both the
      assembly-step (PIGV/PIGO) and remodeling-step (PGAP2/PGAP3) defects the
      GPI-anchored alkaline phosphatase is shed into serum instead of being
      retained at the cell surface, producing the characteristic
      hyperphosphatasia that distinguishes this arm of the group.
    gene:
      preferred_term: PIGV
      term:
        id: hgnc:26031
        label: PIGV
- member: CHIME_syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, mental
      retardation, ear anomalies) is caused by biallelic PIGL variants. PIGL
      encodes the de-N-acetylase that removes the acetyl group from
      N-acetylglucosaminyl-phosphatidylinositol, the second step of GPI anchor
      synthesis — an early assembly-step defect, distinct from the remodeling
      defects of Mabry syndrome.
    gene:
      preferred_term: PIGL
      term:
        id: hgnc:8966
        label: PIGL
- member: Paroxysmal Nocturnal Hemoglobinuria
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Paroxysmal nocturnal hemoglobinuria is the ACQUIRED member: a somatic PIGA
      mutation in a hematopoietic stem cell abolishes the committed first step of
      GPI anchor synthesis (transfer of GlcNAc to phosphatidylinositol). The
      resulting loss of GPI-anchored complement regulators CD55 and CD59 on the
      clonal red cells causes complement-mediated intravascular hemolysis.
      Unlike the germline members it is X-linked-somatic and clonal, not
      inherited, and its phenotype is hematologic rather than a developmental
      encephalopathy.
    gene:
      preferred_term: PIGA
      term:
        id: hgnc:8957
        label: PIGA
- member: Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MCAHS is the severe developmental-and-epileptic-encephalopathy arm of germline
      inherited GPI deficiency, an umbrella over three subtypes defined by the affected
      GPI-pathway gene: MCAHS1 (PIGN, ethanolamine-phosphate transfer), MCAHS2 (PIGA,
      the committed first GlcNAc-transfer step; X-linked and mechanistically distinct
      from the somatic-PIGA clone of PNH), and MCAHS3 (PIGT, GPI transamidase
      attachment). Unlike the Mabry/HPMRS arm, MCAHS does not show persistent
      hyperphosphatasia (serum alkaline phosphatase is normal, or low in PIGT/MCAHS3),
      and the clinical picture is dominated by multiple congenital anomalies and
      early-onset drug-resistant epileptic encephalopathy rather than the bone-enzyme
      abnormality.
- member: Developmental And Epileptic Encephalopathy 38
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DEE38 is the ARV1 arm of inherited GPI deficiency. ARV1 is not a PIG/PGAP
      biosynthetic enzyme but a facilitating component of the GPI-GnT complex
      that initiates GPI-anchor assembly (it associates with PIGQ and promotes
      recruitment of the phosphatidylinositol substrate), so ARV1 loss reduces
      GPI-anchor synthesis at its very first, committed step. Patient neutrophils
      and fibroblasts show reduced surface GPI-anchored proteins, placing DEE38
      among the inherited GPI-deficiency disorders; the phenotype is an
      autosomal-recessive developmental and epileptic encephalopathy with
      progressive cerebral and cerebellar atrophy, without the hyperphosphatasia
      of the Mabry/HPMRS arm. Its membership rests on the NECESSARY GO:0180046
      criterion rather than on MONDO ancestry — MONDO does not yet classify
      MONDO:0014868 under disorder of GPI anchor biosynthesis.
    gene:
      preferred_term: ARV1
      term:
        id: hgnc:29561
        label: ARV1
- member: Developmental and Epileptic Encephalopathy 55
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      PIGP, a subunit of the GPI-GlcNAc transferase complex that catalyses the
      committed first step of GPI assembly — the same step PIGA serves, but
      reached through an autosomal recessive subunit rather than the X-linked
      catalytic one, so the phenotype is a developmental and epileptic
      encephalopathy rather than the somatic-clone haemolytic disease of PIGA.
    gene:
      preferred_term: PIGP
      term:
        id: hgnc:3046
        label: PIGP
- member: Developmental And Epileptic Encephalopathy 77
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DEE77 (PIGQ-CDG, MCAHS4, GPIBD19) is the PIGQ arm of inherited GPI
      deficiency. PIGQ is a component of the GPI-N-acetylglucosaminyltransferase
      complex that performs the first committed step of the pathway — transfer
      of GlcNAc from UDP-GlcNAc onto phosphatidylinositol on the cytoplasmic
      face of the ER — so the lesion sits alongside PIGA, PIGC, PIGH, PIGP and
      PIGY rather than at the mannosyltransferase or remodelling steps. Patient
      granulocytes, leukocytes and fibroblasts show reduced surface GPI-anchored
      proteins, restored by wild-type PIGQ cDNA. The phenotype is a severe
      autosomal recessive developmental and epileptic encephalopathy with
      multiple congenital anomalies, high childhood mortality (median survival
      5.5 years across the 13 published patients), and a consistent craniofacial
      gestalt. It differs from the other first-step members curated here in one
      respect worth flagging: elevated serum alkaline phosphatase is reported in
      62% of PIGQ patients, which the pathway-position account of
      hyperphosphatasia — a Mabry/HPMRS feature arising from
      mannose-bearing incomplete anchors — does not predict for a block this
      early. That tension is recorded as a knowledge gap on the disease entry
      rather than resolved here.
    gene:
      preferred_term: PIGQ
      term:
        id: hgnc:14135
        label: PIGQ
- member: Glycosylphosphatidylinositol Biosynthesis Defect 15
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      GPIBD15 is the GPAA1 arm of inherited GPI deficiency and the only member
      here whose lesion is in the GPI transamidase, the five-subunit complex
      (PIGK, GPAA1, PIGS, PIGT, PIGU) that attaches the completed anchor to
      precursor proteins. The anchor is made but not transferred, so surface
      GPI-anchored proteins fall while serum alkaline phosphatase stays normal
      or low rather than raised, unlike the Mabry/HPMRS arm. Patients have
      developmental delay, hypotonia, early-onset often drug-resistant epilepsy,
      acquired cerebellar atrophy and osteopenia. It meets the NECESSARY
      criterion through attachment of GPI anchor to protein (GO:0016255), a
      component process of GPI anchored protein biosynthesis.
    gene:
      preferred_term: GPAA1
      term:
        id: hgnc:4446
        label: GPAA1