Congenital Disorders of Glycosylation (CDG)

name: Congenital Disorders of Glycosylation
display_name: Congenital Disorders of Glycosylation (CDG)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  The congenital disorders of glycosylation (CDG) are a large group of inborn
  errors of metabolism caused by defects in the synthesis and attachment of
  glycans to proteins and lipids. Defects in the assembly of the lipid-linked
  oligosaccharide precursor, its transfer to nascent proteins (N-linked
  glycosylation), or its remodeling in the Golgi (including O-linked and
  multiple-pathway defects) impair the glycosylation of many client proteins
  simultaneously. The shared consequence is a multisystem disorder, classically
  with neurological involvement (developmental delay, hypotonia, seizures),
  often with hepatic, coagulation, endocrine, and dysmorphic features.
grouping_basis:
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared biosynthetic pathway: each member is a defect in
  protein N-glycosylation. Members are kept as separate Disease entries because
  they disrupt different steps — early and late assembly of the lipid-linked
  oligosaccharide (ALG1, ALG3, ALG9, ALG12), the dolichol/dolichol-phosphate
  carrier and donor supply (DOLK/DK1, MPDU1, DPM2), the nucleotide-sugar
  precursor pool feeding that assembly (PMM2, MPI, PGM1), Golgi nucleotide-sugar
  transport (SLC35A2), Golgi N-glycan branching (MGAT2), and Golgi trafficking
  via the conserved oligomeric Golgi complex (COG1, COG7) and the GARP/EARP
  tether (VPS51). The criteria are NECESSARY (every member perturbs N-linked
  glycosylation); CDG is a pathway-based classification and the grouping does
  not attempt to recapitulate the full MONDO CDG hierarchy.

  Boundary. This grouping is deliberately scoped to protein N-glycosylation
  and its precursor/trafficking supply lines, not to the whole modern CDG
  nosology, which also spans O-glycosylation, GPI-anchor, and glycosphingolipid
  defects. Those are held by sibling groupings — Disorders_of_GPI_Anchor_
  Biosynthesis (Mabry/PIGV, CHIME/PIGL, PNH, MCAHS2) and
  Other_Multiple_Glycosylation_Pathway_Disorders (UGDH, UGP2, UGGT1) — so a
  disorder that a broader CDG reading would pull in here is placed there
  instead, rather than being absent. Peters plus syndrome (B3GLCT) and
  Geleophysic dysplasia sit under the tsr_o_glycosylation_quality_control
  module for the same reason.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015286
      label: congenital disorder of glycosylation
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO congenital-disorder-of-
      glycosylation class. exactMatch records the intended conceptual alignment;
      MONDO descendants without DisMech entries are curation gaps rather than a
      reason to downgrade the mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        14 of the 15 listed members are is-a descendants of MONDO:0015286
        (checked against the 169-term descendant closure of the 2026-08 MONDO
        release). The exception is VPS51-Related Pontocerebellar Hypoplasia-CDG.
        It is bound to MONDO:0032831 pontocerebellar hypoplasia type 13, whose
        causal gene MONDO records as VPS51, but MONDO classifies that term under
        pontocerebellar hypoplasia rather than under congenital disorder of
        glycosylation. It is therefore a member here without being a descendant
        of the mapped class — an upstream classification gap, not a membership
        error, and a candidate MONDO request to add the CDG parent. Additional
        MONDO CDG descendants without DisMech entries should be surfaced as
        curation gaps from this exact mapping.
membership_criteria:
- description: >-
    A member is caused by a defect in the synthesis, attachment, or Golgi
    remodeling of protein N-glycans, and accordingly perturbs N-linked
    glycosylation — either its assembly/transfer step (protein N-linked
    glycosylation) or its downstream Golgi maturation step (N-glycan
    processing).
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Perturbs N-linked glycosylation at the assembly/transfer or Golgi-
      processing step — the shared, machine-checkable biological process across
      the group.
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: Involves protein N-linked glycosylation (assembly/transfer).
      biological_processes:
      - preferred_term: protein N-linked glycosylation
        term:
          id: GO:0006487
          label: protein N-linked glycosylation
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: Involves N-glycan processing (Golgi maturation).
      biological_processes:
      - preferred_term: N-glycan processing
        term:
          id: GO:0006491
          label: N-glycan processing
members:
- member: PMM2-Congenital Disorder of Glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Phosphomannomutase 2 interconverts mannose-6-phosphate and
      mannose-1-phosphate, the step that feeds GDP-mannose into the whole
      lipid-linked oligosaccharide assembly line. Its deficiency (CDG-Ia) is
      therefore upstream of every mannosyltransferase defect in this grouping:
      ALG1, ALG3, ALG9 and ALG12 each lose one step, while PMM2 loss starves all
      of them of donor. It sits alongside MPI and PGM1 as a precursor-supply
      defect rather than an assembly defect, and MPI is its instructive
      counterpart — the adjacent step in the same supply line, but treatable with
      oral mannose where PMM2-CDG is not.

      PMM2-CDG is also the reference case for the group clinically. It is the
      commonest CDG by a wide margin and the one whose phenotype the others are
      described against, and it is where the group's genetic architecture is
      clearest: complete loss of activity is not compatible with survival, so
      patients are hypomorph compound heterozygotes and per-allele residual
      activity sets severity.
    gene:
      preferred_term: PMM2
      term:
        id: hgnc:9115
        label: PMM2
- member: ALG9-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALG9 mannosyltransferase adds mannose residues to the lipid-linked
      oligosaccharide; its deficiency truncates the N-glycan precursor (CDG-Il),
      a classic N-linked assembly defect.
    gene:
      preferred_term: ALG9
      term:
        id: hgnc:15672
        label: ALG9
- member: ALG12-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALG12 is a later mannosyltransferase in LLO assembly; deficiency (CDG-Ig)
      gives a similar N-linked assembly defect at a distinct step from ALG9.
    gene:
      preferred_term: ALG12
      term:
        id: hgnc:19358
        label: ALG12
- member: MPDU1-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MPDU1 is required for utilization of dolichol-phosphate-mannose and
      -glucose donors; its loss (CDG-If) starves multiple LLO-assembly steps of
      activated sugars — a donor-utilization defect.
    gene:
      preferred_term: MPDU1
      term:
        id: hgnc:7207
        label: MPDU1
- member: DK1-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DOLK (dolichol kinase) generates dolichol phosphate, the lipid carrier for
      glycosylation; deficiency (CDG-Im) impairs the supply of the carrier itself,
      with a characteristic dilated cardiomyopathy.
    gene:
      preferred_term: DOLK
      term:
        id: hgnc:23406
        label: DOLK
- member: MGAT2-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MGAT2 adds the second antenna to complex N-glycans in the Golgi; its loss
      (CDG-IIa) is a glycan-processing (type II) defect, contrasting with the
      type I LLO-assembly defects.
    gene:
      preferred_term: MGAT2
      term:
        id: hgnc:7045
        label: MGAT2
- member: COG1-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      COG1 is a subunit of the conserved oligomeric Golgi (COG) complex
      controlling Golgi trafficking and enzyme localization; defects (CDG-IIg)
      disrupt multiple Golgi glycosylation steps simultaneously.
    gene:
      preferred_term: COG1
      term:
        id: hgnc:6545
        label: COG1
- member: COG7-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      COG7 deficiency (CDG-IIe) likewise impairs COG-complex-dependent Golgi
      trafficking, producing a severe multisystem combined N-/O-glycosylation
      defect.
    gene:
      preferred_term: COG7
      term:
        id: hgnc:18622
        label: COG7
- member: ALG1-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALG1 is the beta-1,4-mannosyltransferase that adds the first mannose to
      the cytosolic-face dolichol-linked GlcNAc2 precursor; deficiency (CDG-Ik)
      blocks LLO assembly at its earliest mannosylation step, upstream of the
      ALG3/ALG9/ALG12 elongation reactions.
    gene:
      preferred_term: ALG1
      term:
        id: hgnc:18294
        label: ALG1
- member: ALG3-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALG3 is the first luminal-face mannosyltransferase, acting on
      Man5GlcNAc2-PP-dolichol after flipping; deficiency (CDG-Id) stalls LLO
      elongation at the cytosolic/luminal transition, a distinct step from the
      later luminal ALG9 and ALG12 reactions.
    gene:
      preferred_term: ALG3
      term:
        id: hgnc:23056
        label: ALG3
- member: DPM2-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DPM2 is a regulatory subunit of the dolichol-phosphate-mannose synthase
      complex; deficiency (CDG-Iu) limits synthesis of the Dol-P-Man donor
      itself, upstream of the MPDU1 donor-utilization defect and affecting
      N-glycosylation, O-mannosylation, and GPI-anchor biosynthesis together.
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
- member: MPI-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MPI (mannose-6-phosphate isomerase) interconverts fructose-6-phosphate
      and mannose-6-phosphate; deficiency (CDG-Ib) starves the GDP-mannose
      precursor pool rather than disabling a glycosyltransferase, which is why
      it is the treatable CDG - oral D-mannose bypasses the block.
    gene:
      preferred_term: MPI
      term:
        id: hgnc:7216
        label: MPI
- member: PGM1-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      PGM1 interconverts glucose-1-phosphate and glucose-6-phosphate, linking
      glycogen metabolism to UDP-glucose/UDP-galactose supply; deficiency is a
      mixed type I/type II CDG (both truncated LLO and undergalactosylated
      complex glycans) and the only member with a glycogenosis phenotype
      alongside its glycosylation defect, partially correctable with oral
      D-galactose.
    gene:
      preferred_term: PGM1
      term:
        id: hgnc:8905
        label: PGM1
- member: SLC35A2-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SLC35A2 is the X-linked Golgi UDP-galactose transporter; deficiency is a
      nucleotide-sugar transport defect (type II) producing hypogalactosylated
      glycans, and is distinctive in the group for its somatic mosaic
      brain-limited form causing MOGHE-type refractory epilepsy.
    gene:
      preferred_term: SLC35A2
      term:
        id: hgnc:11022
        label: SLC35A2
- member: VPS51-Related Pontocerebellar Hypoplasia-CDG
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      VPS51 is the shared subunit of the GARP and EARP endosomal tethering
      complexes; deficiency impairs endosome-to-trans-Golgi retrograde traffic
      and therefore Golgi glycosylation-enzyme positioning - the same class of
      trafficking lesion as the COG disorders but at a distinct tether.
    gene:
      preferred_term: VPS51
      term:
        id: hgnc:1172
        label: VPS51
notes: >-
  Differentiating axis: the glycosylation step affected — nucleotide-sugar and
  dolichol precursor supply feeding cytosolic/ER LLO assembly (type I: ALG1,
  ALG3, ALG9, ALG12, MPDU1, DPM2, DOLK, MPI) vs Golgi nucleotide-sugar
  transport, processing, and trafficking (type II: SLC35A2, MGAT2, COG1, COG7,
  VPS51). PGM1-CDG spans both arms (truncated LLO plus undergalactosylated
  complex glycans) and is the group's canonical mixed type I/II member.

  Treatability is a second, orthogonal axis worth preserving as the group
  grows: MPI-CDG (oral D-mannose) and PGM1-CDG (oral D-galactose) are the two
  members with an established substrate-supplementation therapy, which is why
  they matter disproportionately to the group despite being precursor-supply
  rather than glycosyltransferase defects.