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:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      This grouping is deliberately scoped to protein N-glycosylation and its
      precursor and trafficking supply lines, as grouping_rationale states, while
      MONDO:0015286 additionally covers O-linked, GPI-anchor, and
      glycosphingolipid defects. narrowMatch records that asymmetry, which
      skos:exactMatch asserted away: a grouping cannot be deliberately narrower
      than a concept and exactly match it. The exactMatch now sits on the parent
      grouping Disorders of Protein and Lipid Glycosylation, whose scope is the
      whole MONDO class. narrowMatch still counts as curated for MONDO coverage,
      so nothing is retired from the curation queue by this change, and MONDO
      descendants without DisMech entries remain curation gaps rather than a
      reason to change the predicate again.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        18 of the 19 listed members are hierarchical descendants of
        MONDO:0015286, re-derived 2026-09-18. Method note, because it differs
        from the earlier check and is reproducible without a local MONDO build:
        rather than expanding the class's descendant closure and testing members
        against it, each member's own MONDO term was resolved to its ancestor set
        via the OLS hierarchicalAncestors endpoint and MONDO:0015286 looked up in
        it. That is one bounded upward walk per member (13-38 terms each) instead
        of one unbounded downward expansion, and it is what the configured
        ols:mondo adapter can actually serve - the OAK OLS implementation raises
        NotImplementedError for both descendants and ancestors, but the REST
        endpoint underneath answers ancestors directly.
        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 are curation gaps, but are
        no longer derivable from this row: the predicate here is now
        skos:narrowMatch, and scripts/grouping_mondo_gaps.py derives gaps only
        from skos:exactMatch. They are derivable from the parent grouping,
        Disorders of Protein and Lipid Glycosylation, which carries the
        exactMatch.
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: DHRSX-Congenital Disorder of Glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DHRSX-CDG (CDG1DD) is a type I CDG upstream of LLO assembly: the defect is
      in dolichol synthesis itself rather than in transferring sugars onto it.
      DHRSX performs the first and third steps of the three-step conversion of
      polyprenol to dolichol, with SRD5A3 catalysing only the second, so its loss
      raises the polyprenol-to-dolichol ratio and starves every downstream
      dolichol-dependent step at once. It is also the only member with
      pseudoautosomal-recessive inheritance, since DHRSX lies in PAR1 of the X
      and Y chromosomes.

- 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: MOGS-Congenital Disorder of Glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ER glucosidase I (MOGS/GCS1), the first trimming step after the
      lipid-linked oligosaccharide is transferred to protein. Unusually among
      type II CDG it is a trimming rather than an elongation defect, and the
      retained Glc3Man9 precursor produces a hypogammaglobulinemia with a
      paradoxical resistance to enveloped-virus infection rather than the group's
      usual neurologic picture.
    gene:
      preferred_term: MOGS
      term:
        id: hgnc:24862
        label: MOGS
- member: B4GALT1-Congenital Disorder of Glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Golgi beta-1,4-galactosyltransferase 1, which adds the galactose of the
      terminal N-glycan antenna. The lesion is at the outermost elongation step
      rather than in precursor assembly, so the entry's defining features are a
      coagulopathy and an altered lipoprotein profile from undergalactosylated
      client glycoproteins.
    gene:
      preferred_term: B4GALT1
      term:
        id: hgnc:924
        label: B4GALT1
- member: CCDC115-CDG
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Golgi V-ATPase assembly, so the proximal lesion is Golgi luminal pH rather
      than any glycosyltransferase. It sits with the trafficking-and-homeostasis
      arm of this grouping (COG1, COG7, VPS51) and, like them, produces a
      combined N- and O-glycosylation defect; the distinguishing clinical feature
      is hepatopathy with abnormal copper metabolism.
    gene:
      preferred_term: CCDC115
      term:
        id: hgnc:28178
        label: CCDC115
- 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.

  This grouping is now nested: it is a member of Disorders of Protein and Lipid
  Glycosylation (ICIMD category 18), which holds the five glycosylation
  sub-groupings whose boundaries this rationale already cross-references. The
  nesting did not change membership here. It did move the skos:exactMatch to
  MONDO:0015286 up to that parent and downgrade this grouping's own predicate to
  skos:narrowMatch, so the mapping now matches the N-glycan boundary this
  rationale defends.