UGGT1-congenital disorder of glycosylation

name: UGGT1-congenital disorder of glycosylation
creation_date: "2026-07-06T06:04:18Z"
description: >-
  UGGT1-congenital disorder of glycosylation is a recently described autosomal
  recessive N-linked glycosylation quality-control disorder caused by biallelic
  UGGT1 variants. UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1,
  an endoplasmic-reticulum enzyme that reglucosylates incompletely folded
  N-glycoproteins and maintains glycoprotein quality control. Pathogenic
  variants impair UGGT1 glucosylation/catalytic activity, splicing, or ER
  retention, leading to abnormal N-linked glycosylation quality control,
  proteostasis stress, and a multisystem phenotype with developmental delay,
  intellectual disability, seizures, characteristic facial features,
  microcephaly, and variable heart, skeletal, hepatic, and renal involvement.
category: Mendelian
disease_term:
  preferred_term: UGGT1-congenital disorder of glycosylation
synonyms:
- UGGT1-CDG
- UDP-glucose:glycoprotein glucosyltransferase 1 deficiency
parents:
- congenital disorder of glycosylation
classifications:
  icimd_category:
  - classification_value: multiple_glycosylation_pathways
    notes: >-
      Classified as a multiple-glycosylation-pathway disorder because UGGT1
      controls ER quality control of N-linked glycoproteins rather than a single
      terminal glycan structure.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    UGGT1-CDG is caused by biallelic UGGT1 variants.
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from
      ten unrelated families of various ethnic backgrounds as a cause of a
      distinctive CDG of variable severity.
    explanation: >-
      The clinical cohort directly supports biallelic UGGT1 causation.
pathophysiology:
- name: UGGT1 glycoprotein quality-control defect
  description: >-
    Pathogenic UGGT1 variants reduce UDP-glucose:glycoprotein
    glucosyltransferase function, disrupting reglucosylation-based ER quality
    control of N-linked glycoproteins.
  role: trigger
  genes:
  - preferred_term: UGGT1
    term:
      id: hgnc:15663
      label: UGGT1
  molecular_functions:
  - preferred_term: glucosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0046527
      label: glucosyltransferase activity
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme
      critical for maintaining quality control of N-linked glycosylation.
    explanation: >-
      The abstract establishes UGGT1 as an N-linked glycoprotein quality-control
      enzyme.
  downstream:
  - target: Impaired N-glycoprotein folding quality control
    description: >-
      Loss of UGGT1 catalytic activity or ER retention impairs reglucosylation
      of client N-glycoproteins.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40267907
      reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Molecular studies showed that pathogenic UGGT1 variants impair UGGT1
        glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit
        endoplasmic reticulum (ER) retention.
      explanation: >-
        Molecular studies directly support impaired glucosylation/catalytic
        activity and ER retention as proximal mechanisms.
- name: Impaired N-glycoprotein folding quality control
  description: >-
    Defective UGGT1-mediated reglucosylation disturbs ER folding quality control
    for N-linked glycoproteins, producing a broad N-linked glycosylation
    disorder.
  role: central_effector
  biological_processes:
  - preferred_term: protein folding in endoplasmic reticulum
    modifier: ABNORMAL
    term:
      id: GO:0034975
      label: protein folding in endoplasmic reticulum
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      broadening the spectrum of N-linked glycosylation disorders.
    explanation: >-
      The abstract frames UGGT1-CDG as an N-linked glycosylation disorder.
  downstream:
  - target: Multisystem UGGT1-CDG phenotype
    description: >-
      Impaired N-glycoprotein quality control causes neurologic and multisystem
      disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Multisystem UGGT1-CDG phenotype
  description: >-
    UGGT1-CDG manifests with developmental delay, intellectual disability,
    seizures, microcephaly, and variable congenital heart, skeletal, hepatic,
    and renal involvement.
  role: consequence
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cardinal clinical features of UGGT1-CDG involve developmental delay,
      intellectual disability, seizures, characteristic facial features, and
      microcephaly
    explanation: >-
      The abstract directly supports the recurrent neurologic phenotype.
phenotypes:
- name: Global developmental delay
  description: Developmental delay is a cardinal feature of UGGT1-CDG.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cardinal clinical features of UGGT1-CDG involve developmental delay,
      intellectual disability, seizures, characteristic facial features, and
      microcephaly
    explanation: The abstract identifies developmental delay as a cardinal feature.
- name: Intellectual disability
  description: Intellectual disability is part of the cardinal neurologic phenotype.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, intellectual disability, seizures, characteristic
      facial features, and microcephaly
    explanation: The abstract identifies intellectual disability.
- name: Seizures
  description: Seizures are a cardinal feature of UGGT1-CDG.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, intellectual disability, seizures, characteristic
      facial features, and microcephaly
    explanation: The abstract identifies seizures as a cardinal feature.
- name: Microcephaly
  description: Microcephaly is reported in most individuals with available measurements.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microcephaly in the majority (9/11 affected individuals for whom
      measurements were available).
    explanation: The abstract quantifies microcephaly among measured individuals.
- name: Congenital heart malformation
  description: Congenital heart malformations are part of the multisystem UGGT1-CDG phenotype.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals display congenital heart malformations
    explanation: >-
      The cohort reports congenital heart malformations among affected
      individuals.
- name: Scoliosis
  description: Scoliosis is among the reported skeletal abnormalities in UGGT1-CDG.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable skeletal abnormalities including scoliosis
    explanation: >-
      The cohort specifically names scoliosis within the skeletal phenotype.
- name: Abnormality of the liver
  description: Hepatic involvement is reported as part of the UGGT1-CDG multisystem phenotype.
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hepatic and renal involvement
    explanation: >-
      The cohort reports hepatic involvement, captured with the generic HPO
      liver abnormality term because the cached abstract does not specify a
      narrower liver phenotype.
- name: Polycystic kidney dysplasia
  description: Polycystic kidneys are reported in UGGT1-CDG.
  phenotype_term:
    preferred_term: Polycystic kidney dysplasia
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      polycystic kidneys mimicking autosomal recessive polycystic kidney disease.
    explanation: >-
      The cohort explicitly reports polycystic kidneys.
genetic:
- name: UGGT1
  association: Biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: UGGT1
    term:
      id: hgnc:15663
      label: UGGT1
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from
      ten unrelated families of various ethnic backgrounds as a cause of a
      distinctive CDG of variable severity.
    explanation: The cohort establishes UGGT1 as the causal gene for UGGT1-CDG.