UGGT1-congenital disorder of glycosylation

Mendelian MONDO:0980705 Pathograph 21 Show in embeddings browser congenital disorder of glycosylation

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, disrupting N-linked glycoprotein quality control. The associated multisystem phenotype includes developmental delay, intellectual disability, seizures, characteristic facial features, microcephaly, and variable heart, skeletal, hepatic, and renal involvement.

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1
Inheritance
4
Pathophys.
12
Phenotypes
1
Gaps
21
Pathograph
1
Genes
10
Variants
1
Medical Actions
2
Differentials
2
Models
2
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
n linked protein glycosylation
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
UGGT1-CDG is caused by biallelic UGGT1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"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."
The clinical cohort directly supports biallelic UGGT1 causation.
?

Discussions and Knowledge Gaps

1
Which cellular stress and signaling intermediates connect disrupted UGGT1-dependent calnexin/calreticulin quality control to the neurodevelopmental and multisystem phenotype?
KNOWLEDGE GAP OPEN gap_uggt1_quality_control_to_multisystem_phenotypes
Attached to
pathophysiology#Disrupted calnexin-calreticulin folding quality control
Human genetics establishes UGGT1-CDG and the functional assays support deficient enzyme activity and anticipated CNX/CRT-cycle disruption, but the cellular stress, signaling, and tissue-specific intermediates leading to developmental delay, seizures, microcephaly, and other organ findings have not been experimentally resolved.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Other
"The ultimate anticipated impact of all described variants is a disruption to the CRT/CNX cycle"
The authors identify the shared quality-control endpoint as anticipated, leaving its distal disease mechanisms open.
⚙

Pathophysiology

4
Biallelic UGGT1 functional impairment
Biallelic loss-of-function, missense, splice-altering, and ER-retrieval variants reduce functional UGGT1 through catalytic impairment, aberrant splicing and predicted nonsense-mediated decay, or loss of intracellular retention.
UGGT1 hgnc:15663 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UGGT1 (hgnc:15663). hgnc:15663 is a gene from the HUGO Gene Nomenclature Committee.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
UDP-glucose:glycoprotein glucosyltransferase activity GO:0003980 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UDP-glucose:glycoprotein glucosyltransferase activity (GO:0003980). GO:0003980 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced intracellular UGGT1 activity or availability Pathogenic variants reduce enzyme activity or intracellular UGGT1 protein.
Show evidence (1 reference)
PMID:40267907 SUPPORT In Vitro
"Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention."
The study directly tests three variant-dependent routes to UGGT1 dysfunction.
Reduced intracellular UGGT1 activity or availability
Most tested variants reduce catalytic activity; splice-altering variants generate aberrant transcripts, while p.Arg1546* removes the ER retrieval sequence and increases secretion from patient fibroblasts.
UGGT1 hgnc:15663 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UGGT1 (hgnc:15663). hgnc:15663 is a gene from the HUGO Gene Nomenclature Committee.
UDP-glucose:glycoprotein glucosyltransferase activity GO:0003980 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UDP-glucose:glycoprotein glucosyltransferase activity (GO:0003980). GO:0003980 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
UGGT1 variant reglucosylation and catalytic-activity cell models CELL LINE
p.Arg1546* patient-fibroblast ER-retention model PRIMARY CELL CULTURE
Downstream
Impaired N-glycoprotein reglucosylation Reduced enzyme activity lowers UGGT1-dependent client reglucosylation.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT In Vitro
"demonstrating a severe reduction in UGGT1 protein levels in patient WCLs with a concomitant increase in secreted UGGT1 protein"
Patient fibroblasts directly demonstrate defective intracellular retention.
Impaired N-glycoprotein reglucosylation
Reduced UGGT1 function impairs reglucosylation of incompletely folded N-glycoproteins and their re-entry into the calnexin/calreticulin quality-control cycle.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
UGGT1 variant reglucosylation and catalytic-activity cell models CELL LINE
Downstream
Disrupted calnexin-calreticulin folding quality control Failure to reglucosylate incompletely folded clients reduces their return to the calnexin/calreticulin cycle.
Show evidence (1 reference)
PMID:40267907 SUPPORT In Vitro
"pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity"
Cellular and biochemical assays establish deficient reglucosylation.
Disrupted calnexin-calreticulin folding quality control
Impaired reglucosylation disrupts ER quality control for misfolded glycoproteins. Downstream cellular stress and signaling effects are proposed by the authors but are not yet demonstrated as causal bridges to individual human phenotypes.
protein folding in endoplasmic reticulum GO:0034975 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding in endoplasmic reticulum (GO:0034975). GO:0034975 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Global developmental delay UGGT1 quality-control disruption causes the core developmental phenotype through unresolved cellular and tissue intermediates.
Intellectual disability UGGT1 quality-control disruption causes intellectual disability through unresolved cellular and tissue intermediates.
Seizures The disease-defining UGGT1 lesion is associated with seizures through unresolved downstream intermediates.
Microcephaly The disease-defining UGGT1 lesion is associated with microcephaly through unresolved downstream intermediates.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Other
"The ultimate anticipated impact of all described variants is a disruption to the CRT/CNX cycle"
The paper explicitly presents cycle disruption as the anticipated shared consequence; later stress and disease links remain hypotheses.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for UGGT1-congenital disorder of glycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Cardiovascular 1
Congenital heart malformation FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"Congenital heart disease was seen in five affected individuals"
The cohort reports congenital heart malformations among affected individuals.
Genitourinary 1
Genitourinary anomalies OCCASIONAL Abnormality of the genitourinary system HP:0000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genitourinary anomalies, annotated with Abnormality of the genitourinary system (HP:0000119). HP:0000119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"genitourinary anomalies (observed in four affected indi- viduals), including most commonly cryptorchidism in males."
Four of fifteen individuals (27%) supports the OCCASIONAL frequency band.
Head and Neck 2
Microcephaly VERY_FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"microcephaly in the majority (9/11 affected individuals for whom measurements were available)."
The abstract quantifies microcephaly among measured individuals.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"characteristic facial features, and microcephaly in the majority"
The cohort identifies facial dysmorphism among majority features.
Musculoskeletal 1
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"variable skeletal abnormalities including scoliosis"
The cohort specifically names scoliosis within the skeletal phenotype.
Nervous System 4
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"year of life uniformly had severe global developmental delay (GDD)/intellectual disability."
The cohort directly supports severe developmental impairment in survivors.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"year of life uniformly had severe global developmental delay (GDD)/intellectual disability."
The cohort directly supports intellectual disability in survivors.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40267907 SUPPORT Human Clinical
"developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly"
The abstract identifies seizures as a cardinal feature; full-text cohort synthesis reports seizures among findings in over half the cohort, supporting FREQUENT.
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"over half of the cohort include dysmorphic features, micro- cephaly ... and seizures"
The full-text cohort statement directly supports the FREQUENT band.
Atypical behavior VERY_FREQUENT HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"Behavioral traits were almost universally pre- sent and included features associated with autism spec- trum disorder"
The cohort describes behavioral traits as almost universal and enumerates their manifestations.
Other 3
Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"hepatic and renal involvement"
The cohort reports hepatic involvement; the full text includes hepatomegaly with periportal echogenicity or fibrosis in individual cases, but the generic term is retained to cover the variable hepatobiliary presentation.
Polycystic kidney dysplasia OCCASIONAL HP:0000113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic kidney dysplasia (HP:0000113). HP:0000113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"Cystic renal dysplasia and hepatobiliary anomalies ... were reported in two unrelated individuals."
The cohort explicitly reports polycystic kidneys.
Abnormal brain morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"gray matter heterotopia, abnormal myelination, corpus callosum thinning, and cerebellar vermian atrophy versus hypoplasia"
The paper directly lists the nonspecific imaging spectrum.
🧬

Genetic Associations

1
UGGT1 (Biallelic pathogenic variants)
Gene: UGGT1 hgnc:15663 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UGGT1 (hgnc:15663). hgnc:15663 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"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."
The cohort establishes UGGT1 as the causal gene for UGGT1-CDG.
Variants (10)
c.4636C>T (p.Arg1546*) Pathogenic
nonsense
Recurrent homozygous C-terminal nonsense founder variant reported in four unrelated Arab families.
c.381_384del (p.Tyr127*) Pathogenic
deletion
Heterozygous predicted loss-of-function deletion in a compound-heterozygous family.
c.978_979del (p.Ser327Phefs*13) Pathogenic
frameshift
Homozygous frameshift loss-of-function deletion.
c.4081dupC (p.Gln1361Profs*27) Likely Pathogenic
frameshift
Heterozygous frameshift duplication in a compound-heterozygous family.
c.1168_1191del (p.Asp390_Gly397del) Likely Pathogenic
in-frame deletion
Heterozygous in-frame deletion in a compound-heterozygous family.
c.2132C>T (p.Ala711Val) Likely Pathogenic
missense
Homozygous missense variant predicted to alter splicing.
c.2168T>C (p.Phe723Ser) Likely Pathogenic
missense
Heterozygous missense variant in a compound-heterozygous family.
c.3464A>G (p.Gln1155Arg) Likely Pathogenic
missense
Homozygous missense variant.
c.3815G>A (p.Arg1272His) Likely Pathogenic
missense
Homozygous missense variant with RNA evidence of altered splicing.
c.2355+4A>G Uncertain Significance
splice region
Homozygous splice-region variant of uncertain significance in siblings who also carried an FCSK VUS; its contribution remains unresolved.
💊

Medical Actions

1
Supportive multidisciplinary care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
No UGGT1-specific disease-modifying therapy is established. Management is supportive and individualized to seizures, development, nutrition, cardiac, renal, hepatic, orthopedic, respiratory, and behavioral manifestations.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Other
"At present, treatment for CDGs is largely supportive"
The source supports supportive CDG care but does not report UGGT1-specific outcome data.
🔬

Diagnosis

4
Exome or genome sequencing with segregation analysis
Molecular diagnosis requires identification of pathogenic biallelic UGGT1 variants by exome or genome sequencing, with family segregation and variant-specific functional interpretation where necessary.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic UGGT1 variants establish the molecular diagnosis.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"genome sequencing (GS) was performed for families 1–3, while exome sequencing (ES) was done for families 4–10"
The disease cohort was ascertained through both genome and exome sequencing.
Serum transferrin glycosylation analysis (Normal in tested individuals)
Carbohydrate-deficient transferrin screening may be normal in UGGT1-CDG and therefore cannot exclude the diagnosis when clinical suspicion remains high.
Results: A normal transferrin pattern does not exclude UGGT1-CDG.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"and 8) displayed a normal transferrin pattern."
All three tested affected individuals had unremarkable transferrin analysis.
Electroencephalography
EEG evaluates seizures and encephalopathy; abnormalities were present in 8 of 11 tested individuals.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Diffuse slowing, discontinuity, focal or generalized epileptiform discharges, or electrographic seizures may occur.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"abnormal (8/11), including diffuse slowing"
The cohort quantifies frequent EEG abnormalities.
Brain MRI
MRI evaluates the heterogeneous structural brain findings and may be normal.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Findings are nonspecific; normal imaging does not exclude UGGT1-CDG.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"Neuroimaging was reportedly normal in two individuals with the homozygous UGGT1 p.Arg1546* variant"
Normal MRI in molecularly confirmed cases demonstrates limited exclusion value.
📈

Progression

2
Fetal and infantile severe presentation
Likely biallelic null alleles can produce fetal demise, early multiorgan disease, respiratory failure, and infant death.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"bi-allelic UGGT1 loss-of-function variants associated with increased disease severity, including death in infancy."
The cohort supports a severe early null-allele presentation.
Childhood to adulthood in hypomorphic disease
Individuals retaining partial UGGT1 activity may survive beyond infancy with persistent syndromic neurodevelopmental disability; the oldest reported individual was 20 years.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Human Clinical
"survival beyond infancy was seen in affected individuals harboring UGGT1 missense variant(s)"
Residual-function genotypes are associated with survival beyond infancy.
⚖️

Clinical Burden

High
Survivors have severe neurodevelopmental disability, often with seizures and multisystem involvement; biallelic null genotypes can cause fetal demise or infant death. The phenotype is variable, and survival into adulthood is possible.
Show evidence (1 reference)
PMID:40267907 SUPPORT Human Clinical
"bi-allelic UGGT1 loss-of-function variants associated with increased disease severity, including death in infancy."
The cohort directly links null alleles with severe and lethal presentations.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from UGGT1-congenital disorder of glycosylation:

MOGS-congenital disorder of glycosylation
Overlapping Features MOGS-CDG affects an upstream step in the same N-linked glycoprotein quality-control pathway and overlaps through severe neurodevelopmental, seizure, cardiac, hepatic, skeletal, respiratory, craniofacial, and feeding features.
Distinguishing Features
  • Biallelic pathogenic UGGT1 variants favor UGGT1-CDG.
  • Biallelic pathogenic MOGS variants favor MOGS-CDG.
  • A normal transferrin pattern can occur in both and is not discriminating.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Other
"scoliosis, central apnea, craniofacial dysmorphology, and feeding problems"
The paper directly compares shared UGGT1-CDG and MOGS-CDG features.
MAN1B1-congenital disorder of glycosylation
Overlapping Features MAN1B1-CDG overlaps through intellectual disability, dysmorphism, behavioral abnormalities, seizures, and variable liver dysfunction.
Distinguishing Features
  • Biallelic pathogenic UGGT1 variants favor UGGT1-CDG.
  • Biallelic pathogenic MAN1B1 variants favor MAN1B1-CDG.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT Other
"similar clinical features (specifically intellectual disability, dysmorphism, behavioral abnormalities, sei- zures, and variable liver dysfunction) are also observed in MAN1B1-CDG"
The source explicitly names the overlapping MAN1B1-CDG differential.
🧫

Experimental Models

2
UGGT1 variant reglucosylation and catalytic-activity cell models CELL_LINE
Engineered ALG6/UGGT1/UGGT2-deficient cells reconstituted with patient variants and complementary in-vitro enzyme assays measure self- and client reglucosylation and catalytic activity.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Engineered HEK293-derived cell lines
Culture
Monolayer transfection and biochemical catalytic assays
Publication
PMID:40267907
Pathograph links
Reduced intracellular UGGT1 activity or availability
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT In Vitro
"to cause partial to full loss of enzymatic activity of UGGT1"
Variant catalytic assays directly reproduce reduced enzyme activity.
Impaired N-glycoprotein reglucosylation
Show evidence (1 reference)
PMID:40267907 SUPPORT In Vitro
"pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity"
The cell model directly measures deficient client reglucosylation.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT In Vitro
"a cell-based glucosylation assay and an in vitro catalytic activity assay"
The primary study describes the complementary model systems.
p.Arg1546* patient-fibroblast ER-retention model PRIMARY_CELL_CULTURE
Fibroblasts from homozygous p.Arg1546* individuals show reduced intracellular UGGT1 with increased secreted protein, modeling loss of the C-terminal ER retrieval signal.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary fibroblasts from affected individuals and healthy controls
Culture
Fibroblast monolayer with cell-lysate and supernatant immunoblotting
Publication
PMID:40267907
Pathograph links
Reduced intracellular UGGT1 activity or availability
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT In Vitro
"demonstrating a severe reduction in UGGT1 protein levels in patient WCLs with a concomitant increase in secreted UGGT1 protein"
Patient fibroblasts directly reproduce the ER-retention defect.
Show evidence (1 reference)
url:https://europepmc.org/articles/PMC12120171?pdf=render SUPPORT In Vitro
"demonstrating a severe reduction in UGGT1 protein levels in patient WCLs with a concomitant increase in secreted UGGT1 protein"
Secreted UGGT1 in patient culture supernatant supports the primary-cell model.
{ }

Source YAML

click to show 
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, disrupting N-linked glycoprotein quality control. The associated
  multisystem phenotype includes 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
  term:
    id: MONDO:0980705
    label: congenital disorder of glycosylation, type IIcc
synonyms:
- congenital disorder of glycosylation, type IIcc
- CDG2CC
- UGGT1-CDG
- UDP-glucose:glycoprotein glucosyltransferase 1 deficiency
parents:
- congenital disorder of glycosylation
classifications:
  icimd_category:
  - classification_value: n_linked_protein_glycosylation
    notes: >-
      UGGT1 directly controls ER quality control of N-linked glycoproteins; the
      report classifies the condition within the N-linked CDG spectrum rather
      than demonstrating disruption of multiple glycosylation pathways.
    evidence:
    - reference: PMID:40267907
      reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        an enzyme critical for maintaining quality control of N-linked
        glycosylation.
      explanation: The biochemical role supports classification as an N-linked glycosylation quality-control disorder.
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: Biallelic UGGT1 functional impairment
  description: >-
    Biallelic loss-of-function, missense, splice-altering, and ER-retrieval
    variants reduce functional UGGT1 through catalytic impairment, aberrant
    splicing and predicted nonsense-mediated decay, or loss of intracellular
    retention.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: UGGT1
    term:
      id: hgnc:15663
      label: UGGT1
  molecular_functions:
  - preferred_term: UDP-glucose:glycoprotein glucosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0003980
      label: UDP-glucose:glycoprotein 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: 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: The study directly tests three variant-dependent routes to UGGT1 dysfunction.
  downstream:
  - target: Reduced intracellular UGGT1 activity or availability
    description: >-
      Pathogenic variants reduce enzyme activity or intracellular UGGT1 protein.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        to cause partial to full loss of enzymatic activity of UGGT1
      explanation: Variant-specific enzymatic assays support reduced catalytic activity.
- name: Reduced intracellular UGGT1 activity or availability
  description: >-
    Most tested variants reduce catalytic activity; splice-altering variants
    generate aberrant transcripts, while p.Arg1546* removes the ER retrieval
    sequence and increases secretion from patient fibroblasts.
  role: central_effector
  biological_scale: MOLECULAR
  genes:
  - preferred_term: UGGT1
    term:
      id: hgnc:15663
      label: UGGT1
  molecular_functions:
  - preferred_term: UDP-glucose:glycoprotein glucosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0003980
      label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      demonstrating a severe reduction in UGGT1 protein levels in patient WCLs
      with a concomitant increase in secreted UGGT1 protein
    explanation: Patient fibroblasts directly demonstrate defective intracellular retention.
  downstream:
  - target: Impaired N-glycoprotein reglucosylation
    causal_link_type: DIRECT
    description: Reduced enzyme activity lowers UGGT1-dependent client reglucosylation.
    evidence:
    - reference: PMID:40267907
      reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic
        activity
      explanation: The functional assays directly measure impaired UGGT1-dependent glucosylation.
- name: Impaired N-glycoprotein reglucosylation
  description: >-
    Reduced UGGT1 function impairs reglucosylation of incompletely folded
    N-glycoproteins and their re-entry into the calnexin/calreticulin quality-control cycle.
  role: central_effector
  biological_scale: CELLULAR
  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: IN_VITRO
    snippet: >-
      pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic
      activity
    explanation: Cellular and biochemical assays establish deficient reglucosylation.
  downstream:
  - target: Disrupted calnexin-calreticulin folding quality control
    description: >-
      Failure to reglucosylate incompletely folded clients reduces their return
      to the calnexin/calreticulin cycle.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure to create a monoglucosylated N-glycan
    - reduced lectin-chaperone rebinding and ER retention
    evidence:
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The glycan re-binds to CNX/CRT to be retained in the ER.
      explanation: The pathway description identifies reglucosylation as the step enabling cycle re-entry.
- name: Disrupted calnexin-calreticulin folding quality control
  description: >-
    Impaired reglucosylation disrupts ER quality control for misfolded
    glycoproteins. Downstream cellular stress and signaling effects are proposed
    by the authors but are not yet demonstrated as causal bridges to individual
    human phenotypes.
  role: downstream
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: protein folding in endoplasmic reticulum
    modifier: ABNORMAL
    term:
      id: GO:0034975
      label: protein folding in endoplasmic reticulum
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ultimate anticipated impact of all described variants is a disruption
      to the CRT/CNX cycle
    explanation: >-
      The paper explicitly presents cycle disruption as the anticipated shared
      consequence; later stress and disease links remain hypotheses.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: UGGT1 quality-control disruption causes the core developmental phenotype through unresolved cellular and tissue intermediates.
    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 disease-defining study supports a causal lesion-to-CDG link while intermediates remain unknown.
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        year of life uniformly had severe global developmental delay
        (GDD)/intellectual disability.
      explanation: Full-text cohort synthesis identifies severe GDD as a core outcome.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: UGGT1 quality-control disruption causes intellectual disability through unresolved cellular and tissue intermediates.
    evidence:
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        year of life uniformly had severe global developmental delay
        (GDD)/intellectual disability.
      explanation: Full-text cohort synthesis identifies intellectual disability as a core outcome.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The disease-defining UGGT1 lesion is associated with seizures through unresolved downstream intermediates.
    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 clinical cohort places seizures within the causal UGGT1-CDG syndrome.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The disease-defining UGGT1 lesion is associated with microcephaly through unresolved downstream intermediates.
    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 cohort directly quantifies microcephaly in UGGT1-CDG.
phenotypes:
- name: Global developmental delay
  description: Severe global developmental delay or intellectual disability was uniform among individuals surviving the first year.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      year of life uniformly had severe global developmental delay
      (GDD)/intellectual disability.
    explanation: The cohort directly supports severe developmental impairment in survivors.
- name: Intellectual disability
  description: Intellectual disability is part of the cardinal neurologic phenotype.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      year of life uniformly had severe global developmental delay
      (GDD)/intellectual disability.
    explanation: The cohort directly supports intellectual disability in survivors.
- name: Seizures
  description: Seizures are a cardinal feature of UGGT1-CDG.
  frequency: FREQUENT
  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; full-text cohort synthesis reports seizures among findings in over half the cohort, supporting FREQUENT.
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      over half of the cohort include dysmorphic features, micro- cephaly ... and seizures
    explanation: The full-text cohort statement directly supports the FREQUENT band.
- name: Microcephaly
  description: Microcephaly is reported in most individuals with available measurements.
  frequency: VERY_FREQUENT
  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.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital heart disease was seen in five affected individuals
    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; the full text includes
      hepatomegaly with periportal echogenicity or fibrosis in individual cases,
      but the generic term is retained to cover the variable hepatobiliary presentation.
- name: Polycystic kidney dysplasia
  description: Polycystic kidneys are reported in UGGT1-CDG.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Polycystic kidney dysplasia
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic renal dysplasia and hepatobiliary anomalies ... were reported in
      two unrelated individuals.
    explanation: >-
      The cohort explicitly reports polycystic kidneys.
- name: Genitourinary anomalies
  description: Genitourinary anomalies occurred in four of fifteen affected individuals, most often cryptorchidism in males.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Genitourinary anomalies
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      genitourinary anomalies (observed in four affected indi-
      viduals), including most commonly cryptorchidism in
      males.
    explanation: Four of fifteen individuals (27%) supports the OCCASIONAL frequency band.
- name: Abnormal facial shape
  description: Variable craniofacial dysmorphism occurs without a single recognizable gestalt.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characteristic facial features, and microcephaly in the majority
    explanation: The cohort identifies facial dysmorphism among majority features.
- name: Atypical behavior
  description: Reported behaviors include anxiety, stereotypies, self-injury, hyperactivity, and autism-associated traits.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Behavioral traits were almost universally pre-
      sent and included features associated with autism spec-
      trum disorder
    explanation: The cohort describes behavioral traits as almost universal and enumerates their manifestations.
- name: Abnormal brain morphology
  description: Brain MRI abnormalities are nonspecific and include heterotopia, myelination abnormalities, callosal thinning, and vermian atrophy or hypoplasia.
  phenotype_term:
    preferred_term: Abnormal brain morphology
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gray matter heterotopia, abnormal myelination, corpus callosum thinning,
      and cerebellar vermian atrophy versus hypoplasia
    explanation: The paper directly lists the nonspecific imaging spectrum.
genetic:
- name: UGGT1
  association: Biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: UGGT1
    term:
      id: hgnc:15663
      label: UGGT1
  variants:
  - name: c.4636C>T (p.Arg1546*)
    description: Recurrent homozygous C-terminal nonsense founder variant reported in four unrelated Arab families.
    type: nonsense
    clinical_significance: PATHOGENIC
  - name: c.381_384del (p.Tyr127*)
    description: Heterozygous predicted loss-of-function deletion in a compound-heterozygous family.
    type: deletion
    clinical_significance: PATHOGENIC
  - name: c.978_979del (p.Ser327Phefs*13)
    description: Homozygous frameshift loss-of-function deletion.
    type: frameshift
    clinical_significance: PATHOGENIC
  - name: c.4081dupC (p.Gln1361Profs*27)
    description: Heterozygous frameshift duplication in a compound-heterozygous family.
    type: frameshift
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.1168_1191del (p.Asp390_Gly397del)
    description: Heterozygous in-frame deletion in a compound-heterozygous family.
    type: in-frame deletion
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.2132C>T (p.Ala711Val)
    description: Homozygous missense variant predicted to alter splicing.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.2168T>C (p.Phe723Ser)
    description: Heterozygous missense variant in a compound-heterozygous family.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.3464A>G (p.Gln1155Arg)
    description: Homozygous missense variant.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.3815G>A (p.Arg1272His)
    description: Homozygous missense variant with RNA evidence of altered splicing.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.2355+4A>G
    description: Homozygous splice-region variant of uncertain significance in siblings who also carried an FCSK VUS; its contribution remains unresolved.
    type: splice region
    clinical_significance: UNCERTAIN_SIGNIFICANCE
  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.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Survivors have severe neurodevelopmental disability, often with seizures
    and multisystem involvement; biallelic null genotypes can cause fetal demise
    or infant death. The phenotype is variable, and survival into adulthood is possible.
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bi-allelic UGGT1 loss-of-function variants associated with increased
      disease severity, including death in infancy.
    explanation: The cohort directly links null alleles with severe and lethal presentations.
diagnosis:
- name: Exome or genome sequencing with segregation analysis
  description: >-
    Molecular diagnosis requires identification of pathogenic biallelic UGGT1
    variants by exome or genome sequencing, with family segregation and
    variant-specific functional interpretation where necessary.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic UGGT1 variants establish the molecular diagnosis.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genome sequencing (GS) was performed for families 1–3, while exome
      sequencing (ES) was done for families 4–10
    explanation: The disease cohort was ascertained through both genome and exome sequencing.
- name: Serum transferrin glycosylation analysis
  description: >-
    Carbohydrate-deficient transferrin screening may be normal in UGGT1-CDG and
    therefore cannot exclude the diagnosis when clinical suspicion remains high.
  presence: Normal in tested individuals
  results: A normal transferrin pattern does not exclude UGGT1-CDG.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and 8) displayed a normal transferrin pattern.
    explanation: All three tested affected individuals had unremarkable transferrin analysis.
- name: Electroencephalography
  description: EEG evaluates seizures and encephalopathy; abnormalities were present in 8 of 11 tested individuals.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Diffuse slowing, discontinuity, focal or generalized epileptiform discharges, or electrographic seizures may occur.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal (8/11), including diffuse slowing
    explanation: The cohort quantifies frequent EEG abnormalities.
- name: Brain MRI
  description: MRI evaluates the heterogeneous structural brain findings and may be normal.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Findings are nonspecific; normal imaging does not exclude UGGT1-CDG.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuroimaging was reportedly normal in two individuals with the homozygous
      UGGT1 p.Arg1546* variant
    explanation: Normal MRI in molecularly confirmed cases demonstrates limited exclusion value.
treatments:
- name: Supportive multidisciplinary care
  description: >-
    No UGGT1-specific disease-modifying therapy is established. Management is
    supportive and individualized to seizures, development, nutrition, cardiac,
    renal, hepatic, orthopedic, respiratory, and behavioral manifestations.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At present, treatment for CDGs is largely supportive
    explanation: The source supports supportive CDG care but does not report UGGT1-specific outcome data.
differential_diagnoses:
- name: MOGS-congenital disorder of glycosylation
  description: >-
    MOGS-CDG affects an upstream step in the same N-linked glycoprotein
    quality-control pathway and overlaps through severe neurodevelopmental,
    seizure, cardiac, hepatic, skeletal, respiratory, craniofacial, and feeding features.
  distinguishing_features:
  - Biallelic pathogenic UGGT1 variants favor UGGT1-CDG.
  - Biallelic pathogenic MOGS variants favor MOGS-CDG.
  - A normal transferrin pattern can occur in both and is not discriminating.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      scoliosis, central apnea, craniofacial dysmorphology, and feeding problems
    explanation: The paper directly compares shared UGGT1-CDG and MOGS-CDG features.
- name: MAN1B1-congenital disorder of glycosylation
  description: MAN1B1-CDG overlaps through intellectual disability, dysmorphism, behavioral abnormalities, seizures, and variable liver dysfunction.
  distinguishing_features:
  - Biallelic pathogenic UGGT1 variants favor UGGT1-CDG.
  - Biallelic pathogenic MAN1B1 variants favor MAN1B1-CDG.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      similar clinical features (specifically intellectual
      disability, dysmorphism, behavioral abnormalities, sei-
      zures, and variable liver dysfunction) are also observed in
      MAN1B1-CDG
    explanation: The source explicitly names the overlapping MAN1B1-CDG differential.
progression:
- phase: Fetal and infantile severe presentation
  notes: >-
    Likely biallelic null alleles can produce fetal demise, early multiorgan
    disease, respiratory failure, and infant death.
  evidence:
  - reference: PMID:40267907
    reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bi-allelic UGGT1 loss-of-function variants associated with increased
      disease severity, including death in infancy.
    explanation: The cohort supports a severe early null-allele presentation.
- phase: Childhood to adulthood in hypomorphic disease
  notes: >-
    Individuals retaining partial UGGT1 activity may survive beyond infancy
    with persistent syndromic neurodevelopmental disability; the oldest reported individual was 20 years.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      survival beyond infancy was seen in affected individuals harboring UGGT1
      missense variant(s)
    explanation: Residual-function genotypes are associated with survival beyond infancy.
experimental_models:
- name: UGGT1 variant reglucosylation and catalytic-activity cell models
  description: >-
    Engineered ALG6/UGGT1/UGGT2-deficient cells reconstituted with patient
    variants and complementary in-vitro enzyme assays measure self- and client
    reglucosylation and catalytic activity.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Engineered HEK293-derived cell lines
  culture_system: Monolayer transfection and biochemical catalytic assays
  publication: PMID:40267907
  modeled_mechanisms:
  - target: Reduced intracellular UGGT1 activity or availability
    evidence:
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        to cause partial to full loss of enzymatic activity of UGGT1
      explanation: Variant catalytic assays directly reproduce reduced enzyme activity.
  - target: Impaired N-glycoprotein reglucosylation
    evidence:
    - reference: PMID:40267907
      reference_title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic
        activity
      explanation: The cell model directly measures deficient client reglucosylation.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a cell-based glucosylation assay and an in vitro catalytic activity assay
    explanation: The primary study describes the complementary model systems.
- name: p.Arg1546* patient-fibroblast ER-retention model
  description: >-
    Fibroblasts from homozygous p.Arg1546* individuals show reduced intracellular
    UGGT1 with increased secreted protein, modeling loss of the C-terminal ER retrieval signal.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary fibroblasts from affected individuals and healthy controls
  culture_system: Fibroblast monolayer with cell-lysate and supernatant immunoblotting
  publication: PMID:40267907
  modeled_mechanisms:
  - target: Reduced intracellular UGGT1 activity or availability
    evidence:
    - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
      reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        demonstrating a severe reduction in UGGT1 protein levels in patient WCLs
        with a concomitant increase in secreted UGGT1 protein
      explanation: Patient fibroblasts directly reproduce the ER-retention defect.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      demonstrating a severe reduction in UGGT1 protein levels in patient WCLs
      with a concomitant increase in secreted UGGT1 protein
    explanation: Secreted UGGT1 in patient culture supernatant supports the primary-cell model.
datasets: []
discussions:
- discussion_id: gap_uggt1_quality_control_to_multisystem_phenotypes
  prompt: Which cellular stress and signaling intermediates connect disrupted UGGT1-dependent calnexin/calreticulin quality control to the neurodevelopmental and multisystem phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disrupted calnexin-calreticulin folding quality control
  rationale: >-
    Human genetics establishes UGGT1-CDG and the functional assays support
    deficient enzyme activity and anticipated CNX/CRT-cycle disruption, but the
    cellular stress, signaling, and tissue-specific intermediates leading to
    developmental delay, seizures, microcephaly, and other organ findings have
    not been experimentally resolved.
  evidence:
  - reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
    reference_title: "https://europepmc.org/articles/PMC12120171?pdf=render"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ultimate anticipated impact of all described variants is a disruption
      to the CRT/CNX cycle
    explanation: The authors identify the shared quality-control endpoint as anticipated, leaving its distal disease mechanisms open.
references:
- reference: PMID:40267907
  title: "Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation."
- reference: url:https://europepmc.org/articles/PMC12120171?pdf=render
  title: "https://europepmc.org/articles/PMC12120171?pdf=render"
review_notes: >-
  This review uses the only disease-specific primary cohort currently identified:
  15 affected individuals from 10 families reported in 2025. The entry has no
  MONDO identifier because an exact UGGT1-CDG concept was not found in OLS/MONDO;
  it should not be mapped to a broader CDG term merely to fill the slot. The full
  open-access article was fetched only through the sanctioned reference workflow.
  Mechanisms were atomized, and every causal and model edge has direct or explicitly
  partial evidence. Three core neurodevelopmental phenotypes are connected through
  explicitly unknown intermediates, while other phenotype-specific routes remain
  unwired. The unresolved stress and signaling bridge is captured as a structured
  knowledge gap. The paper reports controlled
  genomic deposition to a broad BHCMG/GREGoR dbGaP/AnVIL study, not a clearly
  disease-specific public dataset, so `datasets` is explicitly empty. Normal
  transferrin screening in all three tested families is an important diagnostic
  limitation. Care is supportive; sugar supplementation is a research question,
  not an established UGGT1-CDG treatment. No matching GeneReviews chapter or
  repository deep-research artifact was found.
📚

References & Deep Research

References

2
PMID:40267907
Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
No top-level findings curated for this source.
url:https://europepmc.org/articles/PMC12120171?pdf=render
https://europepmc.org/articles/PMC12120171?pdf=render
No top-level findings curated for this source.