OGT-congenital disorder of glycosylation (OGT-CDG, MRX106) is a syndromic X-linked neurodevelopmental disorder caused by missense variants in OGT, which encodes O-GlcNAc transferase. OGT is the only enzyme that attaches O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of nuclear, cytosolic and mitochondrial proteins; a single opposing enzyme, O-GlcNAcase (OGA), removes it. OGT also catalyses the proteolytic maturation of the transcriptional co-regulator HCF1, itself an X-linked intellectual disability gene. Unlike the N-linked CDGs, the lesion is in cytoplasmic and nuclear O-GlcNAc cycling, so serum transferrin glycosylation is normal. Pathogenic variants fall in the N-terminal tetratricopeptide repeat (TPR) domain, which recognises substrates and partners, or in the C-terminal catalytic domain. TPR variants mostly lower the thermal stability of OGT with modest effects on activity, while catalytic-domain variants markedly reduce glycosyltransferase activity and global O-GlcNAcylation. A recurring finding across patient cells and models is compensatory downregulation of OGA, which keeps steady-state O-GlcNAc levels close to normal at the cost of a disturbed O-GlcNAc homeostasis. Affected males are hemizygous, usually for variants inherited from unaffected carrier mothers with skewed X inactivation; de novo variants occur in males and in heterozygous females with skewed X inactivation. Intellectual disability and developmental delay are present in every reported patient, with speech and language delay, hypotonia, eye anomalies (notably myopia and astigmatism), behavioural problems, brain abnormalities such as microcephaly and a thin corpus callosum, short stature, fifth-finger clinodactyly, long fingers and facial dysmorphism. Mouse, Drosophila and stem-cell models reproduce microcephaly, cortical and synaptic defects and learning deficits, and several of these are partially rescued by blocking OGA. No disease-specific treatment exists.
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name: OGT-Congenital Disorder of Glycosylation
creation_date: "2026-10-01T12:00:00Z"
category: Mendelian
description: >-
OGT-congenital disorder of glycosylation (OGT-CDG, MRX106) is a syndromic
X-linked neurodevelopmental disorder caused by missense variants in OGT,
which encodes O-GlcNAc transferase. OGT is the only enzyme that attaches
O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of
nuclear, cytosolic and mitochondrial proteins; a single opposing enzyme,
O-GlcNAcase (OGA), removes it. OGT also catalyses the proteolytic maturation
of the transcriptional co-regulator HCF1, itself an X-linked intellectual
disability gene. Unlike the N-linked CDGs, the lesion is in cytoplasmic and
nuclear O-GlcNAc cycling, so serum transferrin glycosylation is normal.
Pathogenic variants fall in the N-terminal tetratricopeptide repeat (TPR)
domain, which recognises substrates and partners, or in the C-terminal
catalytic domain. TPR variants mostly lower the thermal stability of OGT with
modest effects on activity, while catalytic-domain variants markedly reduce
glycosyltransferase activity and global O-GlcNAcylation. A recurring finding
across patient cells and models is compensatory downregulation of OGA, which
keeps steady-state O-GlcNAc levels close to normal at the cost of a
disturbed O-GlcNAc homeostasis. Affected males are hemizygous, usually for
variants inherited from unaffected carrier mothers with skewed X
inactivation; de novo variants occur in males and in heterozygous females
with skewed X inactivation.
Intellectual disability and developmental delay are present in every
reported patient, with speech and language delay, hypotonia, eye anomalies
(notably myopia and astigmatism), behavioural problems, brain abnormalities
such as microcephaly and a thin corpus callosum, short stature, fifth-finger
clinodactyly, long fingers and facial dysmorphism. Mouse, Drosophila and
stem-cell models reproduce microcephaly, cortical and synaptic defects and
learning deficits, and several of these are partially rescued by blocking
OGA. No disease-specific treatment exists.
disease_term:
preferred_term: intellectual disability, X-linked 106
term:
id: MONDO:0030907
label: intellectual disability, X-linked 106
parents:
- congenital disorder of glycosylation
- syndromic X-linked intellectual disability
synonyms:
- OGT-CDG
- OGT-XLID
- OGT congenital disorder of glycosylation
- MRX106
- intellectual developmental disorder, X-linked 106, X-linked recessive
- mental retardation, X-linked 106
- X-linked intellectual disability 106
- X-linked mental retardation 106
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
- classification_value: NEUROLOGIC
inheritance:
- name: X-linked recessive
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >-
Familial cases are hemizygous males whose unaffected carrier mothers show
X inactivation skewed away from the variant allele. De novo variants have
been reported in males and in monozygotic female twins who are
heterozygous for a catalytic-domain variant and show a 98:2 X-inactivation
skew; which X is inactivated in the twins is unknown.
evidence:
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "OGT-CDG is an X-linked recessive disorder, and therefore it primarily
affects males."
explanation: States the mode of inheritance.
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "A 98:2 skew in X inactivation was detected in both twins, while the
maternal parent was unaffected."
explanation: The heterozygous female twins with the de novo N567K variant both
had highly skewed X inactivation.
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, being a de novo mutation, which 1 of the 2 chromosomes is predominantly
inactivated remains unclear."
explanation: The twins' variant arose de novo, and the inactivated X is not
known.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The first six reports (2015-2019) described 13 affected individuals from
seven families. By 2026 more than 70 affected individuals were known, and
a community-curated catalogue listed 101 OGT-XLID variants. No population
prevalence estimate has been published.
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Thirteen affected individuals from seven families presenting with previously
unclassified ID and developmental delay were subjected to genetic testing and
found to carry nonsynonymous variants in the OGT gene"
explanation: The pooled case count from the first reports.
- reference: PMID:42209020
reference_title: "Genetic Rescue of Pathogenic O-GlcNAc Dyshomeostasis Associated
with Microcephaly and Motor Deficits."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Although >70 individuals with this condition are now known, we still
lack a clear understanding of how OGT mutations cause the disease."
explanation: Gives the number of known affected individuals by 2026.
- reference: PMID:42107645
reference_title: "Systematic mapping of O-GlcNAc transferase and O-GlcNAcase defines
disease-associated variants."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "This approach positions the O-GlcNAc database as the most current and
comprehensive repository of OGT-XLID mutations (n = 101 OGT-XLID variants)."
explanation: The size of the curated variant catalogue.
genetic:
- name: OGT
gene_term:
preferred_term: OGT
term:
id: hgnc:8127
label: OGT
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_disease_validity:
- validity_classification: MODERATE
classified_by: CLINGEN
external_id: CGGV:assertion_07776d36-7494-4ee4-992e-c6fb82c36749-2024-08-08T160000.000Z
evidence:
- reference: CGGV:assertion_07776d36-7494-4ee4-992e-c6fb82c36749-2024-08-08T160000.000Z
reference_title: "OGT / intellectual disability, X-linked 106 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "OGT | HGNC:8127 | intellectual disability, X-linked 106 | MONDO:0030907
| XL | Moderate"
explanation: >-
The ClinGen Syndromic Disorders Gene Curation Expert Panel classifies
the X-linked OGT relationship with this MONDO term as Moderate (SOP10,
2024-08-08).
association: >-
OGT (Xq13.1) encodes O-GlcNAc transferase. Pathogenic variants are missense
variants in the TPR or catalytic domain, plus one splice variant that
removes TPR residues 155-177. No null allele has been reported, consistent
with OGT being essential in vertebrate embryos.
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In this review, we compile the work from the last few years that clearly
delineates a new syndromic form of ID, which we propose to classify as a novel
Congenital Disorder of Glycosylation (OGT-CDG)."
explanation: Establishes OGT variants as the cause of a distinct syndrome and
proposes the OGT-CDG classification.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Three patients carried de novo variants resulting in single-amino acid
variants in the CD of OGT"
explanation: Catalytic-domain variants arose de novo, while the remaining early
variants were inherited TPR-domain variants.
variants:
- name: "OGT p.Leu254Phe"
description: >-
TPR-domain variant found by X-exome screening and segregating with
intellectual disability in three related males. It distorts the TPR
superhelix and lowers OGT stability; affected lymphoblastoid cells show
reduced OGT and OGA with near-normal global O-GlcNAc.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:28302723
reference_title: "Identification and characterization of a missense mutation
in the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "An X-chromosome exome screen identified a missense mutation, which
encodes an amino acid in the tetratricopeptide repeat, in OGT (759G>T (p.L254F))
that segregates with X-linked intellectual disability (XLID) in an affected
family."
explanation: Segregation of the variant with disease in a family.
- name: "OGT p.Arg284Pro"
description: >-
Hemizygous TPR-domain variant in a male with intellectual disability and
dysmorphic features. The recombinant protein unfolds readily and has
reduced glycosyltransferase and HCF1-processing activity.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:28584052
reference_title: "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding
and exhibited reduced glycosylation activity against a complex array of glycosylation
substrates and proteolytic processing of the transcription factor host cell
factor 1, which is also encoded by an XLID-associated gene."
explanation: Functional evidence for loss of both OGT activities.
- name: "OGT c.463-6T>G"
description: >-
Hemizygous intronic variant causing aberrant splicing; no stable
truncated protein was detected in patient fibroblasts. It corresponds to
the in-frame loss of TPR residues 155-177 that was later modelled in
patient-derived iPSCs.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:28584052
reference_title: "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing,
but no stable truncated protein was detected in the corresponding patient-derived
fibroblasts."
explanation: Shows the splicing consequence of the variant.
- name: "OGT p.Ala259Thr"
description: TPR-domain variant segregating with intellectual disability in a family.
clinical_significance: LIKELY_PATHOGENIC
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked intellectual
disability deregulate genes involved in cell fate determination and signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report the discovery of two additional novel missense mutations
(c.775 G>A, p.A259T, and c.1016 A>G, p.E339G) in the TPR domain of OGT that
segregate with XLID in affected families."
explanation: Reports segregation of the variant with disease.
- name: "OGT p.Glu339Gly"
description: TPR-domain variant segregating with intellectual disability in two brothers.
clinical_significance: LIKELY_PATHOGENIC
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked intellectual
disability deregulate genes involved in cell fate determination and signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report the discovery of two additional novel missense mutations
(c.775 G>A, p.A259T, and c.1016 A>G, p.E339G) in the TPR domain of OGT that
segregate with XLID in affected families."
explanation: Reports segregation of the variant with disease.
- name: "OGT p.Ala319Thr"
description: >-
TPR-domain variant in three brothers with severe intellectual
disability, inherited from their mother. It co-segregates with a missense
variant in MED12, another X-linked intellectual disability gene, so its
causal contribution in this family is uncertain.
clinical_significance: UNCERTAIN_SIGNIFICANCE
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The A319T mutation, present in three individuals with severe ID, was
inherited from the mother but segregated with an uncharacterized missense mutation
in MED12, a gene already implicated in ID"
explanation: Records the confounding MED12 variant in the A319T family.
- name: "OGT p.Asn567Lys"
description: >-
De novo catalytic-domain variant in monozygotic female twins. It lowers
OGT stability and disrupts the substrate-binding site, abolishing
catalytic activity, and impairs HCF1 cleavage in mouse embryonic stem
cells.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Molecular analyses revealed decreased OGT stability and disruption of
the substrate binding site, resulting in loss of catalytic activity."
explanation: Functional evidence that the variant abolishes catalytic activity.
- name: "OGT p.Asn648Tyr"
description: >-
De novo catalytic-domain variant in a male. It does not lower OGT thermal
stability but reduces catalytic activity, and mouse embryonic stem cells
carrying it have reduced OGA and global O-GlcNAc.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, in vitro determination of protein unfolding melting curves
demonstrated that all the XLID variants but the c.1942A>T p.(Asn648Tyr) destabilised
OGT"
explanation: Distinguishes this variant, which is not destabilising, from the
other early variants.
- reference: PMID:31627256
reference_title: "A missense mutation in the catalytic domain of O-GlcNAc transferase
links perturbations in protein O-GlcNAcylation to X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase
(OGA) and global O-GlcNAc levels."
explanation: Cellular consequence of the catalytic-domain variant reported in
this paper (p.Asn648Tyr, as identified in the later review).
- name: "OGT p.Cys921Tyr"
description: >-
Catalytic-domain variant inherited by three brothers with intellectual
disability and absent from their unaffected brother; two of the three
had generalised tonic-clonic seizures beginning around age 40. It
abolishes catalytic activity.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report three brothers affected by OGT-CDG that carry a novel
OGT variant, OGTC921Y, with a mutation in the catalytic core of OGT, which
is absent in their unaffected brother."
explanation: Segregation of the variant with disease in a sibship.
pathophysiology:
- name: OGT TPR Domain Missense Variants
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: protein O-GlcNAc transferase activity
term:
id: GO:0097363
label: protein O-acetylglucosaminyltransferase activity
modifier: DECREASED
description: >-
Hemizygous missense variants in the tetratricopeptide repeats (L254F,
A259T, R284P, A319T, E339G) and an in-frame TPR deletion. They lower the
thermal stability of OGT and alter TPR conformation; L254F shifts the TPR
helix by up to 15 angstroms. Effects on activity are modest and
substrate-dependent: all tested TPR variants still glycosylate the model
substrate CKII alpha, though L254F and R284P modify a complex lysate
substrate less well. Because the TPR domain selects substrates and binding
partners, the variants are thought to alter a subset of OGT interactions
rather than abolish activity.
genetic_context:
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
variant_origin: GERMLINE
zygosity: HEMIZYGOUS
allele_type: missense
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
description: >-
Inherited hemizygous TPR-domain missense variants, plus the c.463-6T>G
splice variant that removes residues 155-177.
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked intellectual
disability deregulate genes involved in cell fate determination and signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Characterization of all five of these XLID missense variants of OGT demonstrates
modest declines in thermodynamic stability and/or activities of the variants."
explanation: Biochemical characterisation of the five TPR variants.
- reference: PMID:29606577
reference_title: "The O-GlcNAc Transferase Intellectual Disability Mutation L254F
Distorts the TPR Helix."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using a multi-disciplinary approach we show that the L254F OGT mutation
leads to conformational changes of the tetratricopeptide repeats and reduced
activity, revealing the molecular mechanisms contributing to pathogenesis."
explanation: Structural and activity consequences of a TPR variant.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, in vitro determination of protein unfolding melting curves
demonstrated that all the XLID variants but the c.1942A>T p.(Asn648Tyr) destabilised
OGT"
explanation: All five TPR variants destabilise OGT in melting-curve assays.
downstream:
- target: Disrupted O-GlcNAc Homeostasis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
TPR variants leave global O-GlcNAc grossly unchanged in patient cells,
but cells lower OGA expression, and in Drosophila the learning deficit
caused by TPR variants is corrected by blocking O-GlcNAc removal. Which
substrates are under-modified is not known.
evidence:
- reference: PMID:28584052
reference_title: "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation
by down-regulating O-GlcNAcase expression."
explanation: Patient fibroblasts with TPR-region variants compensate by lowering
OGA.
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis,
indicating that OGT-CDG mutations affect cognition-relevant habituation via
reduced protein O-GlcNAcylation."
explanation: In flies carrying TPR variants, restoring O-GlcNAc rescues the
behavioural defect, placing reduced O-GlcNAcylation downstream of the variants.
- target: Impaired HCF1 Proteolytic Maturation
causal_link_type: DIRECT
description: Shown for R284P only; the other TPR variants process HCF1 normally.
evidence:
- reference: PMID:28584052
reference_title: "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding
and exhibited reduced glycosylation activity against a complex array of glycosylation
substrates and proteolytic processing of the transcription factor host cell
factor 1, which is also encoded by an XLID-associated gene."
explanation: The recombinant variant processes HCF1 less efficiently.
- target: Dysregulated Developmental Gene Expression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Four TPR variants engineered into human embryonic stem cells deregulate
a shared set of cell-fate and LXR/RXR signalling genes without gross
changes in global O-GlcNAc, OGT or OGA, so the link does not run through
a measurable change in bulk O-GlcNAc.
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked intellectual
disability deregulate genes involved in cell fate determination and signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, analyses of the differential transcriptomes of the OGT variant-expressing
stem cells revealed shared deregulation of genes involved in cell fate determination
and liver X receptor/retinoid X receptor signaling, which has been implicated
in neuronal development."
explanation: TPR variants change gene expression in stem cells.
- name: OGT Catalytic Domain Missense Variants
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: protein O-GlcNAc transferase activity
term:
id: GO:0097363
label: protein O-acetylglucosaminyltransferase activity
modifier: DECREASED
description: >-
Missense variants in the glycosyltransferase domain (N567K, N648Y, C921Y)
alter the substrate- or UDP-GlcNAc-binding region and markedly reduce
catalytic activity on peptide and protein substrates. They arose de novo
(N567K, N648Y) or were inherited (C921Y).
genetic_context:
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
variant_origin: GERMLINE
allele_type: missense
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
description: >-
Hemizygous in males (N648Y, C921Y) and heterozygous with skewed X
inactivation in female twins (N567K).
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Molecular analyses revealed decreased OGT stability and disruption of
the substrate binding site, resulting in loss of catalytic activity."
explanation: N567K abolishes catalytic activity.
- reference: PMID:31627256
reference_title: "A missense mutation in the catalytic domain of O-GlcNAc transferase
links perturbations in protein O-GlcNAcylation to X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The mutation reduces in vitro OGT activity on substrate peptides/protein."
explanation: A second catalytic-domain variant reduces activity.
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report an OGTC921Y variant that co-segregates with XLID and epileptic
seizures, and results in loss of catalytic activity."
explanation: A third catalytic-domain variant abolishes activity.
downstream:
- target: Disrupted O-GlcNAc Homeostasis
causal_link_type: DIRECT
evidence:
- reference: PMID:31627256
reference_title: "A missense mutation in the catalytic domain of O-GlcNAc transferase
links perturbations in protein O-GlcNAcylation to X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase
(OGA) and global O-GlcNAc levels."
explanation: Editing the variant into stem cells lowers both global O-GlcNAc
and OGA.
- reference: PMID:38566589
reference_title: "Neurodevelopmental defects in a mouse model of O-GlcNAc transferase
intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation
and reduced levels of OGT and OGA in the brain."
explanation: The C921Y knock-in mouse shows the same change in brain.
- target: Impaired HCF1 Proteolytic Maturation
causal_link_type: DIRECT
description: Shown for N567K; C921Y does not impair HCF1 cleavage.
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "(C) 3HA-OGTN567K mESCs show impaired HCF1 proteolytic cleavage."
explanation: The variant impairs HCF1 cleavage in mouse embryonic stem cells.
- name: Disrupted O-GlcNAc Homeostasis
biological_scale: MOLECULAR
biological_processes:
- preferred_term: protein O-GlcNAcylation
term:
id: GO:7770074
label: protein O-linked glycosylation via N-acetylglucosamine
modifier: DYSREGULATED
description: >-
O-GlcNAc levels are set by OGT and OGA acting in feedback. Catalytic
variants lower global O-GlcNAcylation in stem cells and brain. In patient
lymphoblastoid cells and fibroblasts, OGA protein and mRNA fall, partly
through enrichment of an OGT-containing mSin3A-HDAC1 repressor complex at
the OGA promoter, which keeps bulk O-GlcNAc near normal. The compensation
is imperfect and variant-specific: some models also raise OGT, and a
reporter screen found that OGT-CDG variants elicit a weaker feedback
response than wild-type or population variants. OGA downregulation has
been proposed as a cellular diagnostic marker.
evidence:
- reference: PMID:28302723
reference_title: "Identification and characterization of a missense mutation in
the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed an enrichment of the OGT-containing transcriptional repressor
complex mSin3A-HDAC1 at the proximal promoter region of OGA and correspondingly
decreased OGA promoter activity in affected cells."
explanation: Mechanism of OGA downregulation in patient cells.
- reference: PMID:28302723
reference_title: "Identification and characterization of a missense mutation in
the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates
with X-linked intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, we have begun to unravel the molecular consequences of the 759G>T
(p.L254F) mutation in OGT that uncovered a compensation mechanism, albeit imperfect,
given the phenotype of affected individuals, to maintain steady-state O-GlcNAc
levels."
explanation: Frames OGA loss as imperfect compensation.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Thus, variants in OGT may lead to reduction of OGA protein/transcript
to maintain O-GlcNAc homoeostasis."
explanation: Review synthesis across variants.
- reference: PMID:39706180
reference_title: "Exploiting O-GlcNAc dyshomeostasis to screen O-GlcNAc transferase
intellectual disability variants."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "OGT-CDG variants generally elicited a lower feedback response than wild-type
and Genome Aggregation Database (gnomAD) OGT variants."
explanation: A shared signature of disturbed feedback across variants.
- reference: PMID:41033462
reference_title: "Zscan4 as a Candidate Conveyor of Early Developmental Defects
in O-GlcNAc Transferase Intellectual Disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In addition to the increased levels of OGT and decreased levels of OGA
reflecting disrupted O-GlcNAc homeostasis, we find that expression of the ID
gene Zscan4 is upregulated."
explanation: Raised OGT and lowered OGA in stem cells carrying patient variants.
downstream:
- target: Dysregulated Developmental Gene Expression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In stem cells carrying catalytic variants, lower O-GlcNAcylation is
accompanied by loss of pluripotency factors, and raised OGT-TET complex
levels by Zscan4 upregulation. Which O-GlcNAc substrates convey these
changes is not established.
evidence:
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed
decreased levels of protein O-GlcNAcylation accompanied by decreased levels
of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase (ALP),
implying reduced self-renewal capacity."
explanation: Hypo-O-GlcNAcylation co-occurs with loss of pluripotency markers.
- target: Impaired Synaptic Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In Drosophila, hypo-O-GlcNAcylation from a patient catalytic variant
impairs neuromuscular junction synaptogenesis, and restoring
O-GlcNAcylation by targeting OGA partially rescues it. The substrates
involved are unknown.
evidence:
- reference: PMID:39535175
reference_title: "Rescuable sleep and synaptogenesis phenotypes in a Drosophila
model of O-GlcNAc transferase intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced
sleep stability."
explanation: Fly evidence that reduced O-GlcNAc impairs synapse formation.
- target: Short stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The C921Y mouse, which has lowered brain O-GlcNAc, is lighter, leaner and
shorter than wild-type littermates. How O-GlcNAc dyshomeostasis restricts
growth is not established.
evidence:
- reference: PMID:38566589
reference_title: "Neurodevelopmental defects in a mouse model of O-GlcNAc transferase
intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Phenotypic characterization of the mice revealed lower body weight associated
with reduced body fat mass, short stature and microcephaly."
explanation: The growth phenotype in a catalytic-variant mouse.
- name: Impaired HCF1 Proteolytic Maturation
biological_scale: MOLECULAR
biological_processes:
- preferred_term: HCF1 proteolytic processing
term:
id: GO:0016485
label: protein processing
modifier: DECREASED
description: >-
OGT glycosylates and then cleaves the HCF1 precursor at its PRO repeats
using the same active site. Reduced HCF1 cleavage has been shown for R284P
(recombinant enzyme) and N567K (recombinant enzyme and mouse embryonic
stem cells, where the HCF1 target GABPA was upregulated), but not for
L254F, A259T, E339G or C921Y. Because HCFC1 is itself an X-linked
intellectual disability gene, misprocessing may contribute for some
variants but is not thought to be the general mechanism.
genes:
- preferred_term: HCFC1
term:
id: hgnc:4839
label: HCFC1
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Changes in HCF1 processing were observed for the c.851G>C p.(Arg284Pro)
and c.1701=/T>A p.(Asn567Lys) variants"
explanation: The two variants with reduced HCF1 processing.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: REFUTE
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "However, while c.1701=/T>A p.(Asn567Lys) appears to affect HCF1 processing,
current data across all variants suggest that HCF1 misprocessing is unlikely
to be the general mechanism by which OGT variants lead to the observed XLID
phenotypes"
explanation: Refutes HCF1 misprocessing as a mechanism shared by all variants.
downstream:
- target: Dysregulated Developmental Gene Expression
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
HCF1 is a transcriptional co-regulator; in N567K stem cells with reduced
HCF1 cleavage, expression of the HCF1 target GABPA was raised.
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide
variants in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, RT-qPCR analysis of GABPA, a known target of HCF1 and
known to mediate synapse-specific gene expression"
explanation: Links HCF1 misprocessing to altered target-gene expression.
- name: Dysregulated Developmental Gene Expression
biological_scale: CELLULAR
cell_types:
- preferred_term: embryonic stem cell
term:
id: CL:0002322
label: embryonic stem cell
biological_processes:
- preferred_term: regulation of gene expression
term:
id: GO:0010468
label: regulation of gene expression
modifier: DYSREGULATED
- preferred_term: stem cell population maintenance
term:
id: GO:0019827
label: stem cell population maintenance
modifier: DYSREGULATED
description: >-
Stem-cell models show variant-dependent transcriptional changes: shared
deregulation of cell-fate, mesoderm and ectoderm development and LXR/RXR
signalling genes for TPR variants in human embryonic stem cells; reduced
Oct4, Sox2 and self-renewal for C921Y in mouse embryonic stem cells; and
Zscan4 upregulation with increased OGT-TET complex in mouse embryonic stem
cells carrying patient variants. Whether these early changes explain the
human brain phenotype is inferred rather than shown.
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked intellectual
disability deregulate genes involved in cell fate determination and signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, analyses of the differential transcriptomes of the OGT variant-expressing
stem cells revealed shared deregulation of genes involved in cell fate determination
and liver X receptor/retinoid X receptor signaling, which has been implicated
in neuronal development."
explanation: TPR variants share a transcriptional signature.
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed
decreased levels of protein O-GlcNAcylation accompanied by decreased levels
of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase (ALP),
implying reduced self-renewal capacity."
explanation: A catalytic variant reduces stem-cell self-renewal.
- reference: PMID:41033462
reference_title: "Zscan4 as a Candidate Conveyor of Early Developmental Defects
in O-GlcNAc Transferase Intellectual Disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This is associated with increased levels of the OGT:10 Eleven (Tet) -
protein complex that regulates DNA methylation and Zscan4 expression."
explanation: A candidate epigenetic route to the expression change.
downstream:
- target: Impaired Neuronal Differentiation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Stem cells carrying patient variants show delayed or altered
differentiation along the neural lineage; the transcriptional changes are
the proposed route, but no study has shown which genes are responsible.
- name: Impaired Neuronal Differentiation
biological_scale: CELLULAR
cell_types:
- preferred_term: neural stem cell
term:
id: CL:0000047
label: neural stem cell
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: neuron differentiation
term:
id: GO:0030182
label: neuron differentiation
modifier: DECREASED
description: >-
N567K mouse embryonic stem cells differentiate more slowly down the
neuronal lineage and form shorter neurites. Patient iPSCs carrying the TPR
deletion keep normal stemness and differentiation potential, but on
differentiation to ectoderm and neural stem cells they show disturbed
O-GlcNAc homeostasis, altered morphology and fewer, larger neural rosettes.
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Editing this mutation into the Drosophila genome results in global changes
in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss
of O-GlcNAcase and delayed differentiation down the neuronal lineage."
explanation: Delayed neuronal differentiation in stem cells carrying N567K.
- reference: PMID:38759397
reference_title: "Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc
transferase associated with intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Further differentiation to neuronal stem cells revealed differences in
morphology between patient and control lines, accompanied by disruption of the
O-GlcNAc pathway."
explanation: Altered neural stem cells derived from patient iPSCs.
downstream:
- target: Abnormal Cortical and Callosal Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed link from the stem-cell differentiation defects to the brain
malformations seen in mouse models; not tested directly.
- name: Abnormal Cortical and Callosal Development
biological_scale: TISSUE
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
- preferred_term: corpus callosum
term:
id: UBERON:0002336
label: corpus callosum
biological_processes:
- preferred_term: brain development
term:
id: GO:0007420
label: brain development
modifier: ABNORMAL
description: >-
Catalytic-variant knock-in mice (C921Y, N648Y) have small brains and
skulls. The C921Y mouse shows reduced cortical thickness, a hypoplastic
corpus callosum and dysplasia of the superficial layers of the cingulate
cortex, with O-GlcNAc dyshomeostasis in brain proteomics. These parallel
the microcephaly and thin corpus callosum reported in patients.
evidence:
- reference: PMID:42770280
reference_title: "Pathogenic O-GlcNAc dyshomeostasis is associated with cortical
malformations and hyperactivity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Structural studies, using micro-computed tomography and magnetic resonance
imaging, revealed reduced skull size, microcephaly, reduced cortical thickness
and hypoplastic corpus callosum."
explanation: Structural brain phenotype of the C921Y mouse.
- reference: PMID:42770280
reference_title: "Pathogenic O-GlcNAc dyshomeostasis is associated with cortical
malformations and hyperactivity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Detailed histological analyses revealed dysplastic changes in the neocortex,
predominantly affecting the superficial layers of the cingulate cortex."
explanation: Cortical dysplasia in the same model.
- reference: PMID:42209020
reference_title: "Genetic Rescue of Pathogenic O-GlcNAc Dyshomeostasis Associated
with Microcephaly and Motor Deficits."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "OgtN648Y/y mice exhibit a reduction in brain, skull, and body size, brain
and blood O-GlcNAc levels, and behavioral defects that recapitulate symptoms
seen in the patient, such as hyperactivity and motor deficits."
explanation: A second catalytic-variant mouse with small brain size.
downstream:
- target: Microcephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced brain growth in mouse models parallels patient microcephaly.
- target: Thin corpus callosum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Callosal hypoplasia in the C921Y mouse parallels the patient finding.
- target: Abnormal brain morphology
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Intellectual disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cortical malformation is a proposed contributor to cognitive impairment;
the C921Y mouse shows associative learning deficits alongside it.
evidence:
- reference: PMID:42770280
reference_title: "Pathogenic O-GlcNAc dyshomeostasis is associated with cortical
malformations and hyperactivity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "These mice show a range of behavioural deficits, including hyperactivity,
impulsivity, and associative learning phenotypes."
explanation: Learning deficits co-occur with cortical malformation in the same
model; the causal link to human cognition is inferred.
- name: Impaired Synaptic Development
biological_scale: CELLULAR
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: synapse assembly
term:
id: GO:0007416
label: synapse assembly
modifier: ABNORMAL
description: >-
In Drosophila larval neuromuscular junctions, TPR-variant alleles increase
bouton number while the C921Y-equivalent catalytic allele reduces bouton
number and junction area, so synapse growth is disturbed in opposite
directions by the two variant classes. The catalytic-allele phenotype and
reduced sleep stability are partially rescued by genetic or chemical OGA
inhibition. The human synaptic correlate has not been examined.
evidence:
- reference: PMID:39535175
reference_title: "Rescuable sleep and synaptogenesis phenotypes in a Drosophila
model of O-GlcNAc transferase intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Both these phenotypes can be partially rescued by genetically or chemically
targeting OGA, suggesting that a balance of OGT/OGA activity is required for
normal neuronal development and function."
explanation: Synaptic and sleep phenotypes depend on the OGT/OGA balance.
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in
Drosophila and demonstrate an important role of O-GlcNAcylation in habituation
learning and synaptic development at the larval neuromuscular junction."
explanation: O-GlcNAc cycling controls synaptic development and learning.
downstream:
- target: Intellectual disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Fly models with patient variants show habituation-learning deficits
alongside synaptic defects; the link to human cognition is inferred.
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Introduction of patient-specific missense mutations into Drosophila
O-GlcNAc transferase using CRISPR/Cas9 gene editing leads to deficits in locomotor
function and habituation learning."
explanation: A learning deficit in flies carrying patient variants.
- target: Sleep disturbance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Flies carrying the C921Y-equivalent allele have reduced sleep stability;
sleep abnormalities are reported in a minority of patients.
evidence:
- reference: PMID:39535175
reference_title: "Rescuable sleep and synaptogenesis phenotypes in a Drosophila
model of O-GlcNAc transferase intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced
sleep stability."
explanation: Sleep instability in a patient-variant fly model.
phenotypes:
- category: Neurological
name: Intellectual disability
frequency: OBLIGATE
description: >-
Present in all 13 individuals of the first seven families, with IQ well
below 70 and severity from mild to severe; all later reviews describe it as
a core feature.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All the patients carrying OGT variants suffer from decreased intellectual
ability with IQ scores well below 70."
explanation: Intellectual disability in every reported patient.
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All patients exhibit core phenotypes of ID and developmental delay, often
impacting their speech and language development."
explanation: A later review confirms ID as a core feature.
- category: Neurological
name: Global developmental delay
frequency: OBLIGATE
description: Present in 13 of 13 individuals in the first pooled cohort.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Developmental delay | 3/3 | 1/1 | 1/1 | 3/3 | 2/2 | 1/1 | 2/2 | 13/13"
explanation: Clinical table row giving 13 of 13.
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All patients exhibit core phenotypes of ID and developmental delay, often
impacting their speech and language development."
explanation: Developmental delay as a core feature.
- category: Neurological
name: Delayed speech and language development
frequency: VERY_FREQUENT
description: >-
Reported in all 8 individuals assessed in the first pooled cohort; language
skills range from delayed to very restricted.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Language delay/problems | NA | NA | NA | 3/3 | 2/2 | 1/1 | 2/2 | 8/8"
explanation: Clinical table row giving 8 of 8 assessed.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In addition, all patients show mental and physical developmental delay,
including intrauterine growth retardation, low birth weight, short stature, drooling,
and delayed and/or very restricted language skills."
explanation: Describes the language impairment.
- category: Neurological
name: Hypotonia
frequency: VERY_FREQUENT
description: >-
Four of five individuals assessed in the first pooled cohort; also
reported in later single cases. Hypotonia was recorded for only 5 of the
13 individuals, so the frequency band rests on a small denominator (4/5).
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Hypotonia | NA | NA | NA | NA | 1/2 | 1/1 | 2/2 | 4/5"
explanation: Clinical table row giving 4 of 5 assessed.
- reference: PMID:41030119
reference_title: "An OGT Missense Variant With Impaired Enzyme Activity in a Child
With Severe Developmental Delay and Hepatoblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report on a child with developmental delay, hypotonia, and dysmorphic
features who was found to carry a hemizygous novel OGT variant."
explanation: Hypotonia in a later case.
- category: Behavioral
name: Atypical behavior
frequency: FREQUENT
description: >-
Behavioural problems in 7 of 11 individuals in the first pooled cohort,
including autism spectrum disorder and ADHD in later reviews.
phenotype_term:
preferred_term: Behavioural problems
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Behavioural problems | 0/3 | 1/1 | 1/1 | 2/3 | 2/2 | 1/1 | NA | 7/11"
explanation: Clinical table row giving 7 of 11.
- category: Behavioral
name: Autism
description: Named as a common secondary feature in a 2024 review; no count given.
phenotype_term:
preferred_term: Autism spectrum disorder
term:
id: HP:0000717
label: Autism
evidence:
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Common secondary features observed in patients with OGT-CDG include behavioral
abnormalities such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity
Disorder (ADHD)."
explanation: Names ASD among the behavioural features.
- category: Behavioral
name: Attention deficit hyperactivity disorder
description: >-
Named as a common secondary feature in a 2024 review; no count given.
Catalytic-variant mice are hyperactive and impulsive.
phenotype_term:
preferred_term: Attention deficit hyperactivity disorder
term:
id: HP:0007018
label: Attention deficit hyperactivity disorder
evidence:
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Common secondary features observed in patients with OGT-CDG include behavioral
abnormalities such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity
Disorder (ADHD)."
explanation: Names ADHD among the behavioural features.
- reference: PMID:42770280
reference_title: "Pathogenic O-GlcNAc dyshomeostasis is associated with cortical
malformations and hyperactivity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "These mice show a range of behavioural deficits, including hyperactivity,
impulsivity, and associative learning phenotypes."
explanation: The C921Y mouse shows hyperactivity and impulsivity.
- category: Neurological
name: Sleep disturbance
description: Two patients in the early cohort had sleep abnormalities.
phenotype_term:
preferred_term: Sleep disturbance
term:
id: HP:0002360
label: Sleep disturbance
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Six patients were reported to have behavioural problems and two patients
presented with sleep abnormalities."
explanation: Reports sleep abnormalities in two patients.
- category: Neurological
name: Seizure
frequency: OCCASIONAL
description: >-
One of 10 individuals in the first pooled cohort had epilepsy, seizures or
dystonia. In the C921Y family two of three affected brothers had
generalised tonic-clonic seizures beginning around age 40.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Epilepsy/seizures/dystonia | 0/3 | 1/1 | NA | 0/3 | 0/2 | 0/1 | NA | 1/10"
explanation: Clinical table row giving 1 of 10.
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although twin 1 has not had an epileptic seizure, twin 2 experienced his
first generalised tonic clonic seizure at around 40 years of age."
explanation: Adult-onset seizures in the C921Y family.
- category: Neurological
name: Abnormal brain morphology
frequency: FREQUENT
description: >-
Brain abnormalities in 5 of 10 individuals in the first pooled cohort,
including microcephaly, enlarged cisterna magna, thin corpus callosum,
periventricular leukomalacia and brain atrophy. The specific findings are
curated as separate phenotypes.
phenotype_term:
preferred_term: Brain abnormalities
term:
id: HP:0012443
label: Abnormal brain morphology
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Brain abnormalities | NA | 1/1 | 1/1 | 0/3 | 0/2 | 1/1 | 2/2 | 5/10"
explanation: Clinical table row giving 5 of 10.
- category: Neurological
name: Microcephaly
frequency: OCCASIONAL
description: Three of 13 individuals in the first pooled cohort.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Three probands with different OGT variants present with microcephaly,
while megacisterna magna was found in two patients."
explanation: Microcephaly in three patients.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Microcephaly | 1/3 | 1/1 | 1/1 | 0/3 | 0/2 | 0/1 | 0/2 | 3/13"
explanation: Clinical table row giving 3 of 13.
- category: Neurological
name: Enlarged cisterna magna
description: Megacisterna magna in two patients of the early cohort.
phenotype_term:
preferred_term: Megacisterna magna
term:
id: HP:0002280
label: Enlarged cisterna magna
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Three probands with different OGT variants present with microcephaly,
while megacisterna magna was found in two patients."
explanation: Megacisterna magna in two patients.
- category: Neurological
name: Thin corpus callosum
frequency: OCCASIONAL
description: >-
One of five individuals assessed in the early cohort; the small
denominator makes the band uncertain.
phenotype_term:
preferred_term: Thin corpus callosum
term:
id: HP:0033725
label: Thin corpus callosum
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Additional anatomical brain abnormalities reported among OGT-XLID patients
include thin corpus callosum, periventricular leukomalacia, brain atrophy, and
cerebral palsy spastic diplegia."
explanation: Thin corpus callosum among the reported brain findings.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Thin corpus callosum | NA | 1/1 | NA | 0/3 | NA | 0/1 | NA | 1/5"
explanation: Clinical table row giving 1 of 5 assessed.
- category: Neurological
name: Periventricular leukomalacia
phenotype_term:
preferred_term: Periventricular leukomalacia
term:
id: HP:0006970
label: Periventricular leukomalacia
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Additional anatomical brain abnormalities reported among OGT-XLID patients
include thin corpus callosum, periventricular leukomalacia, brain atrophy, and
cerebral palsy spastic diplegia."
explanation: Periventricular leukomalacia among the reported brain findings.
- category: Neurological
name: Cerebral atrophy
phenotype_term:
preferred_term: Brain atrophy
term:
id: HP:0002059
label: Cerebral atrophy
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Additional anatomical brain abnormalities reported among OGT-XLID patients
include thin corpus callosum, periventricular leukomalacia, brain atrophy, and
cerebral palsy spastic diplegia."
explanation: Brain atrophy among the reported brain findings.
- category: Ophthalmologic
name: Abnormality of the eye
frequency: FREQUENT
description: >-
Eye abnormalities in 10 of 13 individuals in the first pooled cohort, a
high proportion that the authors note is unusual among XLID syndromes.
Myopia and astigmatism are curated separately.
phenotype_term:
preferred_term: Eye abnormalities
term:
id: HP:0000478
label: Abnormality of the eye
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Eye abnormalities | 3/3 | 1/1 | 1/1 | 2/3 | 0/2 | 1/1 | 2/2 | 10/13"
explanation: Clinical table row giving 10 of 13; the table does not break the
category down by finding.
- category: Ophthalmologic
name: Myopia
phenotype_term:
preferred_term: Myopia
term:
id: HP:0000545
label: Myopia
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Importantly, long fingers and eye abnormalities, including myopia and
astigmatism, were observed in a high proportion of patients with OGT-XLID variants,
while these characteristics are not common in XLID syndromes."
explanation: Myopia is one of the named eye findings.
- category: Ophthalmologic
name: Astigmatism
phenotype_term:
preferred_term: Astigmatism
term:
id: HP:0000483
label: Astigmatism
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Importantly, long fingers and eye abnormalities, including myopia and
astigmatism, were observed in a high proportion of patients with OGT-XLID variants,
while these characteristics are not common in XLID syndromes."
explanation: Astigmatism is one of the named eye findings.
- category: Auditory
name: Abnormality of the ear
frequency: FREQUENT
description: >-
Ear abnormalities or hearing impairment in 5 of 11 individuals in the
first pooled cohort; the table combines the two, and the text adds
hearing impairment and recurrent otitis in some patients.
phenotype_term:
preferred_term: Ear abnormalities or hearing impairment
term:
id: HP:0000598
label: Abnormality of the ear
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Ear abnormalities/hearing impairment | 0/3 | 1/1 | 0/1 | 1/3 | 2/2 | 1/1
| NA | 5/11"
explanation: Clinical table row giving 5 of 11 for the combined category.
- category: Auditory
name: Hearing impairment
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, some patients display visual and hearing impairment, and
suffer from recurrent otitis."
explanation: Hearing impairment in some patients.
- category: Auditory
name: Recurrent otitis media
phenotype_term:
preferred_term: Recurrent otitis
term:
id: HP:0000403
label: Recurrent otitis media
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, some patients display visual and hearing impairment, and
suffer from recurrent otitis."
explanation: Recurrent otitis in some patients.
- category: Growth
name: Short stature
frequency: FREQUENT
description: Six of 10 individuals in the first pooled cohort.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Short stature | 3/3 | 1/1 | NA | 2/3 | 0/2 | 0/1 | NA | 6/10"
explanation: Clinical table row giving 6 of 10.
- category: Growth
name: Intrauterine growth retardation
description: >-
Intrauterine growth retardation and low birth weight are listed among the
early-onset growth features; low birth weight was recorded in 6 of 9
individuals assessed.
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In addition, all patients show mental and physical developmental delay,
including intrauterine growth retardation, low birth weight, short stature, drooling,
and delayed and/or very restricted language skills."
explanation: Names intrauterine growth retardation and low birth weight.
- category: Skeletal
name: Clinodactyly of the 5th finger
frequency: FREQUENT
description: >-
The pooled table records clinodactyly in 9 of 13 individuals without
naming the digit, and the text of the same review specifies fifth-finger
clinodactyly in five; either count falls in the frequent band. One patient
instead had syndactyly and cone-shaped epiphyses.
phenotype_term:
preferred_term: Fifth-finger clinodactyly
term:
id: HP:0004209
label: Clinodactyly of the 5th finger
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Clinodactyly | 3/3 | 0/1 | 1/1 | 1/3 | 1/2 | Syndactyly | 2/2 | 9/13"
explanation: Clinical table row giving 9 of 13.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Clinodactyly of the fifth finger was found in five cases"
explanation: The text specifies fifth-finger clinodactyly in five patients.
- category: Skeletal
name: Long fingers
frequency: FREQUENT
description: Long, thin fingers in 5 of 7 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Long fingers
term:
id: HP:0100807
label: Long fingers
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Long thin fingers | NA | NA | 1/1 | 3/3 | 0/2 | 1/1 | NA | 5/7"
explanation: Clinical table row giving 5 of 7.
- category: Craniofacial
name: Abnormal facial shape
frequency: VERY_FREQUENT
description: >-
Dysmorphic features in 12 of 13 individuals in the first pooled cohort.
Reported features include a triangular, dolichocephalic head with a broad,
high forehead, full lips, broad nasal root, low-set large ears, full or
long philtrum, hypertelorism, frontal hair upsweep and high-arched palate.
Many males have a wide mouth, thin upper lip, full lower lip and smooth
philtrum. The commonest specific features are curated separately.
phenotype_term:
preferred_term: Facial dysmorphism
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Dysmorphic features | 3/3 | 1/1 | 1/1 | 2/3 | 2/2 | 1/1 | 2/2 | 12/13"
explanation: Clinical table row giving 12 of 13.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Dysmorphic facial features identified in probands with OGT-XLID variants
include triangular, dolichocephalic head with broad and high forehead, full lips,
broad nasal root, low set and big ears, full or long philtrum, and hypertelorism"
explanation: Lists the reported facial features.
- category: Craniofacial
name: Dolichocephaly
frequency: FREQUENT
description: Four of 6 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Dolichocephaly
term:
id: HP:0000268
label: Dolichocephaly
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Dolichocephalic head | NA | NA | NA | 2/3 | 2/2 | 0/1 | NA | 4/6"
explanation: Clinical table row giving 4 of 6.
- category: Craniofacial
name: Wide nasal bridge
frequency: FREQUENT
description: Broad nasal root in 3 of 4 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Broad nasal root
term:
id: HP:0000431
label: Wide nasal bridge
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Broad nasal root | NA | NA | 1/1 | NA | 1/2 | 1/1 | NA | 3/4"
explanation: Clinical table row giving 3 of 4.
- category: Growth
name: Small for gestational age
frequency: FREQUENT
description: Low birth weight in 6 of 9 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Low birth weight
term:
id: HP:0001518
label: Small for gestational age
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Low birth weight | NA | 1/1 | NA | 2/3 | 1/2 | 0/1 | 2/2 | 6/9"
explanation: Clinical table row giving 6 of 9; HPO lists low birth weight as
an exact synonym of this term.
- category: Craniofacial
name: Long philtrum
frequency: FREQUENT
description: >-
Full or long philtrum in 5 of 9 individuals assessed in the first pooled
cohort; the table combines the two descriptions.
phenotype_term:
preferred_term: Full or long philtrum
term:
id: HP:0000343
label: Long philtrum
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Full/long philtrum | 1/3 | NA | NA | 2/3 | 2/2 | 0/1 | NA | 5/9"
explanation: Clinical table row giving 5 of 9.
- category: Craniofacial
name: Frontal upsweep of hair
frequency: FREQUENT
description: Frontal hair upsweep in 4 of 9 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Frontal hair upsweep
term:
id: HP:0002236
label: Frontal upsweep of hair
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Frontal hair upsweep | 2/3 | NA | NA | 2/3 | 0/2 | 0/1 | NA | 4/9"
explanation: Clinical table row giving 4 of 9.
- category: Craniofacial
name: Thick vermilion border
frequency: FREQUENT
description: Full lips in 3 of 7 individuals assessed in the first pooled cohort.
phenotype_term:
preferred_term: Full lips
term:
id: HP:0012471
label: Thick vermilion border
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Full lips | 1/3 | NA | 1/1 | NA | 0/2 | 1/1 | NA | 3/7"
explanation: Clinical table row giving 3 of 7.
- category: Craniofacial
name: Coarse facial features
description: >-
Often described in patients with detailed clinical descriptions, together
with drooling, giving a resemblance to storage disorders.
phenotype_term:
preferred_term: Coarse facial features
term:
id: HP:0000280
label: Coarse facial features
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In patients with detailed clinical description, coarse facial features
with drooling are often described, which resembles storage disorders."
explanation: Coarse facies is a recurring description.
- category: Craniofacial
name: Hypertelorism
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Dysmorphic facial features identified in probands with OGT-XLID variants
include triangular, dolichocephalic head with broad and high forehead, full lips,
broad nasal root, low set and big ears, full or long philtrum, and hypertelorism"
explanation: Hypertelorism among the reported facial features.
- category: Craniofacial
name: High palate
phenotype_term:
preferred_term: High-arched palate
term:
id: HP:0000218
label: High palate
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In addition, some patients have frontal hair upsweeps and high-arched
palates."
explanation: High-arched palate in some patients.
- category: Neurological
name: Drooling
description: >-
Listed among the developmental features and often described with coarse
facies; only 1 of 13 is recorded in the pooled table, so the frequency is
uncertain.
phenotype_term:
preferred_term: Drooling
term:
id: HP:0002307
label: Drooling
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In patients with detailed clinical description, coarse facial features
with drooling are often described, which resembles storage disorders."
explanation: Drooling as a described feature.
- category: Genitourinary
name: Abnormality of the genital system
frequency: FREQUENT
description: >-
Genital or reproductive abnormalities in 3 of 8 individuals in the first
pooled cohort; the source does not specify the findings.
phenotype_term:
preferred_term: Genital abnormalities
term:
id: HP:0000078
label: Abnormality of the genital system
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Genital/reproductive abnormalities | 2/3 | 0/1 | 1/1 | NA | 0/2 | 0/1
| NA | 3/8"
explanation: Clinical table row giving 3 of 8.
biochemical:
- name: Serum Transferrin Glycoform Profile
notes: >-
Normal. Transferrin carries only N-glycans, so transferrin isoelectric
focusing does not detect this O-GlcNAc disorder; a normal result excludes
most N-linked CDGs but not OGT-CDG.
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Patients are negative for glycosylated transferrin test results, excluding
most N-linked congenital disorders of glycosylation (CDGs)."
explanation: Transferrin testing is negative in patients.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Since transferrin is only N-glycosylated, it detects only N-glycosylation
disorders associated with sialic acid deficiency and thus not OGT-CDG."
explanation: Explains why the screen is uninformative.
diagnosis:
- name: Exome sequencing
description: >-
Diagnosis rests on finding a hemizygous (male) or heterozygous (female)
OGT variant by exome or genome sequencing. Maternal X-inactivation skew
and functional studies in patient cells support causality for novel
missense variants.
diagnosis_term:
preferred_term: Exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:41030119
reference_title: "An OGT Missense Variant With Impaired Enzyme Activity in a Child
With Severe Developmental Delay and Hepatoblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OGT-CDG was diagnosed by exome sequencing that identified a de novo missense
variant in the OGT gene."
explanation: Exome sequencing made the molecular diagnosis.
- name: Functional assessment of OGA and O-GlcNAc in patient cells
description: >-
Western blotting of patient fibroblasts or lymphoblastoid cells for OGA
and global O-GlcNAc, and in vitro activity assays of the recombinant
variant, have been used to support pathogenicity. Reduced OGA protein has
been proposed as a rapid initial test. A mouse embryonic stem cell
reporter assay of OGT feedback separates pathogenic from population
variants in research settings.
evidence:
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Since patient-derived cells show reduced OGA, we propose western blotting
for OGA protein levels as a rapid initial diagnostic test for OGT-CDG."
explanation: Proposes OGA immunoblotting as a diagnostic test.
- reference: PMID:41030119
reference_title: "An OGT Missense Variant With Impaired Enzyme Activity in a Child
With Severe Developmental Delay and Hepatoblastoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional validation by Western blot on patient-derived fibroblasts showed
reduced O-GlcNAcylation and OGA expression, while significantly reduced enzyme
activity in vitro confirmed the pathogenicity of the variant."
explanation: Fibroblast and enzyme studies used to confirm a novel variant.
- reference: PMID:39706180
reference_title: "Exploiting O-GlcNAc dyshomeostasis to screen O-GlcNAc transferase
intellectual disability variants."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our work enables the prediction of pathogenicity for rapidly emerging
de novo OGT-CDG variants and points to reduced disruption of O-GlcNAc homeostasis
as a common mechanism underpinning OGT-CDG."
explanation: A cell-based assay for classifying variants.
animal_models:
- name: Ogt C921Y knock-in mouse
species: Mus musculus
genotype: CRISPR/Cas9 knock-in of the patient OGT C921Y catalytic-domain variant
(hemizygous males)
publication: PMID:38566589
description: >-
Viable mice carrying a catalytically impaired patient variant. They have
lower global brain O-GlcNAcylation with reduced OGT and OGA, lower body
weight and fat mass, short stature and microcephaly, and in a follow-up
study hyperactivity, impulsivity, associative learning deficits, reduced
cortical thickness, a hypoplastic corpus callosum and superficial-layer
cingulate cortical dysplasia.
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
modeled_mechanisms:
- target: Disrupted O-GlcNAc Homeostasis
relationship: RECAPITULATES
fidelity: HIGH
model_scale: MOLECULAR
description: Brain O-GlcNAc, OGT and OGA are all reduced.
evidence:
- reference: PMID:38566589
reference_title: "Neurodevelopmental defects in a mouse model of O-GlcNAc transferase
intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation
and reduced levels of OGT and OGA in the brain."
explanation: The molecular readout behind this link.
- target: Abnormal Cortical and Callosal Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Microcephaly, thinner cortex, callosal hypoplasia and cingulate
dysplasia.
limitations: >-
Models one catalytic-domain variant; TPR-domain variants, the commoner
inherited class, have not been modelled in mice. Mouse cortical
layering and callosal development differ in scale and timing from human.
evidence:
- reference: PMID:42770280
reference_title: "Pathogenic O-GlcNAc dyshomeostasis is associated with cortical
malformations and hyperactivity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Structural studies, using micro-computed tomography and magnetic resonance
imaging, revealed reduced skull size, microcephaly, reduced cortical thickness
and hypoplastic corpus callosum."
explanation: The structural readout behind this link.
evidence:
- reference: PMID:38566589
reference_title: "Neurodevelopmental defects in a mouse model of O-GlcNAc transferase
intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here, we report the use of a CRISPR/Cas9 genome editing approach to generate
a mouse model carrying a catalytically impaired OGT-CDG variant, C921Y."
explanation: Describes how the model was made.
- name: Ogt N648Y knock-in mouse
species: Mus musculus
genotype: Knock-in of the patient OGT N648Y catalytic-domain variant (OgtN648Y/y),
alone or crossed to catalytically inactive Oga D285A heterozygotes
publication: PMID:42209020
description: >-
Male mice carrying a second patient catalytic variant have reduced brain,
skull and body size, lower brain and blood O-GlcNAc, hyperactivity and
motor deficits. Halving OGA activity genetically partially restores
O-GlcNAc homeostasis, measured as the Ogt/Oga mRNA ratio in brain and
blood.
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
modeled_mechanisms:
- target: Disrupted O-GlcNAc Homeostasis
relationship: RESCUES
fidelity: MODERATE
model_scale: MOLECULAR
description: >-
Crossing to catalytically inactive OGA partially restores O-GlcNAc
homeostasis.
limitations: >-
Rescue was read out as an Ogt/Oga mRNA ratio; whether it corrects the
microcephaly or motor deficits is not reported in the abstract.
evidence:
- reference: PMID:42209020
reference_title: "Genetic Rescue of Pathogenic O-GlcNAc Dyshomeostasis Associated
with Microcephaly and Motor Deficits."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Encouragingly, this partially restored O-GlcNAc homeostasis in brain
and blood as determined by Ogt/Oga mRNA ratio."
explanation: The rescue readout behind this link.
- target: Abnormal Cortical and Callosal Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Reduced brain and skull size.
limitations: >-
Brain size only; cortical layering and the corpus callosum were not
reported for this line in the abstract.
evidence:
- reference: PMID:42209020
reference_title: "Genetic Rescue of Pathogenic O-GlcNAc Dyshomeostasis Associated
with Microcephaly and Motor Deficits."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "OgtN648Y/y mice exhibit a reduction in brain, skull, and body size,
brain and blood O-GlcNAc levels, and behavioral defects that recapitulate
symptoms seen in the patient, such as hyperactivity and motor deficits."
explanation: The brain-size readout behind this link.
evidence:
- reference: PMID:42209020
reference_title: "Genetic Rescue of Pathogenic O-GlcNAc Dyshomeostasis Associated
with Microcephaly and Motor Deficits."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "To achieve this, we first generated a new OGT-CDG mouse line carrying
the N648Y patient variant (OgtN648Y/y)."
explanation: Describes how the model was made.
- name: sxc TPR-variant Drosophila
species: Drosophila melanogaster
genotype: CRISPR/Cas9 knock-in of the TPR variants R284P, A319T and L254F into
super sex combs (sxcR313P, sxcA348T, sxcL283F)
publication: PMID:35500025
description: >-
Flies carrying fly-equivalent alleles of three patient TPR variants have
locomotor and habituation-learning deficits and increased neuromuscular
junction growth. The habituation deficit is corrected by blocking
O-GlcNAc hydrolysis.
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
modeled_mechanisms:
- target: Impaired Synaptic Development
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: CELLULAR
description: TPR alleles alter neuromuscular junction synapse growth.
limitations: >-
The fly larval neuromuscular junction is a glutamatergic peripheral
synapse, not a cortical one, and TPR alleles increase rather than reduce
bouton number.
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc
cycling impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity
in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation
learning and synaptic development at the larval neuromuscular junction."
explanation: The synaptic readout behind this link.
- target: Disrupted O-GlcNAc Homeostasis
relationship: RESCUES
fidelity: LOW
model_scale: ORGANISM
description: >-
Blocking O-GlcNAc hydrolysis corrects the habituation-learning deficit.
limitations: >-
Habituation in larvae is a simple non-associative learning paradigm and
only approximates human cognition.
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc
cycling impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis,
indicating that OGT-CDG mutations affect cognition-relevant habituation via
reduced protein O-GlcNAcylation."
explanation: The rescue readout behind this link.
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "With the same technique we introduced three ID-associated missense mutations
found in the conserved TPR domain of OGT: R284P"
explanation: Describes how the model was made.
- name: sxc C941Y Drosophila
species: Drosophila melanogaster
genotype: sxcC941Y, the fly equivalent of human OGT C921Y
publication: PMID:39535175
description: >-
Flies carrying a patient catalytic-domain variant are hypo-O-GlcNAcylated
and have reduced neuromuscular junction synaptogenesis and less stable
sleep, both partially rescued by genetic or chemical targeting of OGA.
genes:
- preferred_term: OGT
term:
id: hgnc:8127
label: OGT
modeled_mechanisms:
- target: Impaired Synaptic Development
relationship: RECAPITULATES
fidelity: LOW
model_scale: CELLULAR
description: >-
Reduced bouton number and junction area, partially rescued by targeting
OGA.
limitations: >-
Peripheral fly synapse; no human tissue correlate has been examined.
evidence:
- reference: PMID:39535175
reference_title: "Rescuable sleep and synaptogenesis phenotypes in a Drosophila
model of O-GlcNAc transferase intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced
sleep stability."
explanation: The synaptic readout behind this link.
evidence:
- reference: PMID:39535175
reference_title: "Rescuable sleep and synaptogenesis phenotypes in a Drosophila
model of O-GlcNAc transferase intellectual disability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster
carrying a patient-derived OGT mutation in the catalytic domain."
explanation: Describes the model.
experimental_models:
- name: OGT N567K mouse embryonic stem cells
experimental_model_type: CELL_LINE
organism:
preferred_term: mouse
term:
id: NCBITaxon:10090
label: Mus musculus
cell_source: Mouse embryonic stem cells with the N567K variant edited into the endogenous Ogt locus
publication: PMID:31296563
description: >-
Stem cells carrying the twins' catalytic variant lose OGA, show impaired
HCF1 cleavage and differentiate more slowly down the neuronal lineage.
modeled_mechanisms:
- target: Impaired Neuronal Differentiation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Delayed neuronal differentiation of variant stem cells.
limitations: >-
Mouse embryonic stem cells, whose pluripotency network differs from
human; differentiation timing in vitro is a proxy for brain development.
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Editing this mutation into the Drosophila genome results in global
changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads
to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage."
explanation: The differentiation readout behind this link.
- target: Impaired HCF1 Proteolytic Maturation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
description: Reduced proteolytic cleavage of endogenous HCF1.
evidence:
- reference: PMID:31296563
reference_title: "Catalytic deficiency of O-GlcNAc transferase leads to X-linked
intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "(C) 3HA-OGTN567K mESCs show impaired HCF1 proteolytic cleavage."
explanation: The HCF1 readout behind this link.
- name: OGT C921Y mouse embryonic stem cells
experimental_model_type: CELL_LINE
organism:
preferred_term: mouse
term:
id: NCBITaxon:10090
label: Mus musculus
cell_source: Mouse embryonic stem cells carrying the C921Y variant
publication: PMID:37334838
description: >-
Stem cells carrying the C921Y variant have reduced O-GlcNAcylation, Oct4,
Sox2 and alkaline phosphatase, indicating reduced self-renewal.
modeled_mechanisms:
- target: Dysregulated Developmental Gene Expression
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Loss of pluripotency factors and self-renewal.
limitations: >-
Mouse pluripotent cells; the human disorder has not been examined at
this stage, and the TPR variants did not change these markers in human
embryonic stem cells.
evidence:
- reference: PMID:37334838
reference_title: "An O-GlcNAc transferase pathogenic variant linked to intellectual
disability affects pluripotent stem cell self-renewal."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed
decreased levels of protein O-GlcNAcylation accompanied by decreased levels
of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase
(ALP), implying reduced self-renewal capacity."
explanation: The self-renewal readout behind this link.
- name: OGT TPR-variant human embryonic stem cells
experimental_model_type: CELL_LINE
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: Male human embryonic stem cell line with each of five TPR variants engineered by CRISPR/Cas9
publication: PMID:29769320
description: >-
Engineered lines show no gross change in global O-GlcNAc, OGT or OGA but
share deregulated cell-fate and LXR/RXR signalling genes.
modeled_mechanisms:
- target: Dysregulated Developmental Gene Expression
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Shared transcriptional changes across TPR variants.
limitations: >-
Undifferentiated stem cells; neural derivatives were not profiled.
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked
intellectual disability deregulate genes involved in cell fate determination
and signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, analyses of the differential transcriptomes of the OGT variant-expressing
stem cells revealed shared deregulation of genes involved in cell fate determination
and liver X receptor/retinoid X receptor signaling, which has been implicated
in neuronal development."
explanation: The transcriptomic readout behind this link.
- target: Disrupted O-GlcNAc Homeostasis
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
model_scale: MOLECULAR
description: >-
Unlike patient fibroblasts and lymphoblastoid cells, these lines do not
lower OGA.
limitations: >-
Global O-GlcNAc, OGT and OGA were compared only at steady state by Western
blot in undifferentiated embryonic stem cells, a different cell type from
the patient fibroblasts and lymphoblastoid cells in which OGA reduction was
reported; neural derivatives were not profiled.
evidence:
- reference: PMID:29769320
reference_title: "O-GlcNAc transferase missense mutations linked to X-linked
intellectual disability deregulate genes involved in cell fate determination
and signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Investigation of the global O-GlcNAc profile as well as OGT and O-GlcNAc
hydrolase levels by Western blotting showed no gross changes in steady-state
levels in the engineered lines."
explanation: No change in OGA or global O-GlcNAc in this model.
- name: OGT TPR-deletion patient iPSCs with isogenic control
experimental_model_type: IPSC_DERIVED_MODEL
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: Patient-derived induced pluripotent stem cells carrying the TPR deletion (residues 155-177), with a CRISPR/Cas9-corrected isogenic control, differentiated to ectoderm and neural stem cells
publication: PMID:38759397
description: >-
Patient iPSCs have reduced OGT and OGA but normal stemness and
differentiation potential; on neural differentiation they show disturbed
O-GlcNAc homeostasis and altered neural stem cell morphology.
modeled_mechanisms:
- target: Impaired Neuronal Differentiation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Altered morphology of patient-derived neural stem cells.
limitations: >-
Differentiation potential itself was normal; the phenotype is
morphological and limited to early neural stages.
evidence:
- reference: PMID:38759397
reference_title: "Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc
transferase associated with intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Further differentiation to neuronal stem cells revealed differences
in morphology between patient and control lines, accompanied by disruption
of the O-GlcNAc pathway."
explanation: The neural stem cell readout behind this link.
- target: Disrupted O-GlcNAc Homeostasis
relationship: RECAPITULATES
fidelity: HIGH
model_scale: MOLECULAR
description: Reduced OGT and OGA protein in patient cells.
evidence:
- reference: PMID:38759397
reference_title: "Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc
transferase associated with intellectual disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Although the OGT-CDG variant leads to a significant decrease in OGT
and O-GlcNAcase protein levels, there were no changes in differentiation potential
or stemness."
explanation: The O-GlcNAc enzyme readout behind this link.
discussions:
- discussion_id: ogt_cdg_shared_mechanism
kind: OPEN_QUESTION
status: OPEN
prompt: >-
What mechanism do TPR-domain and catalytic-domain OGT variants share,
given that they produce a similar syndrome?
attaches_to:
- pathophysiology#OGT TPR Domain Missense Variants
- pathophysiology#OGT Catalytic Domain Missense Variants
rationale: >-
Catalytic variants clearly reduce glycosyltransferase activity and global
O-GlcNAc, but most TPR variants retain near-normal activity and global
O-GlcNAc, and they alter fly synapse growth in the opposite direction.
Proposed shared mechanisms are disturbed O-GlcNAc feedback, altered
TPR-dependent interactions with substrates and partners, many of which
are themselves intellectual disability genes, and, for some variants,
HCF1 misprocessing. None has been shown to apply to every variant.
evidence:
- reference: PMID:39059494
reference_title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG):
Potential mechanistic targets revealed by evaluating the OGT interactome."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "Overall, studies examining the structure of OGT-CDG variants point toward
domain-specific changes: TPR domain variants have altered structure which could
affect protein-protein interactions, substrate selection, and stability, while
catalytic domain variants have changes in the binding site of substrates."
explanation: Summarises the domain-specific structural effects.
- reference: PMID:33356293
reference_title: "Generation of an Interactome for the Tetratricopeptide Repeat
Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual
Disability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Importantly, the identified TPR interactors are linked to several disease
states but most notably are enriched in pathologies featuring intellectual disability
that may underlie the mechanism by which mutations in OGT lead to XLID."
explanation: TPR interactors are enriched for intellectual disability genes.
- reference: PMID:35863433
reference_title: "Bioinformatic prediction of putative conveyers of O-GlcNAc transferase
intellectual disability."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Here, we used bioinformatic techniques to integrate sequence conservation,
structural data, clinical data, and the available literature to identify 22 candidate
proteins that convey OGT-CDG."
explanation: Proposes specific hypo-O-GlcNAcylated substrates as the shared mechanism.
- discussion_id: ogt_cdg_oga_inhibition
kind: EMERGING_HYPOTHESIS
status: OPEN
prompt: >-
Could inhibiting OGA, or supplementing the hexosamine pathway, treat
OGT-CDG?
attaches_to:
- pathophysiology#Disrupted O-GlcNAc Homeostasis
rationale: >-
Blocking OGA corrects habituation learning in TPR-variant flies, partially
rescues synaptic and sleep phenotypes in catalytic-variant flies, and
partially restores O-GlcNAc homeostasis in N648Y mice. Brain-penetrant
OGA inhibitors exist from neurodegeneration programmes. Glucosamine
supplementation was being explored in the N648Y patient with reported
positive effects, but no outcome data have been published, and no clinical
trial has been registered.
evidence:
- reference: PMID:35500025
reference_title: "Intellectual disability-associated disruption of O-GlcNAc cycling
impairs habituation learning in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This study establishes a critical role for O-GlcNAc cycling and disrupted
O-GlcNAc transferase activity in cognitive dysfunction, and suggests that blocking
O-GlcNAc hydrolysis is a potential strategy to treat OGT-CDG."
explanation: Proposes OGA blockade from fly rescue data.
- reference: PMID:32080367
reference_title: "An intellectual disability syndrome with single-nucleotide variants
in O-GlcNAc transferase."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "For the patient with the c.1942A>T p.(Asn648Tyr) variant, GlcN supplementation
is being explored with some positive effects"
explanation: Anecdotal report of glucosamine use in one patient.
references:
- reference: PMID:32080367
title: An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase.
- reference: PMID:39059494
title: "O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome."
notes: >-
Naming and classification. MONDO:0030907 is labelled "intellectual
disability, X-linked 106" (OMIM:300997) and sits under non-syndromic X-linked
intellectual disability, but the field now treats it as a syndromic
disorder and a congenital disorder of glycosylation (PMID:32080367), so the
entry is named OGT-CDG and listed among dismech's CDG entries while keeping
the MONDO binding. The Non-Syndromic_X-Linked_Intellectual_Disability entry
records the same reclassification. The phenotype frequencies come from the
only published pooled clinical table (13 individuals, 2020); the case count
has since grown past 70, so these frequencies will shift when a larger
cohort is published. A hepatoblastoma in one child with a de novo variant
(PMID:41030119) is not curated as a phenotype because the authors could not
exclude coincidence. A 2024 review also mentions connective-tissue
disorders and ulcerative colitis in some patients without counts or
primary citations; these are not curated. No GeneReviews chapter covers
OGT-CDG. ClinGen's Syndromic Disorders Gene Curation Expert Panel
classifies OGT against this MONDO term as Moderate (X-linked).
No disease-specific treatment has been reported, so the entry carries no
treatments section; candidate approaches are recorded under discussions.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Review round: missing table rows, ClinGen tier, term fixes · 2026-10-01T15:39:09Z · View source
Applied an independent review of the initial curation. Added the remaining PMID:32080367 Table 1 rows as phenotypes: low birth weight 6/9 (HP:0001518 Small for gestational age, whose HPO exact synonyms include Low birth weight), full/long philtrum 5/9 (HP:0000343), frontal hair upsweep 4/9 (HP:0002236), full lips 3/7 (HP:0012471), all FREQUENT; thin corpus callosum given OCCASIONAL with its 1/5 table row. Confirmed in cache/clingen/gene_validity.csv that ClinGen classifies OGT/MONDO:0030907 as Moderate (XL, SOP10, Syndromic Disorders GCEP); cached the record with just clingen-rebuild --csv-only (no manifest change) and recorded it as gene_disease_validity on the OGT row; removed the notes sentence that said no ClinGen record existed and the process wording about the GeneReviews check. Rebound the O-GlcNAc homeostasis process to GO:7770074 (protein O-linked glycosylation via N-acetylglucosamine) and added GO:0010468 regulation of gene expression (DYSREGULATED) to the gene-expression node; both confirmed with runoak. Regraded the PMID:42209020 case-count quote as HUMAN_CLINICAL (BACKGROUND). Added evidence to the cortical-development to ID edge (PMID:42770280, INDIRECT), a RECAPITULATES link from the N648Y mouse to the cortical/callosal node, PMID:35863433 in the shared-mechanism discussion, and a small-denominator note on hypotonia. Not done: PMID:25679214 was not cited because its abstract does not mention OGT (the cache stays because the deep-research report cites it, as do the other six caches the review listed); an OMIM/DOID mappings block, because sibling entries carry only mondo_mappings; Mayfield 2024 variants N806S, S93L, A431V, because they appear only as a list in a table cell.
Create: OGT-Congenital_Disorder_of_Glycosylation · 2026-10-01T15:09:50Z · View source
New entry for OGT-CDG (MONDO:0030907, intellectual disability, X-linked 106; OGT hgnc:8127), named as a CDG following PMID:32080367 and the note in Non-Syndromic_X-Linked_Intellectual_Disability; stub stubs/Intellectual_Disability_X-linked_106.yaml deleted. Deep research: just research-disorder falcon with --fallback; falcon was not configured (no EDISON_API_KEY) and the run fell back to claude_code, written as research/OGT-Congenital_Disorder_of_Glycosylation-deep-research-claude_code.md. Its reference validation resolved 29/30 (PMID:41651253 unresolved and not cited); term validation had no unresolved CURIEs. just preflight-dr returned WARN only because OGA, the counter-enzyme, is mentioned at 54% of OGT; the OGA sections are about this disease, so the report was used. Content: two variant-class root nodes (TPR-domain and catalytic-domain missense) each bound to OGT with molecular_functions GO:0097363 DECREASED, feeding Disrupted O-GlcNAc Homeostasis (OGA downregulation via mSin3A-HDAC1, blunted feedback), Impaired HCF1 Proteolytic Maturation (variant-restricted; the 2020 review's statement that it is not the general mechanism is recorded as REFUTE), stem-cell gene-expression changes, impaired neuronal differentiation, abnormal cortical/callosal development (mouse) and impaired synaptic development (Drosophila), wired to ID, microcephaly, thin corpus callosum, short stature and sleep phenotypes. 33 phenotypes, 8 pathophysiology nodes; frequencies are from the only pooled clinical table (13 patients, PMID:32080367 Table 1), quoted as table rows; ID and developmental delay set OBLIGATE (13/13, and 'All patients' in PMID:39059494). Variants: L254F, R284P, c.463-6T>G, A259T, E339G, A319T (UNCERTAIN_SIGNIFICANCE because it co-segregates with a MED12 variant), N567K, N648Y, C921Y. Models: C921Y and N648Y mice, TPR-variant and C941Y Drosophila, N567K and C921Y mESCs, TPR-variant hESCs, TPR-deletion patient iPSCs. No treatments section (none reported); OGA inhibition and glucosamine recorded as an EMERGING_HYPOTHESIS discussion. GeneReviews: just check-genereviews --online returned NO_CHAPTER. Hepatoblastoma (single case, possibly coincidental) and review-only mentions of connective-tissue disease and ulcerative colitis not curated. Validation: just validate 0 issues (123 snippets, 125 titles); count-verified-snippets 123/123; entity-refs, causal-targets, duplicate-keys, qualifier-terms, coarse-phenotypes OK; gene-activity grounding (baseline origin/main) no newly ungrounded genes; snippet-length, title-snippets, snippet-grading, folded-hyphens, reference-titles, term-cache-integrity, cache-order OK; just validate-disorders passed.
I'm still gathering sources. The curl call needed approval, so I'm switching to WebFetch against the Europe PMC API.
I have the core primary literature. Next I'm checking candidate ontology IDs against the repo's local term caches, then I'll write the report.
Target: OGT-CDG / X-linked intellectual disability 106 (MRX106). MONDO:0030907 (intellectual disability, X-linked 106, confirmed against the local MONDO cache in the draft entry). Category: Mendelian.
Date: 2026-10-01
just fetch-reference PMID:… and just count-verified-snippets.references_cache/ORPHA_*, CGGV_*). The OMIM, Orphanet and ClinGen identifiers below are therefore not confirmed.cache/*/terms.csv during this session.Overview. OGT-CDG is a syndromic X-linked neurodevelopmental disorder caused mainly by missense variants in OGT (Xq13.1). OGT encodes O-GlcNAc transferase, which is the only enzyme that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of nuclear and cytosolic proteins.
Identifiers
| Resource | ID | Status |
|---|---|---|
| MONDO | MONDO:0030907 intellectual disability, X-linked 106 | in the local cache |
| OMIM (phenotype) | 300997, MRX106 | from LOVD and the search results; omim.org returned 403 |
| OMIM (gene) | OGT 300255 | from search results |
| DOID | DOID:0080240 | from search results |
| HGNC | OGT: not in cache/hgnc/terms.csv |
[verify] with runoak; it is commonly given as HGNC:8127, which needs confirming |
| Orphanet / ICD-10 / ICD-11 / MeSH | none found | the search returned no ORPHA code specific to OGT-CDG |
Synonyms: OGT-CDG; OGT-XLID (used in PMID:33329753 and PMID:42107645); OGT-ID (PMID:42770280); MRX106; X-linked intellectual disability 106; mental retardation, X-linked 106.
Data provenance: everything here comes from aggregated case reports and family studies plus model systems, not from EHR data.
Frequencies. The figures come from the Pravata 2020 EJHG review summary (13 patients in 7 families). They were extracted by the secondary tool, so confirm them against the published table before use. Figures in the "~" form are approximate; denominators are the number of patients assessed.
| Phenotype | Frequency | HPO term | Notes |
|---|---|---|---|
| Intellectual disability | 13/13 (100%) | HP:0001249 Intellectual disability [cache] | IQ well below 70 |
| Developmental delay | 13/13 | HP:0001263 Global developmental delay [cache] | |
| Speech/language delay | 8/8 assessed | HP:0000750 Delayed speech and language development [cache] | FCDGC: "often impacting development of speech and language" |
| Dysmorphic facial features | 12/13 | Specific terms: HP:0000154 Wide mouth, HP:0000219 Thin upper lip vermilion, HP:0000179 Thick lower lip vermilion, HP:0000319 Smooth philtrum, HP:0000337 Broad forehead, HP:0000268 Dolichocephaly, HP:0000218 High palate [all cache] | Described as "wide mouth, thin upper lip, full lower lip, smooth philtrum" |
| Eye abnormalities | 10/13 | HP:0000545 Myopia, HP:0000483 Astigmatism, HP:0000540 Hypermetropia, HP:0000646 Amblyopia, HP:0000486 Strabismus [all cache] | High hypermetropia and amblyopia are listed in the MRX106 synopsis |
| 5th-finger clinodactyly / long fingers | 9/13 | HP:0004209 Clinodactyly of the 5th finger; HP:0100807 Long fingers [cache] | |
| Behavioural problems (ASD, ADHD) | 7/11 | HP:0000717 Autism; HP:0007018 Attention deficit hyperactivity disorder [cache] | |
| Short stature | 6/10 | HP:0004322 [cache] | Recapitulated in mice (PMID:38566589) |
| Low birth weight | 6/9 | [verify], not in cache | |
| Hypotonia | 4/5 assessed | HP:0001252 [cache] | Also noted in PMID:41030119 |
| Brain abnormalities (e.g. corpus callosum hypoplasia) | 5/10 | HP:0002079 Hypoplasia of the corpus callosum [cache] | Recapitulated in the C921Y mouse (PMID:42770280) |
| Hearing or ear anomalies | 5/11 | HP:0000365 Hearing impairment [cache] | |
| Genital anomalies | 3/8 | HP:0000028 Cryptorchidism, HP:0000047 Hypospadias [cache] | Which of these is reported needs confirming |
| Microcephaly | 3/13 | HP:0000252 [cache] | Seen in both mouse models (PMID:38566589, PMID:42770280) |
| Seizures / epilepsy | ~1/10 in early cohort | HP:0001250 Seizure [cache] | C921Y "co-segregates with XLID and epileptic seizures" (PMID:37334838) |
| Drooling, coarse facies | qualitative | HP:0002307 Drooling [cache] | "resembles storage disorders" |
| Hepatoblastoma | 1 case | HP:0002884 [cache] | Possibly coincidental (PMID:41030119) |
| Ulcerative colitis, connective-tissue features | anecdotal | — | FCDGC patient page only |
Onset and course. Onset is congenital or in infancy and presents as developmental delay. The course is a static neurodevelopmental disorder; no regression has been reported. Severity ranges from mild to severe ID.
Quality of life. No QoL instrument data have been published. The functional burden comes from lifelong ID, language impairment and behavioural comorbidity.
Gene. OGT (Xq13.1) has an N-terminal tetratricopeptide-repeat (TPR) domain that handles substrate and partner recognition, and a C-terminal glycosyltransferase domain split into two catalytic lobes. OGT also proteolytically matures HCF1 (HCFC1, hgnc:4839 [cache]), which is itself an XLID gene. OGT's counter-enzyme is OGA (gene OGA, formerly MGEA5; HGNC ID [verify]).
Reported variants (from the primary abstracts and the EJHG review table)
| Variant | Domain | Sex / inheritance | Source |
|---|---|---|---|
| p.L254F (c.759G>T as written in the abstract; c.762G>C in the review table) | TPR | males, segregating in a family | PMID:28302723 |
| p.R284P | TPR | hemizygous male | PMID:28584052 |
| c.463-6T>G (splice) | TPR | hemizygous male; aberrant splicing, no stable truncated protein | PMID:28584052 |
| p.A259T (c.775G>A) | TPR | males, family | PMID:29769320 |
| p.E339G (c.1016A>G) | TPR | males, family | PMID:29769320 |
| p.A319T | TPR | males, family (per review table) | Selvan 2018 per the review table; this variant is not in the PMID:29769320 abstract, so source it in the full text first |
| p.N567K | catalytic | monozygotic female twins, skewed X-inactivation | PMID:31296563 |
| p.N648Y | catalytic | male, de novo (per review table) | probably PMID:31627256; the abstract does not name the variant, so confirm |
| p.C921Y | catalytic | co-segregates with XLID and seizures | PMID:37334838 |
| new missense variant, de novo | — | male with hepatoblastoma | PMID:41030119 |
The 2026 OGT/OGA variant catalogue (PMID:42107645, oglcnac.mcw.edu/ogtoga/ogt/) now lists 101 pathogenic OGT-XLID variants curated with clinicians: "we partnered directly with clinicians and researchers to curate the most comprehensive and up-to-date collection of pathogenic OGT-XLID variants (n = 101)."
Variant class and functional effect - Variants are mostly missense, with one splice variant. They are hypomorphic (partial loss of function). Null alleles are expected to be lethal because OGT is essential for vertebrate embryogenesis (PMID:31296563). - TPR variants cause modest instability. PMID:29769320: "modest declines in thermodynamic stability and/or activities." - Catalytic-domain variants cause loss of activity. PMID:31296563: "decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity."
Other genetic features
- Variants are germline; none are somatic.
- Population frequency: pathogenic variants are absent or ultra-rare. gnomAD OGT variants trigger a stronger homeostatic feedback response than OGT-CDG variants (PMID:39706180).
- Curation status: Genomics England PanelApp lists OGT Green (high evidence) for intellectual disability. No ClinGen gene–disease validity record is in the local cache. Because no classification was retrieved, gene_disease_validity should be left empty.
- Epigenetics: none in patients. Mechanistic links run through OGT–TET complexes (PMID:41033462) and through chromatin and Polycomb roles (reviewed in PMID:33329753).
- No chromosomal abnormalities are associated with the disorder.
None known. There is no infectious agent, toxin or lifestyle factor. For a dismech entry, leave environmental: empty rather than inventing a hexosamine or nutrient link.
Parallel hypotheses that are not resolved. These include TPR-interactome disruption (PMID:33356293, PMID:39059494), hypo-O-GlcNAcylation of specific neuronal substrates (22 candidates involved in Ras/MAPK signalling, translational repression, cytoskeleton and chromatin; PMID:35863433), and HCF1 misprocessing, which affects only some variants (PMID:28584052, PMID:31296563). These map naturally to mechanistic_hypotheses with status: EMERGING.
measure_type: CASES_IN_LITERATURE with prevalence_class: ULTRA_RARE or RARE; do not invent a rate.No natural-history data exist. FCDGC: "Due to the rarity of the disease, there is no clear prognosis." Life expectancy is not reported to be shortened. Morbidity is lifelong ID, language impairment, and behavioural and visual issues. A single report of hepatoblastoma (PMID:41030119) raises an unproven question about cancer risk.
| Model | Variant | Recapitulation | Ref |
|---|---|---|---|
| Mouse (Mus musculus) | catalytically impaired OGT-CDG knock-in | decreased brain O-GlcNAc, OGT and OGA; low body weight and fat mass, short stature, microcephaly | PMID:38566589 |
| Mouse | C921Y | hyperactivity, impulsivity, associative-learning deficits; microcephaly, thin cortex, corpus callosum hypoplasia, cingulate dysplasia; proteomic dyshomeostasis | PMID:42770280 |
| Mouse | OGT-CDG × OGA-dead cross | microcephaly and motor deficits; partial genetic rescue of homeostasis | PMID:42209020 |
| Drosophila | patient missense variants (CRISPR) in sxc | locomotor and habituation-learning deficits rescued by OGA blockade; reduced NMJ synaptogenesis and sleep stability, partially rescued | PMID:35500025, PMID:39535175 |
| Drosophila | N567K | global O-GlcNAc proteome changes | PMID:31296563 |
| mESC | N567K, N648Y(?), C921Y, others | loss of OGA, delayed neuronal differentiation; reduced self-renewal (Oct4/Sox2); Zscan4/TET dysregulation | PMID:31296563, PMID:31627256, PMID:37334838, PMID:41033462 |
| hESC (CRISPR) | five TPR variants | transcriptome deregulation of cell-fate and LXR/RXR genes; no gross O-GlcNAc change | PMID:29769320 |
| Human iPSC plus isogenic control | OGT-CDG variant | reduced OGT and OGA; altered neuroectoderm and NSC morphology | PMID:38759397 |
| Patient fibroblasts and LCLs | L254F, R284P, splice, novel | reduced OGA, near-normal global O-GlcNAc | PMID:28302723, PMID:28584052, PMID:41030119 |
Limitations. - Mouse models reproduce growth and structural brain features, but cognitive testing in rodents only approximates human ID. - Fly models lack cortical architecture. - Stem cell compensation may mask phenotypes in early stages (PMID:38759397). - TPR-variant mouse models have not been reported.
For dismech: curate the mouse models under animal_models: and the cell models under experimental_models:. Use modeled_mechanisms targeted at nodes such as "O-GlcNAc Dyshomeostasis", "Impaired Neuronal Differentiation" and "Cortical Malformation", with PARTIALLY_RECAPITULATES where appropriate.
| PMID | Citation |
|---|---|
| 25679214 | Niranjan 2015 PLoS One: X-exome XLID screen |
| 28302723 | Vaidyanathan 2017 JBC: L254F |
| 28584052 | Willems 2017 JBC: R284P and c.463-6T>G |
| 29606577 | Gundogdu 2018 Cell Chem Biol: L254F structure |
| 29769320 | Selvan 2018 JBC: A259T, E339G; hESC |
| 31296563 | Pravata 2019 PNAS: N567K, female twins |
| 31627256 | Pravata 2020 FEBS Lett: catalytic-domain variant |
| 32080367 | Pravata 2020 Eur J Hum Genet: OGT-CDG review and proposal |
| 33329753 | Konzman 2020 Front Genet: review |
| 33356293 | Stephen 2021 J Proteome Res: TPR interactome |
| 35500025 | Fenckova 2022 PLoS Genet: Drosophila |
| 35863433 | Mitchell 2022 JBC: candidate conveyor proteins |
| 37334838 | Omelková 2023 DMM: C921Y |
| 38566589 | Authier 2024 DMM: mouse |
| 38759397 | Murray 2024 Mol Genet Metab: iPSC |
| 39059494 | Mayfield 2024 JBC: review |
| 39535175 | Czajewski 2024 eLife: Drosophila rescue |
| 39706180 | Yuan 2025 Stem Cell Rep: variant screen |
| 41033462 | Pravata 2025 MCP: Zscan4/TET |
| 41030119 | D'Alessio 2026 AJMG A: hepatoblastoma case |
| 41651253 | Ayushma 2026 Neurobiol Dis: HCF-1:OGT axis |
| 42107645 | Kimi 2026 JBC: variant catalogue (n=101) |
| 42209020 | Authier 2026 eNeuro: OGA genetic rescue |
| 42770280 | Authier 2026 eLife: C921Y mouse |
Web sources: FCDGC OGT-CDG page · LOVD MRX106 · PanelApp OGT · DOID:0080240 · Mayfield 2024, JBC · Czajewski 2024, eLife · Europe PMC REST API
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 30 |
| Resolved | 29 |
| Unresolved (possible confabulation) | 1 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 29 |
| On topic | 23 |
| Off topic | 0 |
These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:
PMID:41651253 (1 mention) - Identifier did not resolve to a recordChecked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 50 |
| Resolved | 49 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 6 |
| Terms named correctly | 4 |
| Terms named as a different term | 1 |
| Terms whose name is worth a second look | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
DOID:0080240 (4 mentions) - the report calls it "DOID"; DOID calls it non-syndromic X-linked intellectual disability 106The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
MONDO:0030907 (2 mentions) - the report calls it "intellectual disability, X-linked 106`, confirmed against the local MONDO cache in the draft entry"; MONDO calls it intellectual disability, X-linked 106