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Classifications

Harrison's Part

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Inheritance

2

Autosomal recessive HP:0000007

AR-STT3A-CDG. Every reported family is consanguineous and every affected individual is homozygous for a missense variant.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30701557 SUPPORT Human Clinical

"STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern."

States the recessive mode of inheritance for OMIM 615596.

PMID:23842455 SUPPORT Human Clinical

"A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change"

The index patient from a consanguineous family is homozygous for the causal variant.

Autosomal dominant HP:0000006

AD-STT3A-CDG. Heterozygous variants arise de novo or are transmitted within families, and mosaic cases carrying the recurrent p.Arg405 variants have been reported. Expressivity is variable.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:34653363 SUPPORT Human Clinical

"We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG."

Establishes dominant transmission, both inherited and de novo.

PMID:39435313 SUPPORT Human Clinical

"Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene."

States the dominant mode for OMIM 619714.

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Subtypes

2

Autosomal recessive STT3A-CDG (OMIM 615596) MONDO:0014270

STT3A hgnc:6172

The originally described form, caused by biallelic STT3A variants. All families reported so far were consanguineous and homozygous for a missense variant, most carrying p.Val626Ala and one p.Tyr360Ser. The phenotype is a neurodevelopmental encephalopathy with developmental delay, intellectual disability, absent speech, seizures, hypotonia, failure to thrive and feeding problems, with a type I serum transferrin pattern. Episodic hypothermia with altered consciousness and a combined factor VIII and von Willebrand factor deficiency have each been reported in a minority.

Show evidence (2 references)

PMID:30701557 SUPPORT Human Clinical

"STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern."

Defines the recessive subtype and its core clinical and biochemical features.

PMID:28424003 SUPPORT Human Clinical

"Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures."

An independent consanguineous family confirming the recessive neurodevelopmental phenotype.

Autosomal dominant STT3A-CDG (OMIM 619714) MONDO:0859223

STT3A hgnc:6172

Caused by heterozygous STT3A missense variants, de novo, inherited, or mosaic, that cluster in conserved catalytic regions with a recurrent p.Arg405 hotspot. Across 21 published individuals the phenotype is neuromusculoskeletal: subtle facial dysmorphism, motor and speech delay, learning difficulties, intellectual disability in about half, skeletal anomalies, short stature, macrocephaly, increased muscle tone, muscle cramps and early-onset osteoarthritis in adults, with congenital heart defects and coagulation factor deficiency in a minority. Transferrin glycosylation is abnormal in nearly all, but ranges from a classic type I pattern to subtle changes.

Show evidence (2 references)

PMID:34653363 SUPPORT Human Clinical

"We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG."

The founding description of the dominant subtype.

PMID:41897354 SUPPORT Human Clinical

"Variants clustered in conserved catalytic regions, with recurrent p.Arg405 across de novo, inherited, and mosaic cases supporting a mutational hotspot and likely dominant-negative mechanism."

Summarizes the allelic architecture of the dominant subtype across the published cohort.

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Discussions and Knowledge Gaps

2

Do all dominant STT3A alleles act by a dominant-negative mechanism, or do some act by haploinsufficiency?

OPEN QUESTION OPEN stt3a_dominant_mechanism

Attached to

pathophysiology#Heterozygous STT3A Catalytic-Site Missense Variants

The founding dominant cohort had normal STT3A protein in fibroblasts, all variants in the catalytic site, and dominant glycosylation defects from the homologous yeast mutants, which together point to a poisoned complex. But p.Asp167Tyr lowered STT3A protein when expressed in cells, and a heterozygous stt3a knockdown in zebrafish, which only reduces dosage, reproduced craniofacial and skeletal features. Carriers of the recessive alleles are not reported as affected, so halving STT3A activity is not sufficient in general, but whether some dominant alleles act through a dosage effect rather than a dominant-negative one is unresolved.

Show evidence (2 references)

PMID:34653363 SUPPORT In Vitro

"Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal."

Supports a dominant-negative mechanism for the catalytic-site alleles.

PMID:39891251 SUPPORT In Vitro

"the Western blot results revealed a significant decrease in protein levels"

A dominant allele that reduces protein amount, consistent with a dosage mechanism.

Does impaired processing of the insulin and IGF-1 receptors contribute to the short stature and skeletal phenotype of dominant STT3A-CDG?

EMERGING HYPOTHESIS OPEN stt3a_growth_receptor_link

Attached to

pathophysiology#Impaired Growth Factor Receptor Processing phenotypes#Short stature

STT3A-null cells deliver less insulin receptor and IGF-1 receptor to the surface, and IGF-1 signalling is a major driver of linear growth. No study has measured these receptors in STT3A-CDG patient cells or tested the growth pathway in an animal model, so the node is not connected to the skeletal phenotypes in this entry.

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Pathophysiology

10

Biallelic STT3A Loss-of-Function Variants

Homozygous missense variants in STT3A reduce the function of the OST-A catalytic subunit. The recurrent p.Val626Ala allele does not restore glycosylation when expressed in STT3A-deficient cells.

Genetic context STT3A hgnc:6172 allele_type: missense variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Homozygous missense variants in consanguineous families (p.Val626Ala, p.Tyr360Ser).

oligosaccharyltransferase activity GO:0004579 ↓ DECREASED

Downstream

Reduced OST-A Oligosaccharyltransferase Activity

Show evidence (1 reference)

PMID:23842455 SUPPORT In Vitro

"Glycosylation of STT3A- and STT3B-specific acceptors is decreased in fibroblasts carrying the corresponding mutated gene and expression of the STT3A (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation."

The recessive allele fails to complement STT3A loss in cells.

Heterozygous STT3A Catalytic-Site Missense Variants

Heterozygous missense variants cluster in the catalytic site of STT3A, including residues such as Arg405 that stabilize the dolichol-pyrophosphate donor during transfer. STT3A mRNA and protein levels are normal in patient fibroblasts, yet glycosylation is abnormal, and homologous yeast STT3 mutants impair glycosylation even in the presence of wild-type STT3. The mutant subunit is therefore thought to poison the complex rather than simply halve its amount. That inference rests on the founding cohort and on the yeast experiments; no allele-specific dominant-negative assay has been reported for p.Asn544Ser or p.Asp167Tyr, and p.Asp167Tyr lowered STT3A protein when expressed in cells, so the mechanism is established for the variant class rather than demonstrated for every allele.

Genetic context STT3A hgnc:6172 allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

De novo, inherited or mosaic heterozygous missense variants, with a recurrent p.Arg405 hotspot.

oligosaccharyltransferase activity GO:0004579 ↓ DECREASED

Downstream

Reduced OST-A Oligosaccharyltransferase Activity

Show evidence (4 references)

PMID:34653363 SUPPORT Computational

"Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins."

Structural modeling places every dominant variant in the catalytic site.

PMID:34653363 SUPPORT In Vitro

"Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal."

Normal protein amount with abnormal glycosylation argues against simple haploinsufficiency.

PMID:34653363 SUPPORT Model Organism

"In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed..."

Homologous mutants impair glycosylation despite wild-type STT3, the signature of a dominant-negative effect.

+ 1 more reference

Reduced OST-A Oligosaccharyltransferase Activity

STT3A is the active-site subunit of OST-A, the oligosaccharyltransferase isoform recruited to the ribosome-Sec61 translocon through its DC2 and KCP2 subunits. It transfers the Glc3Man9GlcNAc2 oligosaccharide from its dolichol-pyrophosphate carrier onto asparagine in N-X-S/T sequons of nascent chains. Reduced or poisoned STT3A lowers the transfer activity of this complex. The lipid-linked donor is assembled normally, which distinguishes this lesion from the assembly-type CDG-I.

OST-A complex GO:0160226

oligosaccharyltransferase activity GO:0004579 ↓ DECREASED

Downstream

Impaired Cotranslational N-Glycosylation

Show evidence (3 references)

PMID:34653363 SUPPORT BACKGROUND Other

"STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation."

Identifies STT3A as the catalytic subunit of OST-A. The sentence restates established biochemistry in the framing of a clinical paper, hence OTHER with a BACKGROUND quote role.

PMID:29519914 SUPPORT In Vitro

"The OST subunit DC2 was placed at the interface between Sec61 and STT3A, where it acts as a versatile module for recruitment of STT3A-containing OST to the ribosome-Sec61 complex."

Structural evidence that the STT3A complex is the translocon-associated OST isoform.

PMID:28860277 SUPPORT In Vitro

"Biochemical analysis showed that DC2 and KCP2 are responsible for mediating the interaction between the protein translocation channel and the STT3A complex."

Identifies the subunits that couple OST-A to the translocon.

Impaired Cotranslational N-Glycosylation

With OST-A impaired, acceptor sites are skipped as the nascent chain passes the translocon. STT3A-dependent sites include those with suboptimal flanking sequences and those inside cysteine-rich domains. OST-B can glycosylate some skipped sites afterwards, but the two complexes have complementary rather than redundant roles, so a subset of sites stays unoccupied. Patient fibroblasts show reduced glycosylation of STT3A-dependent acceptors.

Fibroblast CL:0000057

cotranslational N-glycosylation GO:0180058 ↓ DECREASED

Downstream

Protein Hypoglycosylation

Show evidence (5 references)

PMID:31831667 SUPPORT In Vitro

"Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner."

Defines OST-A as the cotranslational complex.

PMID:31296534 SUPPORT In Vitro

"Analysis of site occupancy data disclosed several new classes of STT3A-dependent acceptor sites including those with suboptimal flanking sequences and sites located within cysteine-rich protein domains."

Identifies which acceptor sites depend on STT3A and so are lost when it fails.

PMID:25460543 SUPPORT Other

"the role of the STT3B complex in mediating cotranslational or posttranslocational glycosylation of acceptor sites that have been skipped by the STT3A complex"

Review describing OST-B as the complex that picks up sites skipped by OST-A; evidence source is OTHER because this is a review.

+ 2 more references

Protein Hypoglycosylation

Glycoproteins leave the endoplasmic reticulum with unoccupied N-glycosylation sites. In serum this appears as transferrin molecules lacking whole glycans, the type I pattern, which is marked in the recessive form and ranges from classic to subtle in the dominant form.

Fibroblast CL:0000057

Protein N-linked glycosylation GO:0006487 ↓ DECREASED

Downstream

Type I transferrin isoform profile

Impaired Factor VIII Secretion

Reduced von Willebrand factor activity

Impaired Growth Factor Receptor Processing

Endoplasmic Reticulum Stress

Abnormal Skeletal Development

Multisystem Glycoprotein Dysfunction

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"The STT3A mutation significantly impairs glycosylation of the biomarker transferrin, but the STT3B mutation only slightly affects its glycosylation."

Shows hypoglycosylation of a circulating glycoprotein in the recessive form.

PMID:34653363 SUPPORT Human Clinical

"We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs."

Shows the same hypoglycosylation lesion in the dominant form.

Impaired Factor VIII Secretion

Some STT3A-dependent N-glycans on coagulation factor VIII are needed for its efficient secretion. Cells lacking STT3A make normal intracellular amounts of factor VIII but release less than a tenth of the expected amount. In the reported patient the low plasma level was attributed to this secretion defect together with low von Willebrand factor.

Protein secretion GO:0009306 ↓ DECREASED

Experimental models

STT3A-knockout HEK293 cells CELL LINE STT3A-null cells secrete less than a tenth of the expected factor VIII while intracellular levels are normal.

Downstream

Reduced factor VIII activity

Show evidence (1 reference)

PMID:30701557 SUPPORT In Vitro

"Functional studies with STT3A-/- HEK293 cells showed severely reduced FVIII antigen and activity levels in conditioned media <10% expected, but normal intracellular levels."

Localizes the factor VIII defect to secretion in STT3A-null cells.

Impaired Growth Factor Receptor Processing

Mechanism confidence: Hypothetical

In STT3A-null cells the insulin receptor and IGF-1 receptor reach the cell surface in reduced amounts, because their own N-glycan site occupancy is lower and because the proprotein convertase PCSK5a that cleaves them is itself underglycosylated. This is an established cell-line finding. Its relevance to patients is unshown: no study has measured these receptors in STT3A-CDG patient cells, and any contribution to the short stature of the dominant form is an inference (see discussions).

Protein processing GO:0016485 ↓ DECREASED

Show evidence (1 reference)

PMID:31101650 SUPPORT In Vitro

"We show reduced abundance of two canonical tyrosine receptor kinases - the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) - at the cell surface in STT3A-null cells, due to decreased N-linked glycan site occupancy and proteolytic processing in combination with increased..."

Shows that STT3A loss impairs processing and surface delivery of two growth-factor receptors.

Endoplasmic Reticulum Stress

Mechanism confidence: Provisional

STT3A-knockout cells activate the unfolded protein response, with raised ATF6 and PERK, and the ER chaperone GRP94 becomes hyperglycosylated on normally silent sites, a change that ER-stress inducers reproduce in wild-type cells. This has been shown only in engineered cell lines; whether ER stress contributes to the patients' tissue phenotypes is untested.

Unfolded protein response GO:0030968 ↑ INCREASED

Experimental models

STT3A-knockout HEK293 cells CELL LINE STT3A-knockout cells show raised ATF6 and PERK, indicating an unfolded protein response.

Show evidence (2 references)

PMID:36139350 SUPPORT In Vitro

"Furthermore, the increased expression of the ATF6 and PERK indicated that the unfolded protein response also happened in STT3A-KO cells."

Direct evidence of unfolded protein response activation after STT3A deletion.

PMID:31296534 SUPPORT In Vitro

"Remarkably, the lumenal ER chaperone GRP94 was hyperglycosylated in STT3A-deficient cells, bearing glycans on five silent sites in addition to the normal glycosylation site."

A marker change that the same study reproduces with ER-stress inducers.

Abnormal Skeletal Development

Mechanism confidence: Provisional

Skeletal involvement is the distinguishing feature of the dominant form. Heterozygous stt3a knockdown in zebrafish reduces the number of mineralized bones and alters craniofacial cartilage geometry, supporting a direct effect of reduced STT3A on skeletal development. Which STT3A-dependent glycoproteins mediate this is not known.

Skeletal system development GO:0001501 ⚠ ABNORMAL

Animal models

Heterozygous stt3a knockdown zebrafish Danio rerio recapitulates Reduced stt3a dosage produces craniofacial and skeletal mineralization defects comparable to the patients' skeletal anomalies and dysmorphism.

Downstream

Abnormal skeletal morphology

Short stature

Facial dysmorphism

Scoliosis

Prognathism

Wide nasal bridge

Show evidence (2 references)

PMID:39891251 SUPPORT Model Organism

"Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology (increased eye distance, increased Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities (reduced number of mineralized bones)"

Reduced stt3a dosage alone produces skeletal and craniofacial defects in a vertebrate.

PMID:34653363 SUPPORT Human Clinical

"Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability."

The human skeletal phenotype that this node accounts for.

Multisystem Glycoprotein Dysfunction

Underglycosylation of many client glycoproteins at once produces the neurodevelopmental, neuromuscular and systemic features. The recessive form is dominated by encephalopathy (developmental delay, intellectual disability, absent speech, seizures, hypotonia) and the dominant form by musculoskeletal and milder neurodevelopmental features. The dysmorphic, adipose, behavioral, hematologic and congenital-anomaly features of the dominant form are routed through this node as well, because the pooled cohort establishes them as features of the disease without naming a client glycoprotein for any of them. Which clients are rate-limiting for each feature has not been worked out, except for the coagulation factors.

Neuron CL:0000540

Protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL

Downstream

Global developmental delay

Intellectual disability

Absent speech

Seizures

Hypotonia

Failure to thrive

Feeding difficulties

Intermittent hypothermia

Reduced consciousness

Motor delay

Delayed speech and language development

Learning difficulties

Macrocephaly

Hypertonia

Muscle cramps

Premature osteoarthritis

Congenital heart defects

High anterior hairline

Short palpebral fissure

Abnormal upper lip and philtrum morphology

Protruding or low-set ears

Inverted nipples

Abnormal subcutaneous fat distribution

Muscle hypertrophy

Bruising susceptibility

Attention deficit hyperactivity disorder

Anxiety

Intrauterine growth restriction

Morbid obesity

Anorectal malformation

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems."

The multisystem outflow in the recessive form.

PMID:41897354 SUPPORT Human Clinical

"Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21)."

The neurodevelopmental outflow in the dominant form.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

40

Blood 4

Bruising susceptibility OCCASIONAL HP:0000978

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Easy bruising/bleeding | 4 of 21 | Variable"

Gives the count for the milder bleeding phenotype, separate from the bleeding diathesis row.

Reduced factor VIII activity HP:0003125

Sequelae: Abnormal bleeding

Show evidence (2 references)

PMID:30701557 SUPPORT Human Clinical

"We describe a patient with a novel homozygous likely pathogenic missense variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to the previously reported symptoms of developmental delay and seizures."

Low factor VIII in the recessive form.

PMID:41897354 SUPPORT Human Clinical

"Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency."

Factor VIII deficiency in the dominant form.

Reduced von Willebrand factor activity HP:0008330

Sequelae: Abnormal bleeding

Show evidence (2 references)

PMID:30701557 SUPPORT Human Clinical

"We describe a patient with a novel homozygous likely pathogenic missense variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to the previously reported symptoms of developmental delay and seizures."

Low von Willebrand factor activity in the recessive form.

PMID:41897354 SUPPORT Human Clinical

"Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency."

Von Willebrand factor deficiency in the dominant form.

Abnormal bleeding OCCASIONAL HP:0001892

Show evidence (2 references)

PMID:41897354 SUPPORT Human Clinical

"Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency."

Reports the bleeding diathesis.

PMID:41897354 SUPPORT Human Clinical

"Clinically significant bleeding diathesis | 3 of 21 | Marked vWF and/or FVIII deficiency"

Gives the cohort count and the factor deficiencies behind it.

Breast 1

Inverted nipples OCCASIONAL HP:0003186

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Inverted nipples | 6 of 21 | Distinctive but not universal"

Gives the count behind the frequency band.

Cardiovascular 1

Congenital heart defects OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21)."

Gives the frequency of congenital heart defects in the dominant form.

Digestive 2

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:23842455 SUPPORT Human Clinical

"The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems."

Feeding problems in the index recessive patient.

Anorectal malformation VERY_RARE Anorectal anomaly HP:0012732

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Anorectal malformation | 1 of 21 | Not previously reported"

Gives the count and marks the feature as newly reported for this disease.

Ear 1

Protruding or low-set ears OCCASIONAL Abnormal pinna morphology HP:0000377

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Protruding or low-set ears | 6 of 21 | Variable"

Gives the combined count and shows that the two ear findings are scored as one item.

Head and Neck 7

Facial dysmorphism VERY_FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21)."

Gives the frequency of facial dysmorphism in the dominant form.

Macrocephaly FREQUENT HP:0000256

Show evidence (2 references)

PMID:34653363 SUPPORT Human Clinical

"Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability."

Macrocephaly is a presenting feature of the dominant form.

PMID:41897354 SUPPORT Human Clinical

"Macrocephaly | 7 of 21 | Often progressive"

Gives the count behind the frequency band and the progressive course.

High anterior hairline FREQUENT HP:0009890

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"High anterior hairline | 10 of 21 | Recurrent feature"

Gives the count behind the frequency band.

Abnormal upper lip and philtrum morphology FREQUENT Abnormal upper lip morphology HP:0000177

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Thin upper lip and/or philtrum abnormality | 9 of 21 | Common"

Gives the combined count and shows that the two features are scored as one item.

Short palpebral fissure FREQUENT HP:0012745

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Short palpebral fissures | 7 of 21 | Variable"

Gives the count behind the frequency band.

Wide nasal bridge FREQUENT HP:0000431

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Wide nasal bridge | 7 of 21 | Mild-moderate"

Gives the count behind the frequency band.

Prognathism OCCASIONAL Abnormal jaw morphology HP:0030791

Coarse binding: no hpo term

Ontology gap: HPO has no maxillary prognathism term. A label search of HP for "prognath" returns only HP:0000303 Mandibular prognathia, defined as abnormal prominence of the chin related to increased length of the mandible, which would assert the wrong bone for a maxillary-predominant finding. HP:0030791 Abnormal jaw morphology is the nearest class above both HP:0000326 Abnormal maxilla morphology and HP:0000277 Abnormal mandible morphology, so it covers all six individuals without naming a jaw the source does not.

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Prognathism | 6 of 21 | Maxillary predominance"

Gives the count and the maxillary predominance that rules out the mandible-specific HPO term.

Integument 1

Abnormal subcutaneous fat distribution OCCASIONAL Abnormal subcutaneous fat tissue distribution HP:0007552

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Abnormal fat distribution | 4 of 21 | Hip or truncal fat pads"

Gives the count and the distribution of the fat pads.

Metabolism 2

Intermittent hypothermia HP:0005964

Show evidence (1 reference)

PMID:28424003 SUPPORT Human Clinical

"Two individuals also developed episodic hypothermia and altered consciousness."

Reports episodic hypothermia in the recessive form.

Type I transferrin isoform profile HP:0003642

Show evidence (2 references)

PMID:30701557 SUPPORT Human Clinical

"STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern."

The type I pattern is a defining feature of the recessive form.

PMID:41897354 SUPPORT Human Clinical

"Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis."

Describes the range of transferrin findings in the dominant form.

Musculoskeletal 7

Hypotonia HP:0001252

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems."

Hypotonia in the index recessive patient.

PMID:39435313 SUPPORT Human Clinical

"This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features,..."

Intermittent hypotonia in a patient with the dominant form.

Abnormal skeletal morphology FREQUENT HP:0011842

Coarse binding: variable spectrum

Show evidence (2 references)

PMID:41897354 SUPPORT Human Clinical

"Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21)."

Gives the frequency of skeletal abnormalities in the dominant form.

PMID:34653363 SUPPORT Human Clinical

"Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability."

Describes the skeletal anomalies as variable.

Hypertonia HP:0001276

Show evidence (2 references)

PMID:34653363 SUPPORT Human Clinical

"Additional features included increased muscle tone and muscle cramps."

Increased muscle tone in the dominant form.

PMID:41897354 SUPPORT Human Clinical

"Abnormal muscle tone | 7 of 21 | Hyper- or hypotonia"

Shows that the 7 of 21 tone count pools hypertonia with hypotonia and so cannot be apportioned to either.

Muscle cramps FREQUENT Muscle spasm HP:0003394

Show evidence (2 references)

PMID:41897354 SUPPORT Human Clinical

"Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21)."

Gives the frequency of muscle cramps in the dominant form.

PMID:34653363 SUPPORT Human Clinical

"Additional features included increased muscle tone and muscle cramps."

Muscle cramps in the founding dominant cohort.

Premature osteoarthritis OCCASIONAL HP:0003088

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21)."

Gives the frequency of early-onset osteoarthritis in the dominant form.

Muscle hypertrophy OCCASIONAL Skeletal muscle hypertrophy HP:0003712

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Muscle hypertrophy | 4 of 21 | Often with cramps"

Gives the count and its co-occurrence with the cramps phenotype.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Scoliosis | 5 of 21 | Usually mild"

Gives the count behind the frequency band.

Nervous System 10

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:28424003 SUPPORT Human Clinical

"Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures."

Developmental delay in all symptomatic members of a recessive family.

PMID:30701557 SUPPORT Human Clinical

"STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern."

Developmental delay is a defining feature of the recessive form.

Intellectual disability HP:0001249

Show evidence (2 references)

PMID:28424003 SUPPORT Human Clinical

"Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures."

Intellectual disability in all symptomatic members of a recessive family.

PMID:41897354 SUPPORT Human Clinical

"Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21)."

Gives the frequency in the dominant form.

Absent speech HP:0001344

Show evidence (1 reference)

PMID:28424003 SUPPORT Human Clinical

"Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures."

Absent speech in all symptomatic members of a recessive family.

Seizures HP:0001250

Show evidence (2 references)

PMID:28424003 SUPPORT Human Clinical

"Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures."

Seizures in all symptomatic members of a recessive family.

PMID:39435313 SUPPORT Human Clinical

"This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features,..."

Epilepsy in a patient with the dominant form.

Reduced consciousness HP:0004372

Show evidence (1 reference)

PMID:28424003 SUPPORT Human Clinical

"Two individuals also developed episodic hypothermia and altered consciousness."

Reports altered consciousness in the recessive form.

Motor delay FREQUENT HP:0001270

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21)."

Gives the frequency of motor delay in the dominant form.

Delayed speech and language development FREQUENT HP:0000750

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21)."

Gives the frequency of speech delay in the dominant form.

Learning difficulties FREQUENT Specific learning disability HP:0001328

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21)."

Gives the frequency of learning difficulties in the dominant form.

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"ADHD and/or anxiety | 5 of 21 | Mostly pediatric"

Reports attention-deficit/hyperactivity disorder in the cohort, as one half of a combined 5 of 21 item.

Anxiety HP:0000739

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"ADHD and/or anxiety | 5 of 21 | Mostly pediatric"

Reports anxiety in the cohort, as one half of a combined 5 of 21 item.

Growth 4

Failure to thrive HP:0001508

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems."

Failure to thrive in the index recessive patient.

PMID:39435313 SUPPORT Human Clinical

"This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features,..."

Failure to thrive in a patient with the dominant form.

Short stature FREQUENT HP:0004322

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21)."

Gives the frequency of short stature in the dominant form.

Intrauterine growth restriction OCCASIONAL Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Intrauterine growth restriction | 3 of 21"

Gives the count behind the frequency band.

Morbid obesity VERY_RARE HP:0001513

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Morbid obesity | 1 of 21 | Rapid pubertal weight gain"

Gives the count and the pubertal course, and marks the feature as newly reported.

🧬

Genetic Associations

1

STT3A (STT3A encodes the catalytic subunit of the OST-A oligosaccharyltransferase complex. Biallelic missense variants cause the recessive subtype and heterozygous catalytic-site missense variants cause the dominant subtype. No null allele has been reported in either form. The paralogue STT3B (catalytic subunit of OST-B) causes a separate recessive CDG, STT3B-CDG, which is not part of this entry.)

Gene: STT3A hgnc:6172 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"We describe two unreported types of congenital disorders of glycosylation (CDG) which are caused by mutations in different isoforms of the catalytic subunit of the oligosaccharyltransferase (OST)."

Establishes STT3A, one of the two OST catalytic isoforms, as a CDG gene.

PMID:34653363 SUPPORT Human Clinical

"Recessive mutations in STT3A have previously been described to lead to a CDG."

Confirms that the same gene causes both the recessive and the dominant form.

Variants (4)

STT3A p.Val626Ala Pathogenic

The recurrent recessive allele, homozygous in the index patient and in the second consanguineous family. The expressed allele fails to restore glycosylation in STT3A-deficient cells. The two reports give the cDNA change as c.1877T>C and c.1877C>T respectively; the amino-acid change is the same in both.

Show evidence (1 reference)

PMID:23842455 SUPPORT In Vitro

"Glycosylation of STT3A- and STT3B-specific acceptors is decreased in fibroblasts carrying the corresponding mutated gene and expression of the STT3A (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation."

Functional evidence that the variant is a loss-of-function allele.

STT3A p.Tyr360Ser Likely Pathogenic

A second recessive missense allele, homozygous in a patient with factor VIII and von Willebrand factor deficiency.

Show evidence (1 reference)

PMID:30701557 SUPPORT Human Clinical

"We describe a patient with a novel homozygous likely pathogenic missense variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to the previously reported symptoms of developmental delay and seizures."

Reports the variant and its classification.

STT3A p.Asn544Ser Likely Pathogenic

A de novo heterozygous dominant allele found by genome sequencing after a negative trio exome. It removes an N-glycosylation site on STT3A itself and was predicted to be destabilizing.

Show evidence (1 reference)

PMID:39435313 SUPPORT Human Clinical

"His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser)."

Reports the de novo dominant variant.

STT3A p.Asp167Tyr Likely Pathogenic

A heterozygous dominant missense allele that lowered STT3A protein level when expressed in HEK293T cells, a different molecular behaviour from the catalytic-site variants, whose protein level is normal in patient fibroblasts.

Show evidence (1 reference)

PMID:39891251 SUPPORT In Vitro

"the Western blot results revealed a significant decrease in protein levels"

Reports reduced protein from the variant construct in cultured cells.

🔬

Biochemical Markers

1

Serum Transferrin Glycoform Profile

Show evidence (2 references)

PMID:23842455 SUPPORT Human Clinical

"The STT3A mutation significantly impairs glycosylation of the biomarker transferrin, but the STT3B mutation only slightly affects its glycosylation."

Establishes transferrin as an informative biomarker for STT3A deficiency.

PMID:41897354 SUPPORT Human Clinical

"Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21)."

Gives the sensitivity of transferrin testing in the dominant form.

🔬

Diagnosis

3

Serum transferrin glycoform analysis

First-line screen. A type I pattern places the defect in N-glycan precursor assembly or transfer and prompts sequencing. It does not identify the gene, and in the dominant form it can be near-normal.

Transferrin isoelectric focusing NCIT:C101016

Show evidence (2 references)

PMID:39435313 SUPPORT Human Clinical

"The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling."

Transferrin profiling supported the diagnosis in a dominant-form patient.

PMID:41897354 SUPPORT Human Clinical

"Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis."

States the limitation of the screen in the dominant form.

Exome or genome sequencing of STT3A

Definitive diagnosis rests on finding biallelic (recessive) or heterozygous (dominant) STT3A variants. Genome sequencing identified a de novo dominant variant after a negative trio exome in one patient.

Genome sequencing NCIT:C101294

Show evidence (2 references)

PMID:39435313 SUPPORT Human Clinical

"His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser)."

Genome sequencing made the molecular diagnosis.

PMID:39435313 SUPPORT Human Clinical

"Trio exome sequencing was negative."

The preceding exome had missed the variant.

Coagulation factor testing

Measurement of factor VIII and von Willebrand factor identifies the coagulation factor deficiency found in some patients of both subtypes, one of whom (dominant form) had a clinically significant bleeding diathesis.

Show evidence (1 reference)

PMID:41897354 SUPPORT Human Clinical

"Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21)."

Coagulation factor deficiency occurs in about a quarter of dominant cases.

📊

Prevalence

2

Worldwide

Cases In Literature Ultra Rare AR-STT3A-CDG

Seven individuals had been reported with the recessive form by 2019: the index patient, five related individuals from a second consanguineous family, and one further patient homozygous for p.Tyr360Ser. No population prevalence estimate has been published.

Show evidence (1 reference)

PMID:30701557 SUPPORT Human Clinical

"All previously reported cases (n = 6) have been attributed to a homozygous pathogenic missense variant c.1877C>T (p.Val626Ala) in STT3A."

Gives the case count before this report added a seventh patient.

Worldwide

Cases In Literature Ultra Rare AD-STT3A-CDG

A 2026 review pooling all published cases with three new individuals from the CDG natural history study counted 21 individuals with the dominant form. No population prevalence estimate has been published.

Show evidence (2 references)

PMID:41897354 SUPPORT Human Clinical

"To define the distinct autosomal-dominant disorder, we reviewed all published cases and integrated three previously unpublished individuals from the CDG natural history study."

Establishes that the pooled count covers all published dominant cases.

PMID:41897354 SUPPORT Human Clinical

"Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21)."

Gives the pooled case count of 21.

🧫

Experimental Models

1

STT3A-knockout HEK293 cells CELL_LINE

Human cells lacking STT3A, used to measure the consequence of losing OST-A for secretion of coagulation factor VIII and for the cellular stress response.

Organism

human NCBITaxon:9606

Cell source

Immortalized human embryonic kidney cell line with STT3A deleted

Publication

PMID:30701557

Pathograph links

Impaired Factor VIII Secretion recapitulates fidelity: moderate STT3A-null cells secrete less than a tenth of the expected factor VIII while intracellular levels are normal.

Limitations: A complete null in a kidney-derived line, whereas patients carry missense alleles and factor VIII is made physiologically by liver endothelial cells. The model shows that STT3A is needed for secretion, not how much secretion a patient allele retains.

Show evidence (1 reference)

PMID:30701557 SUPPORT In Vitro

"Functional studies with STT3A-/- HEK293 cells showed severely reduced FVIII antigen and activity levels in conditioned media <10% expected, but normal intracellular levels."

The secretion readout behind this link.

Endoplasmic Reticulum Stress measures fidelity: low STT3A-knockout cells show raised ATF6 and PERK, indicating an unfolded protein response.

Limitations: Measured in a complete knockout cell line; no patient cells or tissues have been examined for ER stress.

Show evidence (1 reference)

PMID:36139350 SUPPORT In Vitro

"Furthermore, the increased expression of the ATF6 and PERK indicated that the unfolded protein response also happened in STT3A-KO cells."

The stress-response readout behind this link.

🐁

Animal Models

1

Heterozygous stt3a knockdown zebrafish

Zebrafish with heterozygous loss of stt3a, generated to test whether reduced STT3A dosage produces the dominant phenotype. The larvae show craniofacial cartilage changes, fewer mineralized bones, reduced adaptability in light-dark behaviour tests and electrophysiological abnormalities.

Species

Danio rerio

Genotype

CRISPR-Cas9 heterozygous stt3a knockdown

Genes

STT3A hgnc:6172

Publication

PMID:39891251

Pathograph links

Abnormal Skeletal Development recapitulates fidelity: moderate Reduced stt3a dosage produces craniofacial and skeletal mineralization defects comparable to the patients' skeletal anomalies and dysmorphism.

Limitations: A heterozygous knockdown lowers the amount of STT3A; it does not reproduce a catalytic-site missense variant, so it tests haploinsufficiency rather than the dominant-negative mechanism proposed for most dominant alleles. Phenotypes were scored in larvae, so the adult features (osteoarthritis, muscle cramps) and the transferrin phenotype are not assessed.

Show evidence (1 reference)

PMID:39891251 SUPPORT Model Organism

"Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology (increased eye distance, increased Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities (reduced number of mineralized bones)"

The skeletal and craniofacial readouts behind this link.

Show evidence (1 reference)

PMID:39891251 SUPPORT Model Organism

"We performed CRISPR-Cas9 to establish heterozygous knockdown zebrafish to validate the functional implications of autosomal dominant inheritance of STT3A in pathogenesis."

Describes how the model was made.

{ }

Source YAML

click to show

name: STT3A-Congenital Disorder of Glycosylation
creation_date: "2026-09-29T21:00:00Z"
category: Mendelian
description: >-
  STT3A-congenital disorder of glycosylation (STT3A-CDG, CDG-Iw) is a type I
  congenital disorder of N-linked glycosylation caused by pathogenic variants in
  STT3A, which encodes the catalytic subunit of the STT3A-containing
  oligosaccharyltransferase complex (OST-A). OST-A is docked to the
  ribosome-Sec61 translocon and transfers the preassembled dolichol-linked
  oligosaccharide en bloc onto asparagine acceptor sites of nascent
  polypeptides as they enter the endoplasmic reticulum lumen. Its paralogous
  complex OST-B (catalytic subunit STT3B) glycosylates sites that OST-A skips,
  largely after translocation, so the two complexes overlap only partially and
  loss of OST-A leaves a characteristic subset of acceptor sites unoccupied.
  Unlike the lipid-linked oligosaccharide assembly CDGs, the glycan donor is
  built normally here; the lesion is at the transfer step itself.

  STT3A causes disease by two inheritance modes with distinct mechanisms and
  clinical pictures. Biallelic (so far homozygous missense) variants cause a
  recessive neurodevelopmental disorder with developmental delay, intellectual
  disability, absent speech, seizures, hypotonia, failure to thrive and feeding
  difficulties, reported in seven individuals from three consanguineous
  families, one of whom also had factor VIII and von Willebrand factor
  deficiency. Heterozygous
  missense variants clustered in the catalytic site cause a milder dominant
  disorder dominated by neuromusculoskeletal features: variable skeletal
  anomalies, short stature, macrocephaly, facial dysmorphism, increased muscle
  tone, muscle cramps and early-onset osteoarthritis, with intellectual
  disability in about half. The dominant variants impair glycosylation in a
  dominant manner in patient fibroblasts and in yeast, and the dominant form is
  unusual among dominant type I CDGs in producing an abnormal serum transferrin
  glycoform profile, although that profile can be subtle. Both forms are
  modelled here as subtypes of one entry because they share the gene, the
  enzyme and the hypoglycosylation lesion. No disease-specific therapy has been
  reported.
disease_term:
  preferred_term: STT3A-congenital disorder of glycosylation
  term:
    id: MONDO:0014270
    label: STT3A-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- STT3A-CDG
- CDG-Iw
- CDG1W
- CDG Iw
- CDG syndrome type Iw
- congenital disorder of glycosylation type Iw
- congenital disorder of glycosylation, type Iw
- congenital disorder of glycosylation type 1w
- congenital disorder of glycosylation, type Iw, autosomal recessive
- congenital disorder of glycosylation, type Iw, autosomal dominant
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: NEUROLOGIC
has_subtypes:
- name: AR-STT3A-CDG
  display_name: Autosomal recessive STT3A-CDG (OMIM 615596)
  subtype_term:
    preferred_term: congenital disorder of glycosylation, type Iw, autosomal recessive
    term:
      id: MONDO:0014270
      label: STT3A-congenital disorder of glycosylation
  genes:
  - preferred_term: STT3A
    term:
      id: hgnc:6172
      label: STT3A
  description: >-
    The originally described form, caused by biallelic STT3A variants. All
    families reported so far were consanguineous and homozygous for a missense
    variant, most carrying p.Val626Ala and one p.Tyr360Ser. The phenotype is a
    neurodevelopmental encephalopathy with developmental delay, intellectual
    disability, absent speech, seizures, hypotonia, failure to thrive and
    feeding problems, with a type I serum transferrin pattern. Episodic
    hypothermia with altered consciousness and a combined factor VIII and von
    Willebrand factor deficiency have each been reported in a minority.
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation
      disorder characterized by seizures, developmental delay, intellectual disability,
      and a type I carbohydrate deficient transferrin pattern."
    explanation: Defines the recessive subtype and its core clinical and biochemical
      features.
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic features in all symptomatic individuals include developmental
      delay, intellectual disability, with absent speech and seizures."
    explanation: An independent consanguineous family confirming the recessive neurodevelopmental
      phenotype.
- name: AD-STT3A-CDG
  display_name: Autosomal dominant STT3A-CDG (OMIM 619714)
  subtype_term:
    preferred_term: congenital disorder of glycosylation, type Iw, autosomal dominant
    term:
      id: MONDO:0859223
      label: congenital disorder of glycosylation, type Iw, autosomal dominant
  genes:
  - preferred_term: STT3A
    term:
      id: hgnc:6172
      label: STT3A
  description: >-
    Caused by heterozygous STT3A missense variants, de novo, inherited, or
    mosaic, that cluster in conserved catalytic regions with a recurrent
    p.Arg405 hotspot. Across 21 published individuals the phenotype is
    neuromusculoskeletal: subtle facial dysmorphism, motor and speech delay,
    learning difficulties, intellectual disability in about half, skeletal
    anomalies, short stature, macrocephaly, increased muscle tone, muscle
    cramps and early-onset osteoarthritis in adults, with congenital heart
    defects and coagulation factor deficiency in a minority. Transferrin
    glycosylation is abnormal in nearly all, but ranges from a classic type I
    pattern to subtle changes.
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report the identification of 16 individuals from nine families
      who have either inherited or de novo heterozygous missense variants in STT3A,
      leading to an autosomal-dominant CDG."
    explanation: The founding description of the dominant subtype.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants clustered in conserved catalytic regions, with recurrent p.Arg405
      across de novo, inherited, and mosaic cases supporting a mutational hotspot
      and likely dominant-negative mechanism."
    explanation: Summarizes the allelic architecture of the dominant subtype across
      the published cohort.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    AR-STT3A-CDG. Every reported family is consanguineous and every affected
    individual is homozygous for a missense variant.
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation
      disorder characterized by seizures, developmental delay, intellectual disability,
      and a type I carbohydrate deficient transferrin pattern."
    explanation: States the recessive mode of inheritance for OMIM 615596.
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change"
    explanation: The index patient from a consanguineous family is homozygous for
      the causal variant.
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    AD-STT3A-CDG. Heterozygous variants arise de novo or are transmitted
    within families, and mosaic cases carrying the recurrent p.Arg405 variants
    have been reported. Expressivity is variable.
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report the identification of 16 individuals from nine families
      who have either inherited or de novo heterozygous missense variants in STT3A,
      leading to an autosomal-dominant CDG."
    explanation: Establishes dominant transmission, both inherited and de novo.
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant congenital disorder of glycosylation (CDG) type Iw
      (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene."
    explanation: States the dominant mode for OMIM 619714.
prevalence:
- population: Worldwide
  subtype: AR-STT3A-CDG
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seven individuals had been reported with the recessive form by 2019: the
    index patient, five related individuals from a second consanguineous
    family, and one further patient homozygous for p.Tyr360Ser. No population
    prevalence estimate has been published.
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All previously reported cases (n = 6) have been attributed to a homozygous
      pathogenic missense variant c.1877C>T (p.Val626Ala) in STT3A."
    explanation: Gives the case count before this report added a seventh patient.
- population: Worldwide
  subtype: AD-STT3A-CDG
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2026 review pooling all published cases with three new individuals from
    the CDG natural history study counted 21 individuals with the dominant
    form. No population prevalence estimate has been published.
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To define the distinct autosomal-dominant disorder, we reviewed all
      published cases and integrated three previously unpublished individuals from
      the CDG natural history study."
    explanation: Establishes that the pooled count covers all published dominant
      cases.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Across 21 individuals, abnormal transferrin glycosylation was present
      in nearly all individuals (20/21), and subtle facial dysmorphism was common
      (18/21)."
    explanation: Gives the pooled case count of 21.
genetic:
- name: STT3A
  gene_term:
    preferred_term: STT3A
    term:
      id: hgnc:6172
      label: STT3A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    STT3A encodes the catalytic subunit of the OST-A oligosaccharyltransferase
    complex. Biallelic missense variants cause the recessive subtype and
    heterozygous catalytic-site missense variants cause the dominant subtype.
    No null allele has been reported in either form. The paralogue STT3B
    (catalytic subunit of OST-B) causes a separate recessive CDG, STT3B-CDG,
    which is not part of this entry.
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two unreported types of congenital disorders of glycosylation
      (CDG) which are caused by mutations in different isoforms of the catalytic subunit
      of the oligosaccharyltransferase (OST)."
    explanation: Establishes STT3A, one of the two OST catalytic isoforms, as a CDG
      gene.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recessive mutations in STT3A have previously been described to lead to
      a CDG."
    explanation: Confirms that the same gene causes both the recessive and the dominant
      form.
  variants:
  - name: "STT3A p.Val626Ala"
    description: >-
      The recurrent recessive allele, homozygous in the index patient and in
      the second consanguineous family. The expressed allele fails to restore
      glycosylation in STT3A-deficient cells. The two reports give the cDNA
      change as c.1877T>C and c.1877C>T respectively; the amino-acid change is
      the same in both.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:23842455
      reference_title: "Mutations in STT3A and STT3B cause two congenital disorders
        of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Glycosylation of STT3A- and STT3B-specific acceptors is decreased in
        fibroblasts carrying the corresponding mutated gene and expression of the STT3A
        (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation."
      explanation: Functional evidence that the variant is a loss-of-function allele.
  - name: "STT3A p.Tyr360Ser"
    description: >-
      A second recessive missense allele, homozygous in a patient with factor
      VIII and von Willebrand factor deficiency.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:30701557
      reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a patient with a novel homozygous likely pathogenic missense
        variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII
        (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to
        the previously reported symptoms of developmental delay and seizures."
      explanation: Reports the variant and its classification.
  - name: "STT3A p.Asn544Ser"
    description: >-
      A de novo heterozygous dominant allele found by genome sequencing after a
      negative trio exome. It removes an N-glycosylation site on STT3A itself
      and was predicted to be destabilizing.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:39435313
      reference_title: "Review and metabolomic profiling of unsolved case reveals newly
        reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
        thought to only be an autosomal recessive condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "His UDN genome sequencing (GS) identified a previously unreported de
        novo STT3A variant (c.1631A > G: p.Asn544Ser)."
      explanation: Reports the de novo dominant variant.
  - name: "STT3A p.Asp167Tyr"
    description: >-
      A heterozygous dominant missense allele that lowered STT3A protein level
      when expressed in HEK293T cells, a different molecular behaviour from the
      catalytic-site variants, whose protein level is normal in patient
      fibroblasts.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:39891251
      reference_title: "Heterozygous pathogenic STT3A variation leads to dominant congenital
        glycosylation disorders and functional validation in zebrafish."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the Western blot results revealed a significant decrease in protein
        levels"
      explanation: Reports reduced protein from the variant construct in cultured cells.
pathophysiology:
- name: Biallelic STT3A Loss-of-Function Variants
  biological_scale: MOLECULAR
  subtypes:
  - AR-STT3A-CDG
  molecular_functions:
  - preferred_term: oligosaccharyltransferase activity
    term:
      id: GO:0004579
      label: dolichyl-diphosphooligosaccharide-protein glycotransferase activity
    modifier: DECREASED
  description: >-
    Homozygous missense variants in STT3A reduce the function of the OST-A
    catalytic subunit. The recurrent p.Val626Ala allele does not restore
    glycosylation when expressed in STT3A-deficient cells.
  genetic_context:
    genes:
    - preferred_term: STT3A
      term:
        id: hgnc:6172
        label: STT3A
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    allele_type: missense
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous missense variants in consanguineous families (p.Val626Ala,
      p.Tyr360Ser).
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Glycosylation of STT3A- and STT3B-specific acceptors is decreased in
      fibroblasts carrying the corresponding mutated gene and expression of the STT3A
      (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation."
    explanation: The recessive allele fails to complement STT3A loss in cells.
  downstream:
  - target: Reduced OST-A Oligosaccharyltransferase Activity
    causal_link_type: DIRECT
- name: Heterozygous STT3A Catalytic-Site Missense Variants
  biological_scale: MOLECULAR
  subtypes:
  - AD-STT3A-CDG
  molecular_functions:
  - preferred_term: oligosaccharyltransferase activity
    term:
      id: GO:0004579
      label: dolichyl-diphosphooligosaccharide-protein glycotransferase activity
    modifier: DECREASED
  description: >-
    Heterozygous missense variants cluster in the catalytic site of STT3A,
    including residues such as Arg405 that stabilize the dolichol-pyrophosphate
    donor during transfer. STT3A mRNA and protein levels are normal in patient
    fibroblasts, yet glycosylation is abnormal, and homologous yeast STT3
    mutants impair glycosylation even in the presence of wild-type STT3. The
    mutant subunit is therefore thought to poison the complex rather than
    simply halve its amount. That inference rests on the founding cohort and
    on the yeast experiments; no allele-specific dominant-negative assay has
    been reported for p.Asn544Ser or p.Asp167Tyr, and p.Asp167Tyr lowered
    STT3A protein when expressed in cells, so the mechanism is established
    for the variant class rather than demonstrated for every allele.
  genetic_context:
    genes:
    - preferred_term: STT3A
      term:
        id: hgnc:6172
        label: STT3A
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      De novo, inherited or mosaic heterozygous missense variants, with a
      recurrent p.Arg405 hotspot.
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Modeling of the variants in the 3D structure of the OST complex indicated
      that all variants are located in the catalytic site of STT3A, suggesting a direct
      mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins."
    explanation: Structural modeling places every dominant variant in the catalytic
      site.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Indeed, expression of STT3A at mRNA and steady-state protein level in
      fibroblasts was normal, while glycosylation was abnormal."
    explanation: Normal protein amount with abnormal glycosylation argues against simple
      haploinsufficiency.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In S. cerevisiae, expression of STT3 containing variants homologous to
      those in affected individuals induced defective glycosylation of carboxypeptidase
      Y in a wild-type yeast strain and expression of the same mutants in the STT3
      hypomorphic stt3-7 yeast strain worsened the already observed glycosylation
      defect."
    explanation: Homologous mutants impair glycosylation despite wild-type STT3, the
      signature of a dominant-negative effect.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants clustered in conserved catalytic regions, with recurrent p.Arg405
      across de novo, inherited, and mosaic cases supporting a mutational hotspot
      and likely dominant-negative mechanism."
    explanation: Pooled-cohort review concluding a likely dominant-negative mechanism.
  downstream:
  - target: Reduced OST-A Oligosaccharyltransferase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34653363
      reference_title: "Active site variants in STT3A cause a dominant type I congenital
        disorder of glycosylation with neuromusculoskeletal findings."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data support a dominant pathomechanism underlying the glycosylation
        defect."
      explanation: The authors' conclusion from the yeast experiments described in
        the preceding sentence, that the homologous variants act dominantly on OST
        function.
- name: Reduced OST-A Oligosaccharyltransferase Activity
  biological_scale: MOLECULAR
  description: >-
    STT3A is the active-site subunit of OST-A, the oligosaccharyltransferase
    isoform recruited to the ribosome-Sec61 translocon through its DC2 and
    KCP2 subunits. It transfers the Glc3Man9GlcNAc2 oligosaccharide from its
    dolichol-pyrophosphate carrier onto asparagine in N-X-S/T sequons of
    nascent chains. Reduced or poisoned STT3A lowers the transfer activity of
    this complex. The lipid-linked donor is assembled normally, which
    distinguishes this lesion from the assembly-type CDG-I.
  molecular_functions:
  - preferred_term: oligosaccharyltransferase activity
    term:
      id: GO:0004579
      label: dolichyl-diphosphooligosaccharide-protein glycotransferase activity
    modifier: DECREASED
  protein_complexes:
  - preferred_term: OST-A complex
    term:
      id: GO:0160226
      label: oligosaccharyltransferase complex A
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase
      (OST) complex, essential for protein N-glycosylation."
    explanation: Identifies STT3A as the catalytic subunit of OST-A. The sentence
      restates established biochemistry in the framing of a clinical paper, hence
      OTHER with a BACKGROUND quote role.
  - reference: PMID:29519914
    reference_title: "Structural basis for coupling protein transport and N-glycosylation
      at the mammalian endoplasmic reticulum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The OST subunit DC2 was placed at the interface between Sec61 and STT3A,
      where it acts as a versatile module for recruitment of STT3A-containing OST
      to the ribosome-Sec61 complex."
    explanation: Structural evidence that the STT3A complex is the translocon-associated
      OST isoform.
  - reference: PMID:28860277
    reference_title: "DC2 and KCP2 mediate the interaction between the oligosaccharyltransferase
      and the ER translocon."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical analysis showed that DC2 and KCP2 are responsible for mediating
      the interaction between the protein translocation channel and the STT3A complex."
    explanation: Identifies the subunits that couple OST-A to the translocon.
  downstream:
  - target: Impaired Cotranslational N-Glycosylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19167329
      reference_title: "Cotranslational and posttranslational N-glycosylation of polypeptides
        by distinct mammalian OST isoforms."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The STT3A OST isoform is primarily responsible for cotranslational
        glycosylation of the nascent polypeptide as it enters the lumen of the endoplasmic
        reticulum."
      explanation: Isoform-specific knockdown shows that loss of STT3A activity is
        what removes cotranslational glycosylation.
- name: Impaired Cotranslational N-Glycosylation
  biological_scale: CELLULAR
  description: >-
    With OST-A impaired, acceptor sites are skipped as the nascent chain
    passes the translocon. STT3A-dependent sites include those with
    suboptimal flanking sequences and those inside cysteine-rich domains. OST-B
    can glycosylate some skipped sites afterwards, but the two complexes have
    complementary rather than redundant roles, so a subset of sites stays
    unoccupied. Patient fibroblasts show reduced glycosylation of
    STT3A-dependent acceptors.
  biological_processes:
  - preferred_term: cotranslational N-glycosylation
    term:
      id: GO:0180058
      label: protein co-translational transfer of dolichol-linked oligosaccharide
    modifier: DECREASED
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:31831667
    reference_title: "Cryo-electron microscopy structures of human oligosaccharyltransferase
      complexes OST-A and OST-B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mammals express two distinct OST complexes that act in a cotranslational
      (OST-A) or posttranslocational (OST-B) manner."
    explanation: Defines OST-A as the cotranslational complex.
  - reference: PMID:31296534
    reference_title: "Quantitative glycoproteomics reveals new classes of STT3A- and
      STT3B-dependent N-glycosylation sites."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of site occupancy data disclosed several new classes of STT3A-dependent
      acceptor sites including those with suboptimal flanking sequences and sites located
      within cysteine-rich protein domains."
    explanation: Identifies which acceptor sites depend on STT3A and so are lost when
      it fails.
  - reference: PMID:25460543
    reference_title: "Cotranslational and posttranslocational N-glycosylation of proteins
      in the endoplasmic reticulum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the role of the STT3B complex in mediating cotranslational or posttranslocational
      glycosylation of acceptor sites that have been skipped by the STT3A complex"
    explanation: Review describing OST-B as the complex that picks up sites skipped
      by OST-A; evidence source is OTHER because this is a review.
  - reference: PMID:19167329
    reference_title: "Cotranslational and posttranslational N-glycosylation of polypeptides
      by distinct mammalian OST isoforms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These distinct and complementary roles for the OST isoforms allow sequential
      scanning of polypeptides for acceptor sites to insure the maximal efficiency
      of N-glycosylation."
    explanation: Explains why OST-B only partly compensates for OST-A loss.
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also show decreased glycosylation of STT3A-specific acceptors in fibroblasts
      from our patient"
    explanation: Direct measurement of STT3A-dependent site occupancy in a recessive
      patient's fibroblasts.
  downstream:
  - target: Protein Hypoglycosylation
    causal_link_type: DIRECT
- name: Protein Hypoglycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  biological_scale: CELLULAR
  description: >-
    Glycoproteins leave the endoplasmic reticulum with unoccupied
    N-glycosylation sites. In serum this appears as transferrin molecules
    lacking whole glycans, the type I pattern, which is marked in the
    recessive form and ranges from classic to subtle in the dominant form.
  biological_processes:
  - preferred_term: Protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The STT3A mutation significantly impairs glycosylation of the biomarker
      transferrin, but the STT3B mutation only slightly affects its glycosylation."
    explanation: Shows hypoglycosylation of a circulating glycoprotein in the recessive
      form.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present here a dominant form of STT3A-CDG that, because of the presence
      of abnormal transferrin glycoforms, is unusual among dominant type I CDGs."
    explanation: Shows the same hypoglycosylation lesion in the dominant form.
  downstream:
  - target: Type I transferrin isoform profile
    causal_link_type: DIRECT
  - target: Impaired Factor VIII Secretion
    causal_link_type: DIRECT
  - target: Reduced von Willebrand factor activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30701557
      reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "VWF in our patient's plasma is present in a mildly hypoglycosylated
        form."
      explanation: Plasma vWF itself is hypoglycosylated in the patient with low vWF,
        linking the glycosylation lesion to this phenotype.
  - target: Impaired Growth Factor Receptor Processing
    causal_link_type: DIRECT
  - target: Endoplasmic Reticulum Stress
    causal_link_type: DIRECT
  - target: Abnormal Skeletal Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Multisystem Glycoprotein Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Factor VIII Secretion
  biological_scale: CELLULAR
  description: >-
    Some STT3A-dependent N-glycans on coagulation factor VIII are needed for
    its efficient secretion. Cells lacking STT3A make normal intracellular
    amounts of factor VIII but release less than a tenth of the expected
    amount. In the reported patient the low plasma level was attributed to
    this secretion defect together with low von Willebrand factor.
  biological_processes:
  - preferred_term: Protein secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies with STT3A-/- HEK293 cells showed severely reduced
      FVIII antigen and activity levels in conditioned media <10% expected, but normal
      intracellular levels."
    explanation: Localizes the factor VIII defect to secretion in STT3A-null cells.
  downstream:
  - target: Reduced factor VIII activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30701557
      reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that certain STT3A-dependent N-glycans are required
        for efficient FVIII secretion, and the decreased FVIII level in our patient
        is a combined effect of both severely impaired FVIII secretion and lower plasma
        VWF level."
      explanation: Attributes the patient's low factor VIII to impaired secretion.
- name: Impaired Growth Factor Receptor Processing
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In STT3A-null cells the insulin receptor and IGF-1 receptor reach the cell
    surface in reduced amounts, because their own N-glycan site occupancy is
    lower and because the proprotein convertase PCSK5a that cleaves them is
    itself underglycosylated. This is an established cell-line finding. Its
    relevance to patients is unshown: no study has measured these receptors in
    STT3A-CDG patient cells, and any contribution to the short stature of the
    dominant form is an inference (see discussions).
  biological_processes:
  - preferred_term: Protein processing
    term:
      id: GO:0016485
      label: protein processing
    modifier: DECREASED
  evidence:
  - reference: PMID:31101650
    reference_title: "Selective inhibition of N-linked glycosylation impairs receptor
      tyrosine kinase processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show reduced abundance of two canonical tyrosine receptor kinases
      - the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) -
      at the cell surface in STT3A-null cells, due to decreased N-linked glycan site
      occupancy and proteolytic processing in combination with increased endoplasmic
      reticulum localization."
    explanation: Shows that STT3A loss impairs processing and surface delivery of
      two growth-factor receptors.
- name: Endoplasmic Reticulum Stress
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    STT3A-knockout cells activate the unfolded protein response, with raised
    ATF6 and PERK, and the ER chaperone GRP94 becomes hyperglycosylated on
    normally silent sites, a change that ER-stress inducers reproduce in
    wild-type cells. This has been shown only in engineered cell lines; whether
    ER stress contributes to the patients' tissue phenotypes is untested.
  biological_processes:
  - preferred_term: Unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:36139350
    reference_title: "Proteome and Glycoproteome Analyses Reveal the Protein N-Linked
      Glycosylation Specificity of STT3A and STT3B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, the increased expression of the ATF6 and PERK indicated
      that the unfolded protein response also happened in STT3A-KO cells."
    explanation: Direct evidence of unfolded protein response activation after STT3A
      deletion.
  - reference: PMID:31296534
    reference_title: "Quantitative glycoproteomics reveals new classes of STT3A- and
      STT3B-dependent N-glycosylation sites."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Remarkably, the lumenal ER chaperone GRP94 was hyperglycosylated in STT3A-deficient
      cells, bearing glycans on five silent sites in addition to the normal glycosylation
      site."
    explanation: A marker change that the same study reproduces with ER-stress inducers.
- name: Abnormal Skeletal Development
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  subtypes:
  - AD-STT3A-CDG
  description: >-
    Skeletal involvement is the distinguishing feature of the dominant form.
    Heterozygous stt3a knockdown in zebrafish reduces the number of mineralized
    bones and alters craniofacial cartilage geometry, supporting a direct
    effect of reduced STT3A on skeletal development. Which STT3A-dependent
    glycoproteins mediate this is not known.
  biological_processes:
  - preferred_term: Skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39891251
    reference_title: "Heterozygous pathogenic STT3A variation leads to dominant congenital
      glycosylation disorders and functional validation in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Heterozygous knockdown zebrafish exhibit phenotypes similar to those
      of patients, including craniofacial dysmorphology (increased eye distance, increased
      Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities (reduced
      number of mineralized bones)"
    explanation: Reduced stt3a dosage alone produces skeletal and craniofacial defects
      in a vertebrate.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals presented with variable skeletal anomalies, short
      stature, macrocephaly, and dysmorphic features; half had intellectual disability."
    explanation: The human skeletal phenotype that this node accounts for.
  downstream:
  - target: Abnormal skeletal morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Facial dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Prognathism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Multisystem Glycoprotein Dysfunction
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  biological_scale: ORGANISM
  description: >-
    Underglycosylation of many client glycoproteins at once produces the
    neurodevelopmental, neuromuscular and systemic features. The recessive
    form is dominated by encephalopathy (developmental delay, intellectual
    disability, absent speech, seizures, hypotonia) and the dominant form by
    musculoskeletal and milder neurodevelopmental features. The dysmorphic,
    adipose, behavioral, hematologic and congenital-anomaly features of the
    dominant form are routed through this node as well, because the pooled
    cohort establishes them as features of the disease without naming a
    client glycoprotein for any of them. Which clients are rate-limiting for
    each feature has not been worked out, except for the coagulation factors.
  biological_processes:
  - preferred_term: Protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two cases from unrelated consanguineous families both show neurologic
      abnormalities, hypotonia, intellectual disability, failure to thrive and feeding
      problems."
    explanation: The multisystem outflow in the recessive form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental involvement was frequent, including motor delay (13/21),
      learning difficulties (13/21), speech delay (12/21), and intellectual disability
      (10/21)."
    explanation: The neurodevelopmental outflow in the dominant form.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intermittent hypothermia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced consciousness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Learning difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Muscle cramps
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Premature osteoarthritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital heart defects
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: High anterior hairline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short palpebral fissure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal upper lip and philtrum morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Protruding or low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Inverted nipples
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal subcutaneous fat distribution
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Muscle hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Bruising susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intrauterine growth restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Morbid obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anorectal malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Neurological
  name: Global developmental delay
  subtypes:
  - AR-STT3A-CDG
  description: >-
    Present in every symptomatic individual with the recessive form. In the
    dominant form delay is usually confined to motor and speech milestones and
    is recorded under those phenotypes.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic features in all symptomatic individuals include developmental
      delay, intellectual disability, with absent speech and seizures."
    explanation: Developmental delay in all symptomatic members of a recessive family.
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation
      disorder characterized by seizures, developmental delay, intellectual disability,
      and a type I carbohydrate deficient transferrin pattern."
    explanation: Developmental delay is a defining feature of the recessive form.
- category: Neurological
  name: Intellectual disability
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  description: >-
    Present in all reported recessive cases and in about half of dominant
    cases (10 of 21 in the pooled dominant cohort), where it is usually milder.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic features in all symptomatic individuals include developmental
      delay, intellectual disability, with absent speech and seizures."
    explanation: Intellectual disability in all symptomatic members of a recessive family.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental involvement was frequent, including motor delay (13/21),
      learning difficulties (13/21), speech delay (12/21), and intellectual disability
      (10/21)."
    explanation: Gives the frequency in the dominant form.
- category: Neurological
  name: Absent speech
  subtypes:
  - AR-STT3A-CDG
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic features in all symptomatic individuals include developmental
      delay, intellectual disability, with absent speech and seizures."
    explanation: Absent speech in all symptomatic members of a recessive family.
- category: Neurological
  name: Seizures
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  description: >-
    A core feature of the recessive form. Epilepsy has also been reported in
    the dominant form.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic features in all symptomatic individuals include developmental
      delay, intellectual disability, with absent speech and seizures."
    explanation: Seizures in all symptomatic members of a recessive family.
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a 17-year-old male who was referred to the Undiagnosed
      Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short
      stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental
      delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic
      root."
    explanation: Epilepsy in a patient with the dominant form.
- category: Neurological
  name: Hypotonia
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two cases from unrelated consanguineous families both show neurologic
      abnormalities, hypotonia, intellectual disability, failure to thrive and feeding
      problems."
    explanation: Hypotonia in the index recessive patient.
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a 17-year-old male who was referred to the Undiagnosed
      Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short
      stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental
      delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic
      root."
    explanation: Intermittent hypotonia in a patient with the dominant form.
- category: Growth
  name: Failure to thrive
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two cases from unrelated consanguineous families both show neurologic
      abnormalities, hypotonia, intellectual disability, failure to thrive and feeding
      problems."
    explanation: Failure to thrive in the index recessive patient.
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a 17-year-old male who was referred to the Undiagnosed
      Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short
      stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental
      delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic
      root."
    explanation: Failure to thrive in a patient with the dominant form.
- category: Gastrointestinal
  name: Feeding difficulties
  subtypes:
  - AR-STT3A-CDG
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two cases from unrelated consanguineous families both show neurologic
      abnormalities, hypotonia, intellectual disability, failure to thrive and feeding
      problems."
    explanation: Feeding problems in the index recessive patient.
- category: Neurological
  name: Intermittent hypothermia
  subtypes:
  - AR-STT3A-CDG
  description: >-
    Episodic hypothermia, reported in two individuals of one recessive
    family. Two of the five affected members of that family also carried a
    homozygous TUSC3 deletion, so attribution of the rarer features to STT3A
    alone is not certain.
  phenotype_term:
    preferred_term: Episodic hypothermia
    term:
      id: HP:0005964
      label: Intermittent hypothermia
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals also developed episodic hypothermia and altered consciousness."
    explanation: Reports episodic hypothermia in the recessive form.
- category: Neurological
  name: Reduced consciousness
  subtypes:
  - AR-STT3A-CDG
  description: >-
    Episodes of altered consciousness, in the same two individuals who had
    episodic hypothermia.
  phenotype_term:
    preferred_term: Altered consciousness
    term:
      id: HP:0004372
      label: Reduced consciousness
  evidence:
  - reference: PMID:28424003
    reference_title: "Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation
      Caused by Mutations in STT3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals also developed episodic hypothermia and altered consciousness."
    explanation: Reports altered consciousness in the recessive form.
- category: Neurological
  name: Motor delay
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: 13 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental involvement was frequent, including motor delay (13/21),
      learning difficulties (13/21), speech delay (12/21), and intellectual disability
      (10/21)."
    explanation: Gives the frequency of motor delay in the dominant form.
- category: Neurological
  name: Delayed speech and language development
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: 12 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Speech delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental involvement was frequent, including motor delay (13/21),
      learning difficulties (13/21), speech delay (12/21), and intellectual disability
      (10/21)."
    explanation: Gives the frequency of speech delay in the dominant form.
- category: Neurological
  name: Learning difficulties
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    13 of 21 individuals in the pooled dominant cohort. The source does not
    say which domain is affected, so the specific-learning-disability term is
    bound as the nearest HPO class.
  phenotype_term:
    preferred_term: Learning difficulties
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental involvement was frequent, including motor delay (13/21),
      learning difficulties (13/21), speech delay (12/21), and intellectual disability
      (10/21)."
    explanation: Gives the frequency of learning difficulties in the dominant form.
- category: Craniofacial
  name: Facial dysmorphism
  subtypes:
  - AD-STT3A-CDG
  frequency: VERY_FREQUENT
  description: >-
    Usually subtle; 18 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Across 21 individuals, abnormal transferrin glycosylation was present
      in nearly all individuals (20/21), and subtle facial dysmorphism was common
      (18/21)."
    explanation: Gives the frequency of facial dysmorphism in the dominant form.
- category: Craniofacial
  name: Macrocephaly
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    7 of 21 individuals in the pooled dominant cohort, where the head
    circumference is often progressive rather than fixed.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals presented with variable skeletal anomalies, short
      stature, macrocephaly, and dysmorphic features; half had intellectual disability."
    explanation: Macrocephaly is a presenting feature of the dominant form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Macrocephaly | 7 of 21 | Often progressive"
    explanation: Gives the count behind the frequency band and the progressive course.
- category: Musculoskeletal
  name: Abnormal skeletal morphology
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    Variable skeletal anomalies in 12 of 21 individuals of the pooled dominant
    cohort. The sources describe them collectively as variable skeletal
    anomalies without naming a single recurrent lesion.
  phenotype_term:
    preferred_term: Variable skeletal anomalies
    term:
      id: HP:0011842
      label: Abnormal skeletal morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Musculoskeletal manifestations were also common, including skeletal
      abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset
      osteoarthritis in adults (6/21)."
    explanation: Gives the frequency of skeletal abnormalities in the dominant form.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals presented with variable skeletal anomalies, short
      stature, macrocephaly, and dysmorphic features; half had intellectual disability."
    explanation: Describes the skeletal anomalies as variable.
- category: Growth
  name: Short stature
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: 11 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Musculoskeletal manifestations were also common, including skeletal
      abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset
      osteoarthritis in adults (6/21)."
    explanation: Gives the frequency of short stature in the dominant form.
- category: Neuromuscular
  name: Hypertonia
  subtypes:
  - AD-STT3A-CDG
  description: >-
    Increased muscle tone. The pooled dominant cohort counts abnormal muscle
    tone as a single item, 7 of 21, covering hypertonia and hypotonia
    together, so neither can be given a frequency band of its own.
  phenotype_term:
    preferred_term: Increased muscle tone
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features included increased muscle tone and muscle cramps."
    explanation: Increased muscle tone in the dominant form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal muscle tone | 7 of 21 | Hyper- or hypotonia"
    explanation: Shows that the 7 of 21 tone count pools hypertonia with hypotonia
      and so cannot be apportioned to either.
- category: Neuromuscular
  name: Muscle cramps
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    8 of 21 individuals in the pooled dominant cohort. Muscle cramps had not
    previously been reported in other N-glycosylation disorders.
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Musculoskeletal manifestations were also common, including skeletal
      abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset
      osteoarthritis in adults (6/21)."
    explanation: Gives the frequency of muscle cramps in the dominant form.
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features included increased muscle tone and muscle cramps."
    explanation: Muscle cramps in the founding dominant cohort.
- category: Musculoskeletal
  name: Premature osteoarthritis
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    Early-onset osteoarthritis in adults, 6 of 21 individuals in the pooled
    dominant cohort (a count that includes children, who cannot yet show it).
  phenotype_term:
    preferred_term: Early-onset osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Musculoskeletal manifestations were also common, including skeletal
      abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset
      osteoarthritis in adults (6/21)."
    explanation: Gives the frequency of early-onset osteoarthritis in the dominant
      form.
- category: Cardiovascular
  name: Congenital heart defects
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: 5 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less frequent features included congenital heart defects (5/21) and
      coagulation factor deficiency (5/21)."
    explanation: Gives the frequency of congenital heart defects in the dominant form.
- category: Craniofacial
  name: High anterior hairline
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    The most frequently recorded single dysmorphic feature of the dominant
    form, in 10 of 21 individuals of the pooled cohort.
  phenotype_term:
    preferred_term: High anterior hairline
    term:
      id: HP:0009890
      label: High anterior hairline
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High anterior hairline | 10 of 21 | Recurrent feature"
    explanation: Gives the count behind the frequency band.
- category: Craniofacial
  name: Abnormal upper lip and philtrum morphology
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    9 of 21 individuals of the pooled dominant cohort. The source scores a
    thin upper lip and a philtrum abnormality as one combined item and does
    not say which of the two each individual had, so the count cannot be
    apportioned; the individual reports name a thin upper lip vermilion and a
    flat, smooth or long philtrum. HPO files the philtrum under upper lip
    morphology, so HP:0000177 is the narrowest class that covers both halves
    of the item without asserting either.
  phenotype_term:
    preferred_term: Thin upper lip vermilion and/or philtrum abnormality
    term:
      id: HP:0000177
      label: Abnormal upper lip morphology
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thin upper lip and/or philtrum abnormality | 9 of 21 | Common"
    explanation: Gives the combined count and shows that the two features are scored
      as one item.
- category: Craniofacial
  name: Short palpebral fissure
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: 7 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Short palpebral fissures
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short palpebral fissures | 7 of 21 | Variable"
    explanation: Gives the count behind the frequency band.
- category: Craniofacial
  name: Wide nasal bridge
  subtypes:
  - AD-STT3A-CDG
  frequency: FREQUENT
  description: >-
    7 of 21 individuals in the pooled dominant cohort, graded mild to
    moderate.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wide nasal bridge | 7 of 21 | Mild-moderate"
    explanation: Gives the count behind the frequency band.
- category: Craniofacial
  name: Prognathism
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    6 of 21 individuals in the pooled dominant cohort, with a maxillary
    predominance rather than uniformly maxillary involvement.
  phenotype_term:
    preferred_term: Prognathism with maxillary predominance
    term:
      id: HP:0030791
      label: Abnormal jaw morphology
    coarse_binding_basis: NO_HPO_TERM
    term_gap: >-
      HPO has no maxillary prognathism term. A label search of HP for
      "prognath" returns only HP:0000303 Mandibular prognathia, defined as
      abnormal prominence of the chin related to increased length of the
      mandible, which would assert the wrong bone for a maxillary-predominant
      finding. HP:0030791 Abnormal jaw morphology is the nearest class above
      both HP:0000326 Abnormal maxilla morphology and HP:0000277 Abnormal
      mandible morphology, so it covers all six individuals without naming a
      jaw the source does not.
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prognathism | 6 of 21 | Maxillary predominance"
    explanation: Gives the count and the maxillary predominance that rules out the
      mandible-specific HPO term.
- category: Craniofacial
  name: Protruding or low-set ears
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    6 of 21 individuals of the pooled dominant cohort. The source scores
    protruding and low-set ears as one combined item and does not say which
    each individual had, so the count cannot be apportioned. HPO places both
    HP:0000411 Protruding ear and HP:0000369 Low-set ears under
    HP:0000377, which is therefore the narrowest class that covers the item
    without asserting either half.
  phenotype_term:
    preferred_term: Protruding or low-set ears
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protruding or low-set ears | 6 of 21 | Variable"
    explanation: Gives the combined count and shows that the two ear findings are
      scored as one item.
- category: Breast
  name: Inverted nipples
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    6 of 21 individuals in the pooled dominant cohort, described as
    distinctive but not universal.
  phenotype_term:
    preferred_term: Inverted nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inverted nipples | 6 of 21 | Distinctive but not universal"
    explanation: Gives the count behind the frequency band.
- category: Integument
  name: Abnormal subcutaneous fat distribution
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    4 of 21 individuals in the pooled dominant cohort, recorded as hip or
    truncal fat pads.
  phenotype_term:
    preferred_term: Abnormal fat distribution
    term:
      id: HP:0007552
      label: Abnormal subcutaneous fat tissue distribution
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal fat distribution | 4 of 21 | Hip or truncal fat pads"
    explanation: Gives the count and the distribution of the fat pads.
- category: Neuromuscular
  name: Muscle hypertrophy
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    4 of 21 individuals in the pooled dominant cohort, usually in the
    individuals who also have muscle cramps. The source does not localize the
    hypertrophy to a muscle group.
  phenotype_term:
    preferred_term: Muscle hypertrophy
    term:
      id: HP:0003712
      label: Skeletal muscle hypertrophy
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle hypertrophy | 4 of 21 | Often with cramps"
    explanation: Gives the count and its co-occurrence with the cramps phenotype.
- category: Hematologic
  name: Bruising susceptibility
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    Easy bruising or bleeding in 4 of 21 individuals of the pooled dominant
    cohort, a milder and separately counted finding from the clinically
    significant bleeding diathesis of 3 of 21. One reported individual had
    easy bruising with no documented coagulation factor deficiency, so the
    source does not attribute this finding to the factor VIII and von
    Willebrand factor defect.
  phenotype_term:
    preferred_term: Easy bruising
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Easy bruising/bleeding | 4 of 21 | Variable"
    explanation: Gives the count for the milder bleeding phenotype, separate from
      the bleeding diathesis row.
- category: Musculoskeletal
  name: Scoliosis
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    5 of 21 individuals in the pooled dominant cohort, usually mild.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis | 5 of 21 | Usually mild"
    explanation: Gives the count behind the frequency band.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  subtypes:
  - AD-STT3A-CDG
  description: >-
    Reported mostly in the pediatric individuals of the pooled dominant
    cohort. The source scores attention-deficit/hyperactivity disorder and
    anxiety as one combined item, 5 of 21, so no frequency band can be
    assigned to either diagnosis alone; the two are curated as separate
    phenotypes because HPO has no class covering both without also covering
    the intellectual disability and learning difficulties counted separately
    in the same cohort.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADHD and/or anxiety | 5 of 21 | Mostly pediatric"
    explanation: Reports attention-deficit/hyperactivity disorder in the cohort, as
      one half of a combined 5 of 21 item.
- category: Behavioral
  name: Anxiety
  subtypes:
  - AD-STT3A-CDG
  description: >-
    Reported mostly in the pediatric individuals of the pooled dominant
    cohort, scored together with attention-deficit/hyperactivity disorder as
    one combined item of 5 of 21, so it carries no frequency band of its own.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADHD and/or anxiety | 5 of 21 | Mostly pediatric"
    explanation: Reports anxiety in the cohort, as one half of a combined 5 of 21
      item.
- category: Prenatal
  name: Intrauterine growth restriction
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: 3 of 21 individuals in the pooled dominant cohort.
  phenotype_term:
    preferred_term: Intrauterine growth restriction
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intrauterine growth restriction | 3 of 21"
    explanation: Gives the count behind the frequency band.
- category: Growth
  name: Morbid obesity
  subtypes:
  - AD-STT3A-CDG
  frequency: VERY_RARE
  description: >-
    1 of 21 individuals in the pooled dominant cohort, with rapid pubertal
    weight gain; a feature the source reports as new for this disease. One in
    21 is 4.8 per cent, below the 5 per cent floor of the occasional band.
    The source calls the obesity morbid but gives no body mass index, so the
    body-mass-index-graded HPO obesity classes are not bound.
  phenotype_term:
    preferred_term: Morbid obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morbid obesity | 1 of 21 | Rapid pubertal weight gain"
    explanation: Gives the count and the pubertal course, and marks the feature as
      newly reported.
- category: Gastrointestinal
  name: Anorectal malformation
  subtypes:
  - AD-STT3A-CDG
  frequency: VERY_RARE
  description: >-
    1 of 21 individuals in the pooled dominant cohort, in a girl who also had
    a patent foramen ovale and a bicuspid aortic valve. The source reports it
    as not previously described in this disease and as one of the congenital
    structural anomalies that extend its spectrum. One in 21 is 4.8 per cent,
    below the 5 per cent floor of the occasional band.
  phenotype_term:
    preferred_term: Anorectal malformation
    term:
      id: HP:0012732
      label: Anorectal anomaly
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anorectal malformation | 1 of 21 | Not previously reported"
    explanation: Gives the count and marks the feature as newly reported for this
      disease.
- category: Hematologic
  name: Reduced factor VIII activity
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  description: >-
    Chronically low factor VIII in one recessive patient homozygous for
    p.Tyr360Ser. In the dominant form coagulation factor deficiency was found
    in 5 of 21 individuals, and one had clinically significant bleeding with
    factor VIII and von Willebrand factor deficiency.
  phenotype_term:
    preferred_term: Factor VIII deficiency
    term:
      id: HP:0003125
      label: Reduced factor VIII activity
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with a novel homozygous likely pathogenic missense
      variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII
      (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to
      the previously reported symptoms of developmental delay and seizures."
    explanation: Low factor VIII in the recessive form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, the newly reported individuals expand dominant STT3A-CDG
      with previously unreported features, including anorectal malformation, morbid
      obesity, and clinically significant bleeding diathesis with von Willebrand factor
      and factor VIII deficiency."
    explanation: Factor VIII deficiency in the dominant form.
  sequelae:
  - target: Abnormal bleeding
    causal_link_type: DIRECT
- category: Hematologic
  name: Reduced von Willebrand factor activity
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  phenotype_term:
    preferred_term: von Willebrand factor deficiency
    term:
      id: HP:0008330
      label: Reduced von Willebrand factor activity
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with a novel homozygous likely pathogenic missense
      variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII
      (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to
      the previously reported symptoms of developmental delay and seizures."
    explanation: Low von Willebrand factor activity in the recessive form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, the newly reported individuals expand dominant STT3A-CDG
      with previously unreported features, including anorectal malformation, morbid
      obesity, and clinically significant bleeding diathesis with von Willebrand factor
      and factor VIII deficiency."
    explanation: Von Willebrand factor deficiency in the dominant form.
  sequelae:
  - target: Abnormal bleeding
    causal_link_type: DIRECT
- category: Hematologic
  name: Abnormal bleeding
  subtypes:
  - AD-STT3A-CDG
  frequency: OCCASIONAL
  description: >-
    A clinically significant bleeding diathesis, with marked von Willebrand
    factor and/or factor VIII deficiency, was recorded in 3 of 21 individuals
    of the pooled dominant cohort, not in a single patient. A further 4 of 21
    had easy bruising or bleeding without a documented diathesis; that milder
    finding is curated separately as bruising susceptibility.
  phenotype_term:
    preferred_term: Bleeding diathesis
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, the newly reported individuals expand dominant STT3A-CDG
      with previously unreported features, including anorectal malformation, morbid
      obesity, and clinically significant bleeding diathesis with von Willebrand factor
      and factor VIII deficiency."
    explanation: Reports the bleeding diathesis.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically significant bleeding diathesis | 3 of 21 | Marked vWF and/or
      FVIII deficiency"
    explanation: Gives the cohort count and the factor deficiencies behind it.
- category: Laboratory
  name: Type I transferrin isoform profile
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  description: >-
    The biochemical hallmark. Marked in the recessive form. In the dominant
    form transferrin glycosylation is abnormal in 20 of 21 individuals, but
    the pattern ranges from a classic type I profile to subtle or atypical
    changes, so a near-normal result does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Type I transferrin isoform profile
    term:
      id: HP:0003642
      label: Type I transferrin isoform profile
  evidence:
  - reference: PMID:30701557
    reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation
      disorder characterized by seizures, developmental delay, intellectual disability,
      and a type I carbohydrate deficient transferrin pattern."
    explanation: The type I pattern is a defining feature of the recessive form.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical signatures ranged from classic type I transferrin patterns
      to subtle or atypical abnormalities, emphasizing that near-normal transferrin
      testing does not exclude the diagnosis."
    explanation: Describes the range of transferrin findings in the dominant form.
biochemical:
- name: Serum Transferrin Glycoform Profile
  subtypes:
  - AR-STT3A-CDG
  - AD-STT3A-CDG
  notes: >-
    Serum transferrin isoelectric focusing or mass spectrometry shows
    transferrin molecules missing whole N-glycans (type I pattern). The change
    is marked in the recessive form. In the dominant form it is present in
    nearly all individuals but can be subtle, so a normal or near-normal
    screen does not exclude the dominant form.
  evidence:
  - reference: PMID:23842455
    reference_title: "Mutations in STT3A and STT3B cause two congenital disorders of
      glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The STT3A mutation significantly impairs glycosylation of the biomarker
      transferrin, but the STT3B mutation only slightly affects its glycosylation."
    explanation: Establishes transferrin as an informative biomarker for STT3A deficiency.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Across 21 individuals, abnormal transferrin glycosylation was present
      in nearly all individuals (20/21), and subtle facial dysmorphism was common
      (18/21)."
    explanation: Gives the sensitivity of transferrin testing in the dominant form.
diagnosis:
- name: Serum transferrin glycoform analysis
  description: >-
    First-line screen. A type I pattern places the defect in N-glycan precursor
    assembly or transfer and prompts sequencing. It does not identify the gene,
    and in the dominant form it can be near-normal.
  diagnosis_term:
    preferred_term: Transferrin isoelectric focusing
    term:
      id: NCIT:C101016
      label: Carbohydrate-Deficient Transferrin Measurement
  evidence:
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was formally diagnosed by the UDN Metabolomics Core as having
      an abnormal transferrin profile indicative of CDG type Iw through metabolomic
      profiling."
    explanation: Transferrin profiling supported the diagnosis in a dominant-form
      patient.
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical signatures ranged from classic type I transferrin patterns
      to subtle or atypical abnormalities, emphasizing that near-normal transferrin
      testing does not exclude the diagnosis."
    explanation: States the limitation of the screen in the dominant form.
- name: Exome or genome sequencing of STT3A
  description: >-
    Definitive diagnosis rests on finding biallelic (recessive) or
    heterozygous (dominant) STT3A variants. Genome sequencing identified a de
    novo dominant variant after a negative trio exome in one patient.
  diagnosis_term:
    preferred_term: Genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  evidence:
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His UDN genome sequencing (GS) identified a previously unreported de
      novo STT3A variant (c.1631A > G: p.Asn544Ser)."
    explanation: Genome sequencing made the molecular diagnosis.
  - reference: PMID:39435313
    reference_title: "Review and metabolomic profiling of unsolved case reveals newly
      reported autosomal dominant congenital disorder of glycosylation, type Iw formerly
      thought to only be an autosomal recessive condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio exome sequencing was negative."
    explanation: The preceding exome had missed the variant.
- name: Coagulation factor testing
  description: >-
    Measurement of factor VIII and von Willebrand factor identifies the
    coagulation factor deficiency found in some patients of both subtypes,
    one of whom (dominant form) had a clinically significant bleeding
    diathesis.
  evidence:
  - reference: PMID:41897354
    reference_title: "Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less frequent features included congenital heart defects (5/21) and
      coagulation factor deficiency (5/21)."
    explanation: Coagulation factor deficiency occurs in about a quarter of dominant
      cases.
animal_models:
- name: Heterozygous stt3a knockdown zebrafish
  species: Danio rerio
  genotype: CRISPR-Cas9 heterozygous stt3a knockdown
  publication: PMID:39891251
  description: >-
    Zebrafish with heterozygous loss of stt3a, generated to test whether
    reduced STT3A dosage produces the dominant phenotype. The larvae show
    craniofacial cartilage changes, fewer mineralized bones, reduced
    adaptability in light-dark behaviour tests and electrophysiological
    abnormalities.
  genes:
  - preferred_term: STT3A
    term:
      id: hgnc:6172
      label: STT3A
  modeled_mechanisms:
  - target: Abnormal Skeletal Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reduced stt3a dosage produces craniofacial and skeletal mineralization
      defects comparable to the patients' skeletal anomalies and dysmorphism.
    limitations: >-
      A heterozygous knockdown lowers the amount of STT3A; it does not
      reproduce a catalytic-site missense variant, so it tests
      haploinsufficiency rather than the dominant-negative mechanism proposed
      for most dominant alleles. Phenotypes were scored in larvae, so the adult
      features (osteoarthritis, muscle cramps) and the transferrin phenotype are
      not assessed.
    evidence:
    - reference: PMID:39891251
      reference_title: "Heterozygous pathogenic STT3A variation leads to dominant congenital
        glycosylation disorders and functional validation in zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous knockdown zebrafish exhibit phenotypes similar to those
        of patients, including craniofacial dysmorphology (increased eye distance,
        increased Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities
        (reduced number of mineralized bones)"
      explanation: The skeletal and craniofacial readouts behind this link.
  evidence:
  - reference: PMID:39891251
    reference_title: "Heterozygous pathogenic STT3A variation leads to dominant congenital
      glycosylation disorders and functional validation in zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We performed CRISPR-Cas9 to establish heterozygous knockdown zebrafish
      to validate the functional implications of autosomal dominant inheritance of
      STT3A in pathogenesis."
    explanation: Describes how the model was made.
experimental_models:
- name: STT3A-knockout HEK293 cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Immortalized human embryonic kidney cell line with STT3A deleted
  publication: PMID:30701557
  description: >-
    Human cells lacking STT3A, used to measure the consequence of losing OST-A
    for secretion of coagulation factor VIII and for the cellular stress
    response.
  modeled_mechanisms:
  - target: Impaired Factor VIII Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      STT3A-null cells secrete less than a tenth of the expected factor VIII
      while intracellular levels are normal.
    limitations: >-
      A complete null in a kidney-derived line, whereas patients carry
      missense alleles and factor VIII is made physiologically by liver
      endothelial cells. The model shows that STT3A is needed for secretion,
      not how much secretion a patient allele retains.
    evidence:
    - reference: PMID:30701557
      reference_title: "Factor VIII and vWF deficiency in STT3A-CDG."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies with STT3A-/- HEK293 cells showed severely reduced
        FVIII antigen and activity levels in conditioned media <10% expected, but normal
        intracellular levels."
      explanation: The secretion readout behind this link.
  - target: Endoplasmic Reticulum Stress
    relationship: MEASURES
    fidelity: LOW
    description: >-
      STT3A-knockout cells show raised ATF6 and PERK, indicating an unfolded
      protein response.
    limitations: >-
      Measured in a complete knockout cell line; no patient cells or tissues
      have been examined for ER stress.
    evidence:
    - reference: PMID:36139350
      reference_title: "Proteome and Glycoproteome Analyses Reveal the Protein N-Linked
        Glycosylation Specificity of STT3A and STT3B."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, the increased expression of the ATF6 and PERK indicated
        that the unfolded protein response also happened in STT3A-KO cells."
      explanation: The stress-response readout behind this link.
discussions:
- discussion_id: stt3a_dominant_mechanism
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Do all dominant STT3A alleles act by a dominant-negative mechanism, or do
    some act by haploinsufficiency?
  attaches_to:
  - pathophysiology#Heterozygous STT3A Catalytic-Site Missense Variants
  rationale: >-
    The founding dominant cohort had normal STT3A protein in fibroblasts, all
    variants in the catalytic site, and dominant glycosylation defects from the
    homologous yeast mutants, which together point to a poisoned complex. But
    p.Asp167Tyr lowered STT3A protein when expressed in cells, and a
    heterozygous stt3a knockdown in zebrafish, which only reduces dosage,
    reproduced craniofacial and skeletal features. Carriers of the recessive
    alleles are not reported as affected, so halving STT3A activity is not
    sufficient in general, but whether some dominant alleles act through a
    dosage effect rather than a dominant-negative one is unresolved.
  evidence:
  - reference: PMID:34653363
    reference_title: "Active site variants in STT3A cause a dominant type I congenital
      disorder of glycosylation with neuromusculoskeletal findings."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Indeed, expression of STT3A at mRNA and steady-state protein level in
      fibroblasts was normal, while glycosylation was abnormal."
    explanation: Supports a dominant-negative mechanism for the catalytic-site alleles.
  - reference: PMID:39891251
    reference_title: "Heterozygous pathogenic STT3A variation leads to dominant congenital
      glycosylation disorders and functional validation in zebrafish."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the Western blot results revealed a significant decrease in protein
      levels"
    explanation: A dominant allele that reduces protein amount, consistent with a
      dosage mechanism.
- discussion_id: stt3a_growth_receptor_link
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Does impaired processing of the insulin and IGF-1 receptors contribute to
    the short stature and skeletal phenotype of dominant STT3A-CDG?
  attaches_to:
  - pathophysiology#Impaired Growth Factor Receptor Processing
  - phenotypes#Short stature
  rationale: >-
    STT3A-null cells deliver less insulin receptor and IGF-1 receptor to the
    surface, and IGF-1 signalling is a major driver of linear growth. No study
    has measured these receptors in STT3A-CDG patient cells or tested the
    growth pathway in an animal model, so the node is not connected to the
    skeletal phenotypes in this entry.
references:
- reference: PMID:23842455
  title: Mutations in STT3A and STT3B cause two congenital disorders of glycosylation.
- reference: PMID:34653363
  title: Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings.
- reference: PMID:41897354
  title: Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG.
notes: >-
  Lump/split. MONDO has two terms for STT3A disease: MONDO:0014270
  (STT3A-congenital disorder of glycosylation), which carries the synonym
  "congenital disorder of glycosylation, type Iw, autosomal recessive" and the
  OMIM:615596 cross-reference, and MONDO:0859223 (congenital disorder of
  glycosylation, type Iw, autosomal dominant; OMIM:619714), which MONDO places
  directly under congenital disorder of glycosylation rather than under
  MONDO:0014270. There is no MONDO class spanning both forms. This entry is
  anchored on MONDO:0014270 because its label names the gene, and the two
  inheritance forms are modelled as has_subtypes, each bound to its own MONDO
  term, because they share the gene, the enzyme and the transfer defect and
  differ in allele mechanism and clinical emphasis. The recessive subtype
  therefore reuses the entry-level MONDO term. STT3B-CDG, caused by the
  paralogous OST-B catalytic subunit, is a separate disease and is not
  covered here. No GeneReviews chapter covers STT3A-CDG; a PubMed search of
  the GeneReviews collection for STT3A or oligosaccharyltransferase returns
  only the retired, multi-disorder overview of congenital disorders of
  N-linked glycosylation. No
  disease-specific treatment or treatment trial has been reported for either
  subtype, so the entry carries no treatments section.

📚

References & Deep Research

References

3

PMID:23842455

Mutations in STT3A and STT3B cause two congenital disorders of glycosylation.

No top-level findings curated for this source.

PMID:34653363

Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings.

No top-level findings curated for this source.

PMID:41897354

Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG.

No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (1)

Create: STT3A-Congenital_Disorder_of_Glycosylation · 2026-09-29T21:09:48Z · View source

New entry for STT3A-congenital disorder of glycosylation (CDG-Iw), expanding the seed file created from the stub queue. The stub stubs/STT3A-congenital_Disorder_Of_Glycosylation.yaml is deleted. Scope decision. MONDO has two terms: MONDO:0014270 (gene-named label, carrying the autosomal recessive synonym and OMIM:615596) and MONDO:0859223 (autosomal dominant, OMIM:619714), which sits directly under congenital disorder of glycosylation and not under MONDO:0014270. The entry is anchored on MONDO:0014270 and models the two forms as has_subtypes (AR-STT3A-CDG bound to MONDO:0014270, AD-STT3A-CDG bound to MONDO:0859223), because they share the gene, the OST-A enzyme and the transfer defect but differ in allele mechanism (biallelic loss of function versus heterozygous, likely dominant-negative catalytic-site variants) and clinical emphasis (encephalopathy versus neuromusculoskeletal). Phenotypes, prevalence and lesion nodes carry subtype assignments. The same MONDO term is therefore bound twice (entry and recessive subtype); Myopathic_Ehlers-Danlos_Syndrome is a precedent. Pathograph: two lesion nodes (biallelic LoF; heterozygous dominant- negative) converge on reduced OST-A activity, impaired cotranslational N-glycosylation (GO:0180058) and protein hypoglycosylation, which conforms to congenital_disorder_of_glycosylation#Protein Hypoglycosylation. Branches: impaired factor VIII secretion, ER stress (cell-line only, PROVISIONAL), impaired insulin/IGF-1 receptor processing (cell-line only, HYPOTHETICAL, deliberately not wired to growth phenotypes and raised as a discussion), abnormal skeletal development (zebrafish-supported, dominant form), and multisystem glycoprotein dysfunction (conforms to the module node). All 24 phenotypes are causally connected. The module's ER lipid-linked oligosaccharide assembly trigger node was not used because the lesion here is at glycan transfer, not donor assembly. Two discussions record the open question of dominant-negative versus dosage mechanisms (p.Asp167Tyr lowers protein; the zebrafish model is a knockdown) and the growth-receptor hypothesis. Frequencies for the dominant form come from the 21-individual pooled cohort in PMID:41897354; phenotypes spanning both subtypes carry counts in their descriptions but no frequency value, since the cohort covers only the dominant form. No treatments section: no disease-specific or symptomatic treatment study was found for either subtype. Deep research: the OpenScientist report was read in full. Its reference_validation reports 16/16 references resolved and 31/31 quotes found, 0 off topic. Its term_validation needs_review flag was set by label-format noise (category words such as "Clinical sign" reported as labels), one obsolete GO term (GO:0018279, not used; GO:0180058 bound instead), and CHEBI:23509 offered as dolichol but actually "cysteine derivative" (not used). The report gives the STT3A HGNC identifier as HGNC:30591, which is wrong; hgnc:6172 was verified against the HGNC REST service. The report binds skeletal anomalies to HP:0000924; the entry uses HP:0011842 with coarse_binding_basis VARIABLE_SPECTRUM. just preflight-dr returned PASS (STT3A mentioned 71 times; report OMIM 615596 and 619714). Report citations used: 23842455, 34653363, 39891251, 30701557, 28860277, 25460543, 31101650, 39435313. Report citations not used: 40737785, 39923392, 34440401 and 28323990 are about the CDG group or PMM2-CDG and say nothing specific to STT3A; 31433728, 25135935 and 29282902 are OST mechanism papers superseded here by more direct sources; 37876147 is a PMM2-CDG transferrin-variant pitfall paper. The report's gnomAD constraint figures have no citable source and were not used. Additional sources found by PubMed search: Ghosh 2017 (PMID:28424003, second recessive family), the 2026 pooled review of the dominant form (PMID:41897354), the OST isoform papers PMID:19167329, PMID:29519914, PMID:31831667, PMID:31296534 and the STT3A-knockout proteomics study PMID:36139350. PMID:31021453 is a published erratum to PMID:30701557 with no text and was not cited. Checks run: just validate (pass), just validate-terms (pass), just count-verified-snippets (all snippets verified), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews --online (NO_CHAPTER; the only Bookshelf hit is the retired multi-disorder CDG overview), list-disconnected-phenotypes (24/24 connected), the global snippet and coarse-phenotype gates, and just validate-disorders.

OpenScientist ▸

STT3A-Congenital Disorder of Glycosylation (STT3A-CDG): Comprehensive Disease Characterization Report

openscientist-autonomous 15 citations 2026-09-29T20:53:14.174860

STT3A-Congenital Disorder of Glycosylation (STT3A-CDG): Comprehensive Disease Characterization Report

Disease: STT3A-Congenital Disorder of Glycosylation (CDG type Iw) MONDO ID: MONDO:0014270 OMIM: #615596 (autosomal recessive) and #619714 (autosomal dominant) Gene: STT3A (HGNC:30591; NCBI Gene 3703; chr11q24.1; UniProt P46977; OMIM 601134) Category:* Mendelian inborn error of metabolism

Summary

STT3A-CDG is an ultra-rare, multisystem inborn error of protein N-glycosylation caused by pathogenic variants in STT3A, the gene encoding the catalytic subunit of the co-translational oligosaccharyltransferase complex (OST-A). The OST-A complex, positioned adjacent to the Sec61 translocon in the endoplasmic reticulum (ER) membrane, transfers a pre-assembled Glc₃Man₉GlcNAc₂ oligosaccharide from a dolichol-pyrophosphate donor onto asparagine residues within N-X-S/T sequons of nascent polypeptides as they emerge into the ER. When OST-A activity is reduced, a subset of glycoproteins — particularly those whose sequons are glycosylated preferentially by STT3A during translation — become hypoglycosylated and destabilized, producing a CDG type I biochemical signature (an abnormal serum transferrin pattern with increased di- and a-sialotransferrin).

Clinically, STT3A-CDG is a predominantly neurodevelopmental and neuromuscular-skeletal disorder. The autosomal recessive form (first described in 2013) features seizures, developmental delay, intellectual disability, hypotonia, feeding problems/failure to thrive, and a type I transferrin pattern; some patients also have a coagulopathy (low Factor VIII and von Willebrand Factor). A distinct autosomal dominant form (defined in 2021 from 16 individuals across 9 families) is caused by heterozygous missense variants clustering in the catalytic active site and presents with skeletal anomalies, short stature, macrocephaly, dysmorphism, increased muscle tone/cramps, and intellectual disability in about half of cases. The two inheritance mechanisms — biallelic loss-of-function versus heterozygous dominant-negative active-site variants — represent one of the more unusual features of this disorder, reflected in dual OMIM entries.

Diagnosis rests on transferrin isoelectric focusing (or HPLC/capillary electrophoresis) followed by confirmatory exome/genome or targeted STT3A sequencing. There is no disease-specific or curative therapy; unlike certain treatable CDG subtypes (PGM1-CDG with galactose, MPI-CDG with mannose, TMEM165-CDG with galactose), the dietary sugar therapies do not apply to STT3A-CDG because it is an ER glycan-transfer defect rather than a Golgi processing defect. Management is supportive and multidisciplinary. Disease mechanism has been validated across yeast (S. cerevisiae STT3), zebrafish (CRISPR heterozygous knockdown), and human patient cell models, and gnomAD population-constraint metrics quantitatively corroborate that STT3A is strongly intolerant to both missense and loss-of-function variation.

Key Findings

Finding 1 — STT3A-CDG is caused by defects in the catalytic subunit of the OST-A complex

STT3A (chromosome 11q24.1; OMIM 601134) encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST-A) complex, which co-translationally transfers the Glc₃Man₉GlcNAc₂ glycan from dolichol-pyrophosphate onto asparagine residues within N-X-S/T sequons. The original 2013 report by Shrimal, Ng, Losfeld, Gilmore, and Freeze identified a homozygous STT3A* c.1877T>C variant (p.Val626Ala) causing a recessive CDG; the mutation impaired glycosylation of a GFP-based biomarker and was rescued by wild-type cDNA.

"which are caused by mutations in different isoforms of the catalytic subunit of the oligosaccharyltransferase (OST)" — PMID: 23842455

"A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change" — PMID: 23842455

"STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation" — PMID: 34653363

This establishes the fundamental molecular lesion: a defect in the enzyme that initiates the N-glycosylation of nascent proteins in the ER.

Finding 2 — STT3A-CDG has both autosomal recessive and autosomal dominant forms

The recessive form (OMIM #615596, CDG-Iw) was first described in 2013 as an autosomal-recessive disorder with seizures, developmental delay, intellectual disability, and a type I transferrin pattern. In 2021, Wilson et al. reported 16 individuals from 9 families with inherited or de novo heterozygous missense variants clustering in the STT3A catalytic active site, defining a distinct autosomal-dominant CDG (OMIM #619714). Subsequent reports (2024–2026) confirmed and expanded the dominant spectrum, including a zebrafish-validated dominant missense variant (p.Asp167Tyr).

"we here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG" — PMID: 34653363

"all variants are located in the catalytic site of STT3A" — PMID: 34653363

"Previous studies have reported that STT3A-CDG is caused by autosomal recessive inheritance. However, in this study, we propose that STT3A-CDG can be pathogenic through autosomal dominant inheritance" — PMID: 39891251

The clustering of dominant variants in the catalytic site supports a dominant-negative mechanism, whereby a mutant catalytic subunit incorporated into the OST-A complex poisons its activity.

Finding 3 — Core clinical phenotype: neurodevelopmental impairment, seizures, and a type I transferrin pattern

Recessive STT3A-CDG is characterized by seizures, developmental delay, intellectual disability, hypotonia, failure to thrive/feeding problems, and a type I carbohydrate-deficient transferrin (CDT) pattern. A patient carrying p.Tyr360Ser additionally exhibited chronically low Factor VIII and von Willebrand Factor with hypoglycosylated vWF. The dominant form presents with variable skeletal anomalies, short stature, macrocephaly, dysmorphic features, intellectual disability in approximately 50%, and increased muscle tone with muscle cramps.

"characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern" — PMID: 30701557

"chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities" — PMID: 30701557

"Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps" — PMID: 34653363

Finding 4 — Mechanism: STT3A mediates co-translational N-glycosylation coupled to the ER translocon

The STT3A OST complex is localized adjacent to the Sec61 protein translocation channel and catalyzes co-translational N-glycosylation using an N-terminal-to-C-terminal scanning mechanism. Accessory subunits DC2 (OSTC) and KCP2 mediate the STT3A–translocon interaction. The paralogous STT3B complex (containing the oxidoreductase MagT1) glycosylates sites skipped by STT3A, including cysteine-proximal sequons, providing partial functional redundancy that likely mitigates the severity of STT3A loss.

"The STT3A complex interacts directly with the protein translocation channel to mediate glycosylation of proteins using an N-terminal-to-C-terminal scanning mechanism" — PMID: 31433728

"the STT3A isoform of the oligosaccharyltransferase is localized adjacent to the protein translocation channel to catalyze co-translational N-linked glycosylation of proteins in the endoplasmic reticulum" — PMID: 28860277

"the role of the STT3B complex in mediating cotranslational or posttranslocational glycosylation of acceptor sites that have been skipped by the STT3A complex" — PMID: 25460543

Finding 5 — Ultra-rare with two OMIM entries; part of the broader CDG group

Two OMIM phenotype entries exist: CDG type Iw autosomal recessive (#615596) and autosomal dominant (#619714). Only ~6 recessive cases were reported by 2019 (all p.Val626Ala except one p.Tyr360Ser); the dominant cohort added 16 individuals from 9 families in 2021, with further single/small reports since. No formal prevalence or incidence estimate exists for STT3A-CDG specifically. For context, CDG comprise ~200 disorders, of which PMM2-CDG is by far the most common (~60% of all CDG; incidence ~1 in 33,576 in North America/Europe).

"Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714)" — PMID: 39435313

"STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder" — PMID: 30701557

"Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs" — PMID: 40737785

Finding 6 — CDG natural history: multisystem disease with early-childhood mortality risk

In a Frontiers in CDG Consortium (FCDGC) natural-history cohort of 37 deceased CDG patients, all presented with multisystem features including neurological involvement; the majority died within the first three years of life, and about one-third died of cardiopulmonary failure (others from neurological progression, sepsis, or respiratory infection). CDG frequently cause coagulation abnormalities (antithrombin, protein C, factor XI deficiencies) with both bleeding and thrombosis risk. CDG prevalence in childhood epilepsy cohorts is notable (~4.4%), and transferrin isoelectric focusing is a recommended screen.

"The majority of patients involved in this study died during the first three years of life" — PMID: 39923392

"All of the patients presented with multisystem features with involvement of the neurological system" — PMID: 39923392

These mortality data are drawn from the broader CDG group; STT3A-CDG-specific mortality figures are not established.

Finding 7 — Functional models recapitulate the glycosylation defect

In S. cerevisiae, expressing STT3 carrying variants homologous to patient alleles induced defective glycosylation of carboxypeptidase Y in a wild-type strain and worsened the defect in the hypomorphic stt3-7 strain, supporting a dominant pathomechanism. CRISPR-Cas9 heterozygous-knockdown zebrafish modeling p.Asp167Tyr reproduced patient-like phenotypes: craniofacial dysmorphology (increased eye distance, altered ceratohyal angle), reduced mineralized bone, and abnormal locomotion/developmental delay. Patient fibroblasts and HeLa/HEK293T systems show hypoglycosylation of STT3A-specific reporters that is rescued by wild-type STT3A cDNA.

"expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain" — PMID: 34653363

"Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology" — PMID: 39891251

Finding 8 — Downstream consequence: selective hypoglycosylation and destabilization of specific glycoproteins

Selective exo-enzymatic labeling of STT3A/STT3B-deficient cells showed reduced cell-surface abundance of the insulin receptor and IGF-1 receptor (IGF-1R) when N-glycosylation was selectively impaired, linking OST subunit loss to defective receptor tyrosine kinase processing — a plausible molecular driver of the growth and skeletal phenotypes. Clinically, an STT3A-CDG patient exhibited hypoglycosylated von Willebrand Factor and undetectable Factor VIII, demonstrating that hypoglycosylation of specific STT3A-dependent substrates produces measurable protein deficiencies.

"We show reduced abundance of two canonical tyrosine receptor kinases - the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) - at the cell surface" — PMID: 31101650

"VWF in our patient's plasma is present in a mildly hypoglycosylated form" — PMID: 30701557

Finding 9 — Diagnosis by type I transferrin screen followed by molecular sequencing; no dietary therapy available

STT3A-CDG produces a CDG type I serum transferrin pattern (loss of whole N-glycans → increased di-/a-sialotransferrin) detectable by transferrin isoelectric focusing (TIEF), HPLC, or capillary electrophoresis; confirmation requires exome/genome or targeted STT3A sequencing. Because STT3A-CDG is an ER assembly/transfer (CDG-I) defect rather than a Golgi galactosylation defect, dietary therapies effective in specific CDG types (PGM1-CDG galactose; MPI-CDG mannose; TMEM165-CDG galactose) are not applicable; no disease-specific or curative therapy exists, and management is supportive/multidisciplinary.

"a type I carbohydrate deficient transferrin pattern" — PMID: 30701557

"Additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing" — PMID: 23842455

"There are >100 CDGs, but only specific types are treatable" — PMID: 28323990

Finding 10 — Ontology and inheritance annotations

Comprehensive ontology anchors are provided in the annotation tables below (Section 7 and the Ontology Appendix). The gene product identity and musculoskeletal features are supported by:

"STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation" — PMID: 34653363

"variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features" — PMID: 34653363

Finding 11 — gnomAD constraint metrics confirm strong missense and LOF intolerance

gnomAD (GRCh38; gene ENSG00000134910; chr11:125,591,712–125,625,215) constraint for STT3A: pLI = 0.894, LOEUF (oe_lof_upper) = 0.508, observed/expected LoF = 0.381 (90% CI 0.290–0.508), missense Z = 4.78 (oe_mis = 0.624), synonymous Z = 0.96. The high pLI (~0.9) and low LOEUF indicate intolerance to loss-of-function; the very high missense Z-score (>3.09 threshold) indicates strong selection against missense changes. This population-genetic evidence independently corroborates both disease mechanisms — LOF intolerance underpins the recessive (biallelic loss) form, and severe missense constraint is consistent with the dominant active-site missense variants being deleterious.

Section-by-Section Report

1. Disease Information

STT3A-CDG is a Mendelian congenital disorder of glycosylation (CDG type Iw) caused by defective co-translational N-glycosylation. It is a multisystem disease dominated by neurodevelopmental and neuromuscular-skeletal features.

Key identifiers:

Resource	Identifier
MONDO	MONDO:0014270
OMIM (phenotype, AR)	#615596 (CDG type Iw, autosomal recessive)
OMIM (phenotype, AD)	#619714 (CDG type Iw, autosomal dominant)
OMIM (gene)	601134 (STT3A*)
HGNC	HGNC:30591
NCBI Gene	3703
Ensembl	ENSG00000134910
UniProt	P46977
Orphanet	Listed under STT3A-CDG / CDG-Iw

Synonyms / alternative names: CDG-Iw; CDG type Iw; congenital disorder of glycosylation type Iw; STT3A-CDG; oligosaccharyltransferase catalytic subunit STT3A deficiency.

Information source: The disease-level knowledge is derived from aggregated resources (OMIM, Orphanet) and small case series/case reports of individual patients, plus in vitro and model-organism functional studies. Given ultra-rarity, most clinical knowledge comes from published individual patient descriptions rather than EHR-scale or registry-scale datasets.

2. Etiology

Disease causal factors: STT3A-CDG is entirely genetic (Mendelian). It is caused by pathogenic variants in STT3A. Two causal mechanisms operate: - Autosomal recessive — biallelic loss-of-function/hypomorphic variants (e.g., homozygous p.Val626Ala; p.Tyr360Ser). - Autosomal dominant — heterozygous missense variants clustering in the catalytic active site acting through a dominant-negative mechanism (e.g., p.Asp167Tyr).

Genetic risk factors: The causal variants are themselves the risk determinants. STT3A is strongly constrained against both LOF (pLI 0.894) and missense (Z = 4.78) variation, consistent with pathogenicity of the reported alleles.

Environmental risk factors: None established. As a Mendelian glycosylation defect, disease onset is determined by genotype, not exposure.

Protective factors: No genetic or environmental protective factors are established. Mechanistically, the partial functional redundancy provided by the paralogous STT3B/OST-B complex (which glycosylates some sites skipped by STT3A) may buffer the loss of STT3A activity and could contribute to phenotypic variability, but this is a mechanistic inference rather than a documented protective factor.

Gene–environment interactions: None documented for STT3A-CDG.

3. Phenotypes

Phenotypes differ between the recessive and dominant forms. All are congenital/early-onset; severity is variable; the neurodevelopmental component is generally non-progressive but with lifelong disability.

Phenotype	Type	HPO term	Form / frequency	Onset
Seizures	Clinical sign	HP:0001250	Recessive (core)	Neonatal/infantile
Intellectual disability	Behavioral/cognitive	HP:0001249	Both; ~50% in dominant	Childhood
Global developmental delay	Clinical sign	HP:0001263	Both (core)	Infantile
Hypotonia	Clinical sign	HP:0001252	Recessive	Neonatal
Failure to thrive / feeding problems	Clinical sign	HP:0001508	Recessive	Neonatal/infantile
Short stature	Physical	HP:0004322	Dominant	Childhood
Macrocephaly	Physical	HP:0000256	Dominant	Childhood
Skeletal anomalies/dysplasia	Physical	HP:0000924	Dominant	Childhood
Increased muscle tone / cramps	Clinical sign	HP:0001276	Dominant	Childhood
Dysmorphic facial features	Physical	HP:0001999	Dominant	Congenital
Abnormal bleeding / coagulopathy	Laboratory/clinical	HP:0001928 / HP:0000132	Recessive (subset)	Variable
Factor VIII deficiency	Laboratory	HP:0003125	Recessive (subset)	Variable
Abnormal type I transferrin	Laboratory	— (CDG biomarker)	Both	Congenital

Quality of life impact: Intellectual disability, seizures, and (in the dominant form) skeletal disease and muscle cramps materially impair daily functioning, communication, and mobility. Coagulopathy in the recessive form carries bleeding risk. Disease-specific QoL instrument data (EQ-5D/SF-36/PROMIS) are not available for this ultra-rare disorder.

4. Genetic / Molecular Information

Causal gene: STT3A (chr11q24.1; OMIM *601134). Encodes the catalytic subunit of the OST-A complex.

Pathogenic variants (reported):

Variant (protein)	cDNA	Type	Inheritance	Mechanism
p.Val626Ala	c.1877T>C	Missense	Autosomal recessive (homozygous)	Loss/reduction of catalytic function
p.Tyr360Ser	—	Missense	Autosomal recessive	Loss of function; coagulopathy
p.Asp167Tyr	—	Missense (active site)	Autosomal dominant	Dominant-negative (zebrafish-validated)
Multiple active-site missense	—	Missense	Autosomal dominant	Dominant-negative (16 individuals/9 families)

Variant classification: Reported disease alleles are classified pathogenic/likely pathogenic per ACMG/AMP; the strong missense constraint (Z = 4.78) and active-site clustering support functional deleteriousness.

Allele frequency: Pathogenic variants are absent or ultra-rare in gnomAD, consistent with a severe Mendelian disorder.

Somatic vs germline: All reported variants are germline (inherited or de novo).

Functional consequence: Recessive alleles = loss of function/hypomorphic; dominant active-site alleles = dominant-negative (mutant subunit incorporated into OST-A poisons complex activity).

Modifier genes: No formal modifiers established. The paralog STT3B (OST-B complex) provides partial substrate redundancy and is a plausible biological modifier of severity (mechanistic inference).

Epigenetic information: No disease-specific DNA methylation or histone-modification data available.

Chromosomal abnormalities: None associated; STT3A-CDG is a single-gene disorder, not a copy-number/structural disorder.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents are implicated in STT3A-CDG. It is a purely genetic disorder.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A pathogenic STT3A variant (biallelic LOF in the recessive form, or a heterozygous active-site missense variant in the dominant form) alters the catalytic subunit of the OST-A complex.
In the dominant form, the mutant subunit is incorporated into the OST-A complex and acts as a dominant-negative, reducing complex activity below the ~50% expected from simple haploinsufficiency (inferred from active-site clustering and yeast data). In the recessive form, biallelic loss directly reduces OST-A catalytic output.
Reduced OST-A activity impairs co-translational transfer of the Glc₃Man₉GlcNAc₂ glycan from dolichol-PP onto N-X-S/T sequons of nascent polypeptides at the Sec61 translocon.
This results in substrate-selective hypoglycosylation — a subset of glycoproteins (those glycosylated preferentially by STT3A during translation) carry fewer N-glycans. The paralogous STT3B/OST-B complex partially compensates by post-translocationally glycosylating some skipped sites, limiting but not preventing the defect (branch: redundancy modulates severity).
Hypoglycosylation destabilizes or reduces the folding/surface expression of affected glycoproteins — demonstrated for von Willebrand Factor and Factor VIII (patient plasma) and for the insulin receptor and IGF-1R (cell models).
Loss of specific glycoprotein functions leads to the clinical phenotype:
Reduced RTK (insulin receptor, IGF-1R) surface expression → contributes to growth failure and skeletal/short-stature phenotype (inferred mechanistic link).
Hypoglycosylated coagulation factors (vWF, FVIII) → produces bleeding tendency/coagulopathy.
Impaired glycosylation of neuronal/CNS glycoproteins → produces seizures, developmental delay, intellectual disability, hypotonia (mechanism inferred; the precise CNS substrates are not fully mapped).
The abnormal transferrin glycoform (loss of whole N-glycans) produces the diagnostic type I serum transferrin pattern used for screening.

Molecular pathways / processes: Protein N-linked glycosylation via oligosaccharyltransferase (GO:0006487); dolichyl-diphosphooligosaccharide–protein glycotransferase activity (GO:0004579); co-translational protein N-linked glycosylation (GO:0018279). Downstream: receptor tyrosine kinase signaling (insulin/IGF-1R), coagulation cascade.

Protein dysfunction: Loss of function (recessive) or dominant-negative (dominant active-site variants) of the STT3A catalytic subunit; secondary misfolding/destabilization of hypoglycosylated client glycoproteins.

Subcellular site: Endoplasmic reticulum membrane (GO:0005789), adjacent to the Sec61 translocon.

Cell types / GO terms: Broadly all secretory cells, with clinically prominent effects in neurons (CL:0000540), osteoblasts/chondrocytes (skeletal), and hepatocytes/endothelium (coagulation-factor synthesis).

7. Anatomical Structures Affected

Level	Structure	Ontology	Manifestation
Organ/system	Nervous system	UBERON:0001016	Seizures, DD, ID, hypotonia
Organ	Brain	UBERON:0000955	Neurodevelopmental impairment
System	Musculoskeletal	—	Short stature, skeletal anomalies, macrocephaly, muscle cramps
System	Hematologic/coagulation	—	Bleeding tendency, FVIII/vWF deficiency (recessive subset)
System	Growth/endocrine	—	Failure to thrive, growth failure
Tissue	Nervous tissue	—	CNS dysfunction
Tissue	Bone/cartilage	—	Reduced mineralization (zebrafish), skeletal dysplasia
Cell	Neuron	CL:0000540	Impaired glycoprotein processing
Subcellular	ER membrane	GO:0005789	Site of defective glycosylation

Lateralization: Manifestations are systemic/bilateral, not lateralized.

8. Temporal Development

Onset: Congenital/neonatal-to-infantile. The type I transferrin abnormality is present from birth; seizures, hypotonia, and feeding problems present in infancy in the recessive form; skeletal/growth and dysmorphic features become apparent in childhood in the dominant form.
Onset pattern: Chronic, insidious (developmental).
Progression: The neurodevelopmental disability is generally stable/non-progressive but lifelong; skeletal features evolve with growth. No defined disease "stages."
Disease course: Chronic, lifelong. Within the broader CDG group, the most severe/multisystem presentations carry early-childhood mortality risk (majority of deceased CDG patients died in the first three years — PMID: 39923392), though STT3A-CDG-specific survival data are not established.
Critical periods / remission: No spontaneous remission; early developmental and rehabilitative intervention is the window of opportunity.

9. Inheritance and Population

Epidemiology: Ultra-rare; ~6 recessive cases reported by 2019 and 16 dominant individuals (9 families) in 2021, with subsequent small reports. No formal prevalence/incidence estimate exists for STT3A-CDG. For context, PMM2-CDG (the most common CDG) has an incidence of ~1 in 33,576 in North America/Europe and accounts for ~60% of all CDG (PMID: 40737785).
Inheritance: Both autosomal recessive (OMIM #615596) and autosomal dominant (OMIM #619714).
Penetrance / expressivity: Variable expressivity is documented (e.g., ~50% of dominant-form individuals have intellectual disability); penetrance appears high for the biochemical phenotype but variable for specific clinical features.
Anticipation: Not applicable (no repeat expansion).
Founder effects / consanguinity: The recurrent recessive p.Val626Ala allele appears in multiple unrelated recessive cases; consanguinity is relevant to recessive presentations, as with most rare AR disorders. No formally described founder population.
Carrier frequency: Not established; pathogenic alleles are ultra-rare in gnomAD.
Demographics: No specific ethnic predilection, geographic clustering, or sex bias reported; both sexes affected.

10. Diagnostics

Biochemical screening: Serum transferrin analysis by isoelectric focusing (TIEF), HPLC, or capillary electrophoresis shows a CDG type I pattern (increased di- and a-sialotransferrin from loss of whole N-glycans).

"a type I carbohydrate deficient transferrin pattern" — PMID: 30701557

Molecular confirmation: Exome/genome sequencing or targeted STT3A sequencing is required for definitive diagnosis; some OST-subunit CDG may be missed by transferrin analysis alone.

"Additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing" — PMID: 23842455

Ancillary labs: Coagulation studies (FVIII, vWF) in patients with bleeding; these may reveal hypoglycosylated coagulation factors.

Genetic testing modalities: WES and WGS are both high-yield; targeted single-gene testing or CDG/neurodevelopmental gene panels can be used once biochemically suspected. CMA, karyotyping, FISH, mtDNA testing, and repeat-expansion testing are not applicable (single-gene point-variant disorder).

Differential diagnosis: Other CDG type I disorders (PMM2-CDG, ALG-group, DDOST-CDG, RPN1-CDG, STT3B-CDG), which share the type I transferrin pattern and neurodevelopmental phenotype. Transferrin protein variants can produce misleading patterns (PMID: 37876147); neuraminidase treatment helps resolve these. Diagnosis is refined by identifying the causal gene.

Screening: No routine newborn screening for STT3A-CDG. TIEF has been proposed as a useful screen in childhood epilepsy cohorts given the ~4.4% CDG prevalence in that population (PMID: 34440401).

11. Outcome / Prognosis

Survival/mortality: No STT3A-CDG-specific survival statistics. Within the CDG group broadly, severe multisystem presentations carry substantial early-childhood mortality (majority of deceased CDG patients died in the first three years, ~one-third from cardiopulmonary failure — PMID: 39923392).
Morbidity/disability: Lifelong neurodevelopmental disability (intellectual disability, seizures), skeletal disease and short stature (dominant form), and bleeding risk (recessive subset).
Complications: Seizure-related morbidity, feeding/growth failure, bleeding events, orthopedic complications.
Prognostic factors: Genotype (recessive vs dominant form; residual OST-A activity), presence of coagulopathy, and severity of neurological involvement. No validated prognostic biomarkers beyond the biochemical/genetic diagnosis.
Recovery potential: No reversal of the underlying defect; supportive care and rehabilitation can improve function.

12. Treatment

There is no disease-specific or curative therapy for STT3A-CDG. Management is supportive and multidisciplinary:

Pharmacotherapy: Symptomatic — anti-seizure medications for epilepsy; standard management of feeding/growth issues; hematologic management (e.g., factor replacement/DDAVP considerations) for bleeding in the recessive subset. (NCIT: anticonvulsant therapy; supportive care.)
Dietary sugar therapies do NOT apply. Galactose (PGM1-CDG, TMEM165-CDG) and mannose (MPI-CDG) are effective only in specific CDG subtypes; STT3A-CDG is an ER glycan-transfer (CDG-I) defect not amenable to these.

"There are >100 CDGs, but only specific types are treatable" — PMID: 28323990

Advanced/experimental therapeutics: No approved gene, cell, or RNA-based therapy; no STT3A-CDG-specific clinical trials identified.
Supportive/rehabilitative care: Physical, occupational, and speech therapy; developmental support; orthopedic and nutritional management; multidisciplinary metabolic clinic follow-up.
Personalized medicine: Genotype (dominant vs recessive) informs genetic counseling and family planning but not, at present, a targeted pharmacologic strategy.

13. Prevention

Primary prevention: Not possible for a Mendelian disorder beyond reproductive planning. Genetic counseling is central — recurrence risk is 25% for AR families and up to 50% for AD transmission (with de novo cases in the dominant form).
Secondary prevention: Early biochemical (TIEF) and molecular diagnosis enables early developmental intervention and complication surveillance (seizures, bleeding, growth).
Tertiary prevention: Anticipatory management of seizures, feeding/growth, bleeding risk, and orthopedic complications.
Genetic screening: Carrier testing and prenatal/preimplantation genetic testing are available for families with a known pathogenic variant. No population-based newborn screening exists.
Immunization/public health/environmental: Not applicable.

14. Other Species / Natural Disease

Taxonomy / orthologs: STT3A is deeply conserved. Orthologs and functional equivalents exist in mouse (Stt3a), zebrafish (stt3a), and the single STT3 gene in S. cerevisiae (yeast). These orthologs are central to disease modeling (below).
Natural disease in other species: No naturally occurring animal disease specifically attributed to STT3A variants is documented (no OMIA entry noted for STT3A-CDG). Disease knowledge in animals comes from engineered models, not spontaneous disease.
Comparative biology / conservation: The strong evolutionary conservation of STT3 catalytic function — from yeast to human — underlies the ability to model patient variants in S. cerevisiae and zebrafish and validates conservation of the disease mechanism.
Transmission / zoonosis: Not applicable (non-infectious genetic disorder).

15. Model Organisms

Model	Type	Genetic strategy	Phenotype recapitulation	Reference
S. cerevisiae (yeast)	Cellular/in vivo	Express STT3 with patient-homologous variants; hypomorphic stt3-7 background	Defective glycosylation of carboxypeptidase Y; dominance demonstrated	PMID: 34653363
Zebrafish (Danio rerio)	Vertebrate	CRISPR-Cas9 heterozygous knockdown modeling p.Asp167Tyr	Craniofacial dysmorphology, reduced mineralized bone, abnormal locomotion/developmental delay — mirrors patient features	PMID: 39891251
Human patient fibroblasts	In vitro	Endogenous patient variants	Hypoglycosylation of STT3A-specific reporters; rescued by WT STT3A cDNA	PMID: 23842455
HeLa / HEK293T	In vitro cell line	STT3A/STT3B knockout; reporter constructs	Isoform-specific glycosylation defects; RTK surface loss	PMID: 31101650; PMID: 29282902

"expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain" — PMID: 34653363

"Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology" — PMID: 39891251

Model limitations: Yeast lacks the STT3A/STT3B paralog split and multicellular phenotypes; zebrafish knockdown models capture skeletal/craniofacial and behavioral features but not the full neurodevelopmental/coagulation spectrum. No mouse knock-in model of a patient variant is established in the reviewed literature.

Mechanistic Model / Interpretation

 STT3A pathogenic variant
  /                    \
       Biallelic LOF                Heterozygous active-site
       (recessive)                  missense (dominant)
    |                             |
    |                    mutant subunit incorporated
    |                    into OST-A complex
    |                             |
    v                             v
Reduced OST-A catalytic activity (dominant-negative in AD)
          |
          v
   Impaired co-translational transfer of Glc3Man9GlcNAc2
   onto N-X-S/T sequons at the Sec61 translocon (ER membrane)
          |
      [ STT3B/OST-B partial rescue — modulates severity ]
          |
          v
      Substrate-selective HYPOGLYCOSYLATION of STT3A clients
      /            |              \
     v             v               v
   Transferrin      vWF / FVIII      Insulin-R / IGF-1R
   (type I CDT      hypoglycosylated  reduced surface
   biomarker)       & destabilized    expression
     \            |               /
      v           v              v
       DIAGNOSTIC     BLEEDING        GROWTH FAILURE /
       SIGNATURE      TENDENCY        SKELETAL PHENOTYPE
          |
          v
   + Impaired glycosylation of CNS glycoproteins (inferred)
          |
          v
   SEIZURES, DEVELOPMENTAL DELAY, INTELLECTUAL DISABILITY, HYPOTONIA

Upstream vs downstream: The upstream lesion is the STT3A variant and consequent reduction of OST-A catalytic activity. Immediately downstream is substrate-selective hypoglycosylation, buffered by STT3B redundancy. Further downstream are the destabilization of specific client glycoproteins (transferrin — diagnostic; vWF/FVIII — coagulopathy; insulin-R/IGF-1R — growth/skeletal), and finally the clinical manifestations. The CNS phenotype is the least mechanistically resolved link (which specific neuronal glycoproteins mediate seizures and cognition remains inferred rather than demonstrated). Population-genetic constraint (pLI 0.894; missense Z 4.78) independently confirms that both loss-of-function and missense perturbation of this gene are under strong purifying selection — the molecular-genetic expectation for a dosage-sensitive, dominantly-and-recessively acting disease gene.

Evidence Base

PMID	Title (abbreviated)	Role in this report
23842455	Mutations in STT3A and STT3B cause two CDGs	Landmark: identifies STT3A as OST catalytic subunit; original recessive p.Val626Ala; sequencing needed for diagnosis
34653363	Active site variants in STT3A cause a dominant type I CDG	Landmark: defines the autosomal-dominant form (16 individuals/9 families); active-site clustering; yeast dominance
39891251	Heterozygous STT3A variation → dominant CDG; zebrafish validation	Confirms dominant inheritance; zebrafish recapitulation of p.Asp167Tyr
30701557	Factor VIII and vWF deficiency in STT3A-CDG	Recessive core phenotype; coagulopathy; hypoglycosylated vWF; OMIM #615596
31433728	N-glycosylation not directly coupled to translocation	STT3A translocon-coupled N→C scanning mechanism
28860277	DC2 and KCP2 mediate OST–translocon interaction	STT3A localization adjacent to translocon; co-translational glycosylation
25460543	Cotranslational and posttranslocational N-glycosylation	STT3B redundancy (glycosylates STT3A-skipped sites)
25135935	Oxidoreductase activity for cysteine-proximal sites	STT3B/MagT1 mechanism explaining substrate selectivity
31101650	Selective inhibition of N-glycosylation impairs RTK processing	Downstream: reduced insulin-R/IGF-1R surface abundance
39435313	Metabolomic profiling reveals AD CDG-Iw	OMIM #619714 for the dominant form
40737785	Incidence/prevalence of PMM2-CDG	Contextualizes STT3A-CDG rarity within CDG
39923392	Causes of mortality in CDG	CDG natural history/mortality context
34440401	CDG prevalence in childhood epilepsy; TIEF	TIEF as screening tool; CDG in epilepsy cohorts
28323990	Galactose in TMEM165-CDG	Only specific CDGs are treatable → not STT3A-CDG
37876147	Misleading transferrin variants	Diagnostic pitfall in transferrin screening
29282902	GFP mutant to monitor STT3B glycosylation	Isoform-specific reporter methodology

Evidence-source types: Human clinical (case series/reports: 23842455, 34653363, 30701557, 39435313); model organism (yeast 34653363; zebrafish 39891251); in vitro/cell biology (31101650, 25460543, 25135935, 28860277, 31433728, 29282902); computational/population-genetic (gnomAD constraint — Finding 11).

Limitations and Knowledge Gaps

Ultra-rarity limits epidemiology. No prevalence, incidence, penetrance quantification, carrier frequency, or survival statistics exist specifically for STT3A-CDG. Mortality data cited are from the pan-CDG group, not STT3A-CDG.
Genotype–phenotype correlation is immature. The number of reported patients (~a few dozen across both forms) is too small to define robust correlations between specific alleles/residual OST-A activity and clinical severity.
The CNS mechanistic link is inferred, not demonstrated. The specific neuronal glycoproteins whose hypoglycosylation causes seizures and cognitive impairment have not been mapped for STT3A-CDG.
No mammalian knock-in model of a patient variant was found in the reviewed literature; the mouse phenotype for patient alleles is undefined.
No therapeutic pipeline. No approved or trial-stage disease-specific therapy exists; the disorder is currently supportive-care only.
Dominant-negative mechanism is supported by yeast/zebrafish and active-site clustering but not fully dissected biochemically in the human OST-A complex (e.g., stoichiometry of mutant incorporation and quantitative activity reduction).
Ontology annotations (HPO/GO/UBERON/CL/CHEBI) are assembled from literature-reported features and standard mappings rather than curated disease-ontology cross-references, and should be verified against current MONDO/HPO releases.

Proposed Follow-up Experiments / Actions

Establish an STT3A-CDG patient registry within the FCDGC/GLYCEN networks to collect natural-history, survival, and genotype–phenotype data prospectively.
Generate a knock-in mouse (or refine the zebrafish) carrying recurrent alleles (p.Val626Ala recessive; p.Asp167Tyr dominant) to model the neurodevelopmental, skeletal, and coagulation phenotypes and to serve as a preclinical therapeutic platform.
Map the STT3A-dependent glycoproteome of neural tissue (glycoproteomics/glycomics on patient iPSC-derived neurons and organoids) to identify the specific hypoglycosylated CNS substrates driving seizures and cognitive impairment.
Quantify the dominant-negative effect biochemically by reconstituting OST-A complexes with defined ratios of wild-type and mutant STT3A and measuring transfer activity and complex assembly.
Systematic coagulation-factor glycosylation study across STT3A-CDG patients to determine the frequency and severity of the vWF/FVIII phenotype and inform bleeding-risk management.
Explore proteostasis/chaperone modulators (e.g., ER quality-control or STT3B-upregulation strategies) as candidate therapeutic approaches leveraging the STT3B redundancy branch.
Refine and validate the ontology annotation set (HPO frequencies, CL/UBERON/CHEBI/NCIT terms) against the latest MONDO, HPO, and Orphanet releases for knowledge-base ingestion.

Ontology Appendix

Category	Term	ID
Disease	STT3A-CDG	MONDO:0014270; OMIM #615596 (AR), #619714 (AD)
Gene	STT3A	HGNC:30591; NCBI Gene 3703; UniProt P46977; OMIM *601134
Biological process	Protein N-linked glycosylation via OST	GO:0006487
Molecular function	Dolichyl-diphosphooligosaccharide–protein glycotransferase	GO:0004579
Biological process	Co-translational protein N-linked glycosylation	GO:0018279
Cellular component	Endoplasmic reticulum membrane	GO:0005789
Anatomy	Nervous system	UBERON:0001016
Anatomy	Brain	UBERON:0000955
Cell type	Neuron	CL:0000540
Phenotype	Seizure	HP:0001250
Phenotype	Intellectual disability	HP:0001249
Phenotype	Global developmental delay	HP:0001263
Phenotype	Hypotonia	HP:0001252
Phenotype	Failure to thrive	HP:0001508
Phenotype	Short stature	HP:0004322
Phenotype	Macrocephaly	HP:0000256
Phenotype	Abnormal skeletal morphology	HP:0000924
Phenotype	Hypertonia	HP:0001276
Phenotype	Factor VIII deficiency	HP:0003125
Chemical	Dolichol	CHEBI:23509
Chemical	Asparagine	CHEBI:22653
Chemical	N-acetylglucosamine	CHEBI:506227

Report compiled from 11 confirmed findings and 33 reviewed papers across a 5-iteration autonomous investigation. Evidence sources span human clinical case series, yeast and zebrafish model organisms, in vitro cell biology, and computational population-genetic constraint analysis.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	31
Quoted claims found in source	31
Quoted claims not found in source	0
References weighed for topical relevance	16
On topic	9
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	25
Resolved	23
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	22
Terms named correctly	4
Terms named as a different term	13
Terms whose name is worth a second look	5

Terms the report names something else

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:

MONDO:0014270 (3 mentions) - the report calls it "MONDO"; MONDO calls it STT3A-congenital disorder of glycosylation
HP:0001250 (2 mentions) - the report calls it "Clinical sign", "Seizure"; HP calls it Seizure
HP:0001249 (2 mentions) - the report calls it "Behavioral/cognitive", "Intellectual disability"; HP calls it Intellectual disability
HP:0001263 (2 mentions) - the report calls it "Clinical sign", "Global developmental delay"; HP calls it Global developmental delay
HP:0001252 (2 mentions) - the report calls it "Clinical sign", "Hypotonia"; HP calls it Hypotonia
HP:0001508 (2 mentions) - the report calls it "Clinical sign", "Failure to thrive"; HP calls it Failure to thrive
HP:0004322 (2 mentions) - the report calls it "Physical", "Short stature"; HP calls it Short stature
HP:0000256 (2 mentions) - the report calls it "Physical", "Macrocephaly"; HP calls it Macrocephaly
HP:0000924 (2 mentions) - the report calls it "Physical", "Abnormal skeletal morphology"; HP calls it Abnormality of the skeletal system
HP:0001276 (2 mentions) - the report calls it "Clinical sign", "Hypertonia"; HP calls it Hypertonia
HP:0001999 (1 mention) - the report calls it "Physical"; HP calls it Abnormal facial shape
HP:0003125 (2 mentions) - the report calls it "Laboratory", "Factor VIII deficiency"; HP calls it Reduced factor VIII activity
CHEBI:23509 (1 mention) - the report calls it "Dolichol"; CHEBI calls it cysteine derivative

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0018279 (obsolete protein N-linked glycosylation via asparagine) (2 mentions) - replaced by GO:0006487

Terms whose name is worth a second look

The 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:

GO:0006487 (2 mentions) - the report calls it "Protein N-linked glycosylation via OST"; GO calls it protein N-linked glycosylation
GO:0004579 (2 mentions) - the report calls it "Dolichyl-diphosphooligosaccharide–protein glycotransferase"; GO calls it dolichyl-diphosphooligosaccharide-protein glycotransferase activity
GO:0018279 (2 mentions) - the report calls it "Co-translational protein N-linked glycosylation"; GO calls it obsolete protein N-linked glycosylation via asparagine
GO:0005789 (3 mentions) - the report calls it "ER membrane", "Endoplasmic reticulum membrane"; GO calls it endoplasmic reticulum membrane, and lists "ER membrane" among its other names
CHEBI:506227 (1 mention) - the report calls it "N-acetylglucosamine"; CHEBI calls it N-acetyl-D-glucosamine

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001250 - called "Clinical sign", "Seizure"
HP:0001249 - called "Behavioral/cognitive", "Intellectual disability"
HP:0001263 - called "Clinical sign", "Global developmental delay"
HP:0001252 - called "Clinical sign", "Hypotonia"
HP:0001508 - called "Clinical sign", "Failure to thrive"
HP:0004322 - called "Physical", "Short stature"
HP:0000256 - called "Physical", "Macrocephaly"
HP:0000924 - called "Physical", "Abnormal skeletal morphology"
HP:0001276 - called "Clinical sign", "Hypertonia"
HP:0003125 - called "Laboratory", "Factor VIII deficiency"
GO:0005789 - called "ER membrane", "Endoplasmic reticulum membrane"

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Subtypes

Discussions and Knowledge Gaps

Pathophysiology

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Phenotypes

Genetic Associations

Biochemical Markers

Diagnosis

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Experimental Models

Animal Models

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References & Deep Research

References

Deep Research

STT3A-Congenital Disorder of Glycosylation (STT3A-CDG): Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1 — STT3A-CDG is caused by defects in the catalytic subunit of the OST-A complex

Finding 2 — STT3A-CDG has both autosomal recessive and autosomal dominant forms

Finding 3 — Core clinical phenotype: neurodevelopmental impairment, seizures, and a type I transferrin pattern

Finding 4 — Mechanism: STT3A mediates co-translational N-glycosylation coupled to the ER translocon

Finding 5 — Ultra-rare with two OMIM entries; part of the broader CDG group

Finding 6 — CDG natural history: multisystem disease with early-childhood mortality risk

Finding 7 — Functional models recapitulate the glycosylation defect

Finding 8 — Downstream consequence: selective hypoglycosylation and destabilization of specific glycoproteins

Finding 9 — Diagnosis by type I transferrin screen followed by molecular sequencing; no dietary therapy available

Finding 10 — Ontology and inheritance annotations

Finding 11 — gnomAD constraint metrics confirm strong missense and LOF intolerance

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Ontology Appendix

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently