EDEM3-Congenital Disorder of Glycosylation

Mendelian MONDO:0030423 Pathograph 10 Show in embeddings browser hereditary disease congenital disorder of glycosylation

EDEM3-CDG (congenital disorder of glycosylation type 2v) is an autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in EDEM3, an endoplasmic reticulum alpha-1,2-mannosidase of the glycoside hydrolase 47 family. EDEM3 trims mannose from high-mannose N-glycans, chiefly Man8GlcNAc2 isomer B to Man7-5GlcNAc2, which marks misfolded glycoproteins for ER-associated degradation (ERAD); it also trims total cellular glycoproteins. Twelve affected individuals from seven families have been described, all with developmental delay or intellectual disability and speech delay, half with hypotonia, and most with mild facial dysmorphism (hypoplastic alae nasi, thin upper lip, increased nasal height). Brain MRI was normal where performed. Unlike most CDGs, transferrin isoform screening is normal; diagnosis rests on a distinctive plasma high-mannose N-glycan profile with reduced Man3-Man7 species, a raised Man9:Man3 ratio and a reduced Man3:Man4 ratio. Patient cells also show blunted PERK induction under ER stress. How loss of mannose trimming leads to the neurodevelopmental phenotype is not known.

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1
Inheritance
5
Pathophys.
15
Phenotypes
3
Gaps
10
Pathograph
1
Genes
3
Variants
1
Medical Actions
2
Differentials
2
Models
1
Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
Affected individuals are homozygous or compound heterozygous for EDEM3 variants, and unaffected parents are heterozygous carriers. In one family homozygosity arose from maternal uniparental isodisomy of chromosome 1.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34143952 SUPPORT Human Clinical
"Sanger sequencing showed that the affected individuals were either homozygous or compound heterozygous for the identified EDEM3 variants. The unaffected parents were all heterozygous carriers."
Biallelic variants in affected children with carrier parents establish recessive inheritance.
PMID:34143952 SUPPORT Human Clinical
"In family 4, a bi-allelic nonsense variant, c.940A>T (p.Arg314∗), was found, resulting from maternal uniparental isodisomy of chromosome 1."
Uniparental isodisomy as an alternative route to homozygosity.
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Discussions and Knowledge Gaps

3
How does loss of EDEM3 mannose trimming cause developmental delay and intellectual disability when brain MRI is normal?
KNOWLEDGE GAP edem3_cdg_neurodevelopmental_mechanism
Attached to
pathophysiology#Deficient ER Mannose Trimming phenotypes#Neurodevelopmental Delay
Every mechanistic study of EDEM3 deficiency has used fibroblasts, lymphoblastoid cells, plasma or cancer cell lines. No neural cell or organoid model exists, and the knockout mouse has no obvious neurological phenotype, so the causal edges from the glycan defect to the developmental phenotypes rest on genetic association alone. Measuring ERAD substrate clearance and ER stress in patient-derived neurons would test whether slower ERAD, altered stress signalling, or a change in the glycosylation of specific neural glycoproteins is responsible.
Does EDEM3 loss blunt or activate the unfolded protein response?
KNOWLEDGE GAP edem3_cdg_upr_direction
Attached to
pathophysiology#Blunted PERK-Mediated Unfolded Protein Response
Patient lymphoblastoid cells show blunted PERK induction under tunicamycin, which the authors read either as an impaired response or as increased capacity to clear misfolded protein. EDEM3 knockout hepatoma cells instead show ER stress and apoptosis. The comparison uses three patient cell lines and a cancer cell line, so the direction in the tissues that matter is unknown.
Why does the Edem3 knockout mouse reproduce most of the human glycan defect but not the neurodevelopmental phenotype or the reduced Man3:Man4 ratio?
HUMAN MODEL MISMATCH edem3_cdg_mouse_mismatch
Attached to
pathophysiology#Altered Plasma and Cellular High-Mannose N-Glycan Profile
The mouse shares the reduced Man5:Man9, Man6:Man9 and Man7:Man9 ratios but not the reduced Man3:Man4 ratio, and its largest change is at a different trimming step, which the authors attribute to a difference in substrate specificity between human and mouse EDEM3. It shows only reduced brain and body weight. Whether the missing neurological phenotype reflects species differences in EDEM3 substrates, compensation by EDEM1, or insufficiently detailed behavioural testing is untested.
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Pathophysiology

5
Biallelic EDEM3 Loss-of-Function Variants
Mostly protein-truncating EDEM3 variants (frameshift, nonsense and splice donor) that trigger nonsense-mediated mRNA decay, leaving about 17-18% of normal transcript and no detectable EDEM3 protein in patient cells. One family carries two missense variants in the GH47 mannosidase domain. EDEM1, which performs an overlapping trimming step, is not upregulated.
Genetic context EDEM3 hgnc:16787 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns EDEM3 (hgnc:16787). hgnc:16787 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Deficient ER Mannose Trimming
Show evidence (3 references)
PMID:34143952 SUPPORT In Vitro
"and could be rescued with cycloheximide (CHX), an inhibitor of NMD, suggesting that the bi-allelic c.1859del frameshift variant triggers NMD"
Cycloheximide rescue of EDEM3 mRNA in patient lymphoblastoid cells shows the frameshift allele is degraded by nonsense-mediated decay.
PMID:34143952 SUPPORT In Vitro
"These demonstrated the absence of EDEM3 in individual IV-4 (family 1) and individual II-1 (family 3) consistent with loss of function of EDEM3 (Figure 3C)."
No EDEM3 protein on immunoblot of patient fibroblasts.
PMID:34143952 SUPPORT In Vitro
"EDEM1 levels were at 97% of normal levels (p = 0.9373) in fibroblast cell lines from affected individuals (Figure 2C)."
The paralog EDEM1 is not upregulated to compensate.
Deficient ER Mannose Trimming
Without EDEM3, alpha-1,2-linked mannose is not trimmed from Man8GlcNAc2 isomer B to Man7-5GlcNAc2, and Man5GlcNAc2 is not trimmed to Man4GlcNAc2, with accumulation of Glc1Man5GlcNAc2 in patient fibroblasts. The authors suggest that this Man5 species may come from the lipid-linked oligosaccharide precursor rather than from trimming, which would imply an additional effect on precursor synthesis; this is speculative. In purified enzyme assays EDEM3 alone converts M8B to M7, M6 and M5 and is a major alpha-1,2-mannosidase for this second trimming step.
EDEM3 hgnc:16787 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EDEM3 (hgnc:16787). hgnc:16787 is a gene from the HUGO Gene Nomenclature Committee.
mannose trimming involved in glycoprotein ERAD pathway GO:1904382 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mannose trimming involved in glycoprotein ERAD pathway (GO:1904382). GO:1904382 is a biological process from the Gene Ontology. ↓ DECREASED
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity GO:0004571 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased mannosyl-oligosaccharide 1,2-alpha-mannosidase activity (GO:0004571). GO:0004571 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
EDEM3-CDG patient fibroblasts with EDEM3 complementation PRIMARY CELL CULTURE Patient fibroblasts fail to trim M8B and M5 during the chase.
Downstream
Altered Plasma and Cellular High-Mannose N-Glycan Profile
Impaired Glycoprotein ER-Associated Degradation Inferred for patients. Mannose trimming generates the glycan signal that targets misfolded glycoproteins for ERAD, and loss of EDEM1 and EDEM3 together delays ERAD in cultured cells, but degradation of ERAD substrates has not been measured in EDEM3-CDG patient cells.
Neurodevelopmental Delay The link from the glycan defect to the neurodevelopmental phenotype rests on genetic association only. The intervening cellular steps are unknown, no neural model of EDEM3 deficiency exists, and the authors state that the mechanism remains to be determined.
Blunted PERK-Mediated Unfolded Protein Response Proposed link. The authors connect the Glc1Man5GlcNAc2 accumulation seen in patient fibroblasts to an impaired unfolded protein response, and offer two readings of the blunted PERK induction: an impaired response, or an increased capacity to eliminate misfolded proteins. Neither has been tested.
Show evidence (3 references)
PMID:34698634 SUPPORT In Vitro
"Thus, EDEM3 is a major α1,2-mannosidase for the second step from M8B."
Purified-enzyme assays identify EDEM3 as the main enzyme for the step lost in patients.
PMID:34143952 SUPPORT In Vitro
"In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2."
A second trimming defect, at Man5GlcNAc2, in patient fibroblasts.
PMID:16431915 SUPPORT In Vitro
"Overexpression of EDEM3 also greatly stimulates mannose trimming not only from misfolded alpha1-AT null (Hong Kong) but also from total glycoproteins"
EDEM3 trims total cellular glycoproteins, not only ERAD substrates, which explains why its loss changes the global N-glycan profile.
Altered Plasma and Cellular High-Mannose N-Glycan Profile
Secreted and cellular glycoproteins carry fewer trimmed high-mannose glycans. Patient plasma shows reduced Man3-Man7 species with normal or mildly raised Man8 and Man9, giving reduced Man5:Man9, Man6:Man9, Man7:Man9 and Man3:Man4 ratios and a raised Man9:Man3 ratio. Transferrin glycosylation, the standard CDG screen, is normal.
N-glycan processing GO:0006491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal N-glycan processing (GO:0006491). GO:0006491 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Edem3 knockout mouse Mouse partially recapitulates Plasma shows reduced Man5:Man9, Man6:Man9 and Man7:Man9 ratios, as in patients, and brain shows reduced Man5:Man9 and Man6:Man9. Mouse plasma and brain also show raised Man8 and Man9, which only some patients have.
Downstream
Abnormal High-Mannose N-Glycan Level
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"The N-glycan profiles from affected individuals showed decreased levels of low mannose N-glycan species M3–M7 (Figure 3C) with preserved normal M8 and M9 or sometimes mildly increased abundance of M9 as compared to control subjects."
Plasma N-glycan profiling in all 12 affected individuals.
Impaired Glycoprotein ER-Associated Degradation
Trimmed high-mannose glycans are the signal recognised by the lectins that deliver misfolded glycoproteins to ERAD. EDEM3 overexpression accelerates ERAD of misfolded glycoproteins, and combined EDEM1 and EDEM3 loss delays it. Slower clearance of misfolded glycoproteins is therefore the expected consequence of EDEM3 loss, but it has not been measured in patient cells.
ERAD pathway GO:0036503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ERAD pathway (GO:0036503). GO:0036503 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:16431915 SUPPORT In Vitro
"EDEM3 accelerates glycoprotein ERAD in transfected HEK293 cells, as shown by increased degradation of misfolded alpha1-antitrypsin variant (null (Hong Kong)) and of TCRalpha."
EDEM3 promotes ERAD of misfolded glycoproteins.
Blunted PERK-Mediated Unfolded Protein Response
Lymphoblastoid cells from affected individuals induce PERK (EIF2AK3) mRNA less than control cells after tunicamycin (measured by quantitative PCR only); ATF6 and IRE1 changes were not significant (three patient and three control lines). In contrast, EDEM3 knockout in hepatoma cells activates ER stress and apoptosis, so the direction of the stress response appears to depend on the cell type.
PERK-mediated unfolded protein response GO:0036499 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased PERK-mediated unfolded protein response (GO:0036499). GO:0036499 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:34143952 SUPPORT In Vitro
"Affected individuals’ mRNA from family 1 showed significantly decreased induction of PERK expression when compared to controls (p = 0.020), whereas ATF6 and IRE1 did not change significantly (p = 0.423 and p = 0.091, respectively)."
Blunted PERK induction in patient lymphoblastoid cells.
PMID:39838427 REFUTE INDIRECT In Vitro
"In turn, significant UPR activation and apoptosis occur in EDEM3 knockout cells."
In EDEM3 knockout hepatoma cells, EDEM3 loss activates rather than blunts ER stress signalling. The cells are a cancer line, not patient cells, so this may reflect cell context rather than contradict the patient finding.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for EDEM3-Congenital Disorder of Glycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Digestive 2
Gastroesophageal Reflux OCCASIONAL HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
Reflux in 3 of 12.
Feeding Difficulties OCCASIONAL HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968), qualified as infantile onset. HP:0011968 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
Early feeding difficulty in 2 of 12.
Head and Neck 8
Underdeveloped Nasal Alae FREQUENT HP:0000430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Underdeveloped nasal alae (HP:0000430). HP:0000430 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Hypoplastic alae nasi in 9 of 12.
Thin Upper Lip FREQUENT Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Thin upper lip in 9 of 12.
Increased Nasal Height FREQUENT Long nose HP:0003189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased nasal height, annotated with Long nose (HP:0003189). HP:0003189 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Increased nasal height in 8 of 12.
Narrow Palpebral Fissures FREQUENT HP:0045025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow palpebral fissure (HP:0045025). HP:0045025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Narrow palpebral fissures in 6 of 12.
Epicanthus FREQUENT HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Epicanthal folds in 6 of 12.
Bulbous Nasal Tip FREQUENT Bulbous nose HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Bulbous nasal tip in 6 of 12.
Short Philtrum FREQUENT HP:0000322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short philtrum (HP:0000322). HP:0000322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Short philtrum in 6 of 12.
Retrognathia FREQUENT HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the..."
Retrognathia in 6 of 12.
Metabolism 1
Abnormal High-Mannose N-Glycan Level VERY_FREQUENT HP:0410356 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal high-mannose N-glycan level (HP:0410356). HP:0410356 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"M9:M3 was increased in all 12 affected individuals."
Raised Man9:Man3 ratio in 12 of 12.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Hypotonia was present in six out of 12 persons."
Hypotonia in 6 of 12.
Nervous System 3
Neurodevelopmental Delay VERY_FREQUENT HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34143952 SUPPORT Human Clinical
"All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
Developmental delay or intellectual disability in 12 of 12.
PMID:34143952 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) of affected individuals from families 2, 3, and 5 did not detect structural abnormalities or myelination defects."
Normal brain MRI where performed.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
Intellectual disability is part of the combined 12-of-12 count.
Delayed Speech and Language Development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
Speech delay in 12 of 12.
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Genetic Associations

1
EDEM3 (Biallelic EDEM3 variants cause EDEM3-CDG. Most are protein-truncating and shown to cause loss of function; one family carries two missense variants in the GH47 mannosidase domain whose plasma glycan profile matches the truncating cases, but whose effect on the protein was not tested.)
Gene: EDEM3 hgnc:16787 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EDEM3 (hgnc:16787). hgnc:16787 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3"
Gene discovery by exome sequencing and GeneMatcher across seven families.
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Variants

3
EDEM3 c.1859del
Frameshift deletion p.(Ile620Thrfs*7) (NM_025191.3), homozygous in two Portuguese Romani families that share a 3.16 Mb homozygous haplotype around EDEM3; one heterozygote was found among 96 Portuguese Romani controls, suggesting a founder allele.
Show evidence (2 references)
PMID:34143952 SUPPORT Human Clinical
"In affected individuals from families 1 and 2, a bi-allelic frameshift deletion, c.1859del (p.Ile620Thrfs∗7), was identified in EDEM3 (GenBank: NM_025191.3; Figure 1)."
Identifies the variant and its transcript.
PMID:34143952 SUPPORT Human Clinical
"Because families 1 and 2 are of Portuguese Romani origin, this suggests a possible founder effect."
Possible founder origin.
Other EDEM3 protein-truncating variants
Families 3 to 6 carry c.2001dup p.(Ala668Serfs*9) with c.1369del p.(Arg457Glufs*28); homozygous c.940A>T p.(Arg314*) by maternal uniparental isodisomy; c.853+1G>T with c.1407T>A p.(Tyr469*); and homozygous c.1382_1385del p.(Phe461Serfs*23) (NM_025191.3).
Show evidence (2 references)
PMID:34143952 SUPPORT Human Clinical
"Additionally, two frameshift variants, c.2001dup (p.Ala668Serfs∗9) and c.1369del (p.Arg457Glufs∗28), were identified in family 3."
Family 3 genotype.
PMID:34143952 SUPPORT Human Clinical
"In family 5, a canonical splice site donor variant, c.853+1G>T, and a nonsense variant, c.1407T>A (p.Tyr469∗), were identified, and in family 6, a bi-allelic frameshift deletion, c.1382_1385del (p.Phe461Serfs∗23) was identified."
Family 5 and 6 genotypes; the family 4 variant is cited under inheritance.
EDEM3 p.Asp61Gly and p.Asp456Asn
The only missense genotype reported: compound heterozygous c.182A>G p.(Asp61Gly) and c.1366G>A p.(Asp456Asn), both in the GH47 mannosidase domain. The individual has the same plasma N-glycan profile as those with truncating variants.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Finally, in family 7, the compound heterozygous changes c.182A>G (p.Asp61Gly) and c.1366G>A (p.Asp456Asn) were identified."
Identifies the missense genotype.
🗃️

External Assertions

1
OMIM congenital disorder of glycosylation, type IIv record
OMIM disease record OMIM:619493
OMIM phenotype identifier for EDEM3-CDG, taken from the MONDO:0030423 cross-references.
💊

Medical Actions

1
Gastrostomy Tube Feeding
Action: percutaneous endoscopic gastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is percutaneous endoscopic gastrostomy, annotated with Gastrostomy Tube Procedure (NCIT:C157864). NCIT:C157864 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy Tube Procedure NCIT:C157864
No disease-specific treatment exists. Early feeding difficulties were managed with nasogastric tube feeding, and one individual needed a percutaneous endoscopic gastrostomy.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
Tube feeding and gastrostomy in the published cohort.
🔬

Biochemical Markers

2
Plasma N-linked Man9:Man3 ratio (INCREASED)
Reference Ranges
1.16–2.92 {ratio} (controls, method as published)
Normal range reported alongside the one affected individual whose Man5:Man9 and Man6:Man9 ratios were normal; that individual's Man9:Man3 ratio was 3.30.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"One of the 12 EDEM3-CDG-affected individuals showed normal plasma of M5:M9 and M6:M9 ratios but also showed the lowest plasma N-linked M3:M4 ratio at 0.27 (normal 0.39–0.56) and a significantly increased M9:M3 ratio at 3.30 (normal 1.16–2.92) in this cohort."
States the normal Man9:Man3 range used by the assay.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Instead, M9:M3 ratio is increased in all 12 affected individuals, providing a more sensitive diagnostic biomarker than M8 or M9 abundance in plasma."
The Man9:Man3 ratio as the most sensitive plasma marker.
Plasma N-linked Man3:Man4 ratio (DECREASED)
Reference Ranges
0.39–0.56 {ratio} (controls, method as published)
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"One of the 12 EDEM3-CDG-affected individuals showed normal plasma of M5:M9 and M6:M9 ratios but also showed the lowest plasma N-linked M3:M4 ratio at 0.27 (normal 0.39–0.56) and a significantly increased M9:M3 ratio at 3.30 (normal 1.16–2.92) in this cohort."
States the normal Man3:Man4 range used by the assay.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Interestingly, M3:M4 ratio was also reduced in all 12 affected individuals tested, consistent with a possible role of EDEM3 in trimming M5 to shorter polymannose glycans, as suggested by the pulse chase data."
Reduced Man3:Man4 ratio in 12 of 12.
🔬

Diagnosis

2
Plasma N-glycan profiling
Semiquantitative plasma N-glycan analysis shows the characteristic ratios (raised Man9:Man3; reduced Man3:Man4, Man5:Man9, Man6:Man9 and Man7:Man9). It can confirm variants of uncertain significance found by exome sequencing. The standard transferrin isoform screen for CDG is normal and does not detect the disorder.
Show evidence (3 references)
PMID:34143952 SUPPORT Human Clinical
"The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing."
Plasma N-glycan profiling as a clinically available confirmatory test.
PMID:34143952 SUPPORT Human Clinical
"Of note, human transferrin was normally glycosylated in the common clinical screening test for CDG in the three affected individuals from family 3."
The routine transferrin screen misses EDEM3-CDG.
PMID:34143952 SUPPORT Human Clinical
"Therefore, the combination of high M9:M3 and low M3:M4 ratios might also provide diagnostic clues for EDEM3-CDG when M5:M9 and M6:M9 ratios are normal."
Ratios to use when the commoner markers are normal.
Exome sequencing
All reported individuals were identified by exome sequencing and gene matching.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families"
Route to diagnosis in the published cohort.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Twelve affected individuals from seven families in the single published series, two of them of Portuguese Romani origin. No later case reports are known.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3"
The total number of reported cases.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from EDEM3-Congenital Disorder of Glycosylation:

Type I CDG with raised Man3 and Man4 (PMM2-, MPI-, ALG3- and ALG9-CDG)
Overlapping Features Type I CDGs raise plasma Man3 and Man4 and usually give an abnormal transferrin pattern, whereas EDEM3-CDG lowers Man3, lowers the Man3:Man4 ratio and leaves transferrin normal.
Show evidence (1 reference)
PMID:34143952 SUPPORT Human Clinical
"Increases of M3 and M4 abundances have been reported as important diagnostic biomarkers for type I CDG subtypes, including PMM2-CDG, MPI-CDG, ALG3-CDG, and ALG9-CDG."
The opposite direction of the Man3 and Man4 change separates these disorders from EDEM3-CDG.
Nonsyndromic intellectual disability
Overlapping Features The clinical picture (developmental delay, speech delay, mild dysmorphism, normal MRI) is non-specific; exome sequencing and plasma N-glycan profiling distinguish EDEM3-CDG.
🧫

Experimental Models

1
EDEM3-CDG patient fibroblasts with EDEM3 complementation PRIMARY_CELL_CULTURE
Skin fibroblasts from affected individuals in families 1 and 3, studied by [2-3H]mannose pulse-chase N-glycan analysis before and after re-expression of wild-type EDEM3.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:34143952
Pathograph links
Deficient ER Mannose Trimming recapitulates fidelity: high observes: cellular Patient fibroblasts fail to trim M8B and M5 during the chase.
Limitations: Fibroblasts are not neural cells, so the model says nothing about the neurodevelopmental phenotype.
Show evidence (1 reference)
PMID:34143952 SUPPORT In Vitro
"After 2 h of chase, the peaks for M7 and M4 did not appear in the cells of affected individuals (Figure 3B), indicating that the 1,2-alpha mannose residues were not removed from the M8B and M5 N-glycans during the chase, which is consistent with the absence of the biological function of EDEM3..."
The trimming defect measured directly in patient cells.
🐁

Animal Models

1
Edem3 knockout mouse
Edem3 knockout mice have no obvious phenotype but show reduced brain and body weight, skewed genotype ratios, and plasma and brain N-glycan changes that overlap with, but differ from, those in patients.
Species
Mouse
Genotype
Edem3 -/-
Publication
PMID:34143952
Pathograph links
Altered Plasma and Cellular High-Mannose N-Glycan Profile partially recapitulates fidelity: moderate observes: organism Plasma shows reduced Man5:Man9, Man6:Man9 and Man7:Man9 ratios, as in patients, and brain shows reduced Man5:Man9 and Man6:Man9. Mouse plasma and brain also show raised Man8 and Man9, which only some patients have.
Limitations: The mouse does not reproduce the reduced Man3:Man4 ratio, its most significant change is in the Man6:Man7 ratio rather than the human Man7:Man8 ratio, and it has no obvious neurodevelopmental phenotype.
Show evidence (2 references)
PMID:34143952 SUPPORT Model Organism
"Similar to affected individuals, plasma from mice showed decreased ratios of M5:M9, M6:M9, and M7:M9 (p < 0.02; Figure S5B)."
The knockout mouse reproduces the main plasma glycan ratios.
+ 1 more reference
Show evidence (1 reference)
PMID:34143952 SUPPORT Model Organism
"Although Edem3 KO mice did not present with any obvious phenotype, subtle changes have been noted, such as reduced weight of brains and body and largely skewed ratios of homozygous KO pups versus heterozygous and wild-type pups."
The whole-animal phenotype of the knockout.
{ }

Source YAML

click to show 
name: EDEM3-Congenital Disorder of Glycosylation
creation_date: "2026-09-28T15:00:00Z"
category: Mendelian
description: >-
  EDEM3-CDG (congenital disorder of glycosylation type 2v) is an autosomal
  recessive neurodevelopmental disorder caused by biallelic loss-of-function
  variants in EDEM3, an endoplasmic reticulum alpha-1,2-mannosidase of the
  glycoside hydrolase 47 family. EDEM3 trims mannose from high-mannose
  N-glycans, chiefly Man8GlcNAc2 isomer B to Man7-5GlcNAc2, which marks
  misfolded glycoproteins for ER-associated degradation (ERAD); it also trims
  total cellular glycoproteins. Twelve affected individuals from seven families
  have been described, all with developmental delay or intellectual disability
  and speech delay, half with hypotonia, and most with mild facial dysmorphism
  (hypoplastic alae nasi, thin upper lip, increased nasal height). Brain MRI was
  normal where performed. Unlike most CDGs, transferrin isoform screening is
  normal; diagnosis rests on a distinctive plasma high-mannose N-glycan profile
  with reduced Man3-Man7 species, a raised Man9:Man3 ratio and a reduced
  Man3:Man4 ratio. Patient cells also show blunted PERK induction under ER
  stress. How loss of mannose trimming leads to the neurodevelopmental
  phenotype is not known.
parents:
- hereditary disease
- congenital disorder of glycosylation
disease_term:
  preferred_term: congenital disorder of glycosylation, type 2v
  term:
    id: MONDO:0030423
    label: congenital disorder of glycosylation, type 2v
synonyms:
- EDEM3-CDG
- CDG2V
- CDG-IIv
- congenital disorder of glycosylation type IIv
external_assertions:
- name: OMIM congenital disorder of glycosylation, type IIv record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:619493
  description: >-
    OMIM phenotype identifier for EDEM3-CDG, taken from the MONDO:0030423
    cross-references.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for EDEM3
    variants, and unaffected parents are heterozygous carriers. In one family
    homozygosity arose from maternal uniparental isodisomy of chromosome 1.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing showed that the affected individuals were either homozygous or compound heterozygous for the identified EDEM3 variants. The unaffected parents were all heterozygous carriers."
    explanation: >-
      Biallelic variants in affected children with carrier parents establish
      recessive inheritance.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family 4, a bi-allelic nonsense variant, c.940A>T (p.Arg314∗), was found, resulting from maternal uniparental isodisomy of chromosome 1."
    explanation: >-
      Uniparental isodisomy as an alternative route to homozygosity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twelve affected individuals from seven families in the single published
    series, two of them of Portuguese Romani origin. No later case reports
    are known.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3"
    explanation: >-
      The total number of reported cases.
pathophysiology:
- name: Biallelic EDEM3 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Mostly protein-truncating EDEM3 variants (frameshift, nonsense and splice
    donor) that trigger nonsense-mediated mRNA decay, leaving about 17-18% of
    normal transcript and no detectable EDEM3 protein in patient cells. One
    family carries two missense variants in the GH47 mannosidase domain. EDEM1,
    which performs an overlapping trimming step, is not upregulated.
  genetic_context:
    gene:
      preferred_term: EDEM3
      term:
        id: hgnc:16787
        label: EDEM3
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Deficient ER Mannose Trimming
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "After 2 h of chase, the peaks for M7 and M4 did not appear in the cells of affected individuals (Figure 3B), indicating that the 1,2-alpha mannose residues were not removed from the M8B and M5 N-glycans during the chase, which is consistent with the absence of the biological function of EDEM3 (Figure 3A)."
      explanation: >-
        Pulse-chase labelling of patient fibroblasts shows the trimming
        products fail to appear when EDEM3 is lost.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "and could be rescued with cycloheximide (CHX), an inhibitor of NMD, suggesting that the bi-allelic c.1859del frameshift variant triggers NMD"
    explanation: >-
      Cycloheximide rescue of EDEM3 mRNA in patient lymphoblastoid cells shows
      the frameshift allele is degraded by nonsense-mediated decay.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These demonstrated the absence of EDEM3 in individual IV-4 (family 1) and individual II-1 (family 3) consistent with loss of function of EDEM3 (Figure 3C)."
    explanation: >-
      No EDEM3 protein on immunoblot of patient fibroblasts.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "EDEM1 levels were at 97% of normal levels (p = 0.9373) in fibroblast cell lines from affected individuals (Figure 2C)."
    explanation: >-
      The paralog EDEM1 is not upregulated to compensate.
- name: Deficient ER Mannose Trimming
  biological_scale: MOLECULAR
  genes:
  - preferred_term: EDEM3
    term:
      id: hgnc:16787
      label: EDEM3
  description: >-
    Without EDEM3, alpha-1,2-linked mannose is not trimmed from Man8GlcNAc2
    isomer B to Man7-5GlcNAc2, and Man5GlcNAc2 is not trimmed to Man4GlcNAc2,
    with accumulation of Glc1Man5GlcNAc2 in patient fibroblasts. The authors
    suggest that this Man5 species may come from the lipid-linked
    oligosaccharide precursor rather than from trimming, which would imply an
    additional effect on precursor synthesis; this is speculative. In purified
    enzyme assays EDEM3 alone converts M8B to M7, M6 and M5 and is a major
    alpha-1,2-mannosidase for this second trimming step.
  molecular_functions:
  - preferred_term: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
    term:
      id: GO:0004571
      label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: mannose trimming involved in glycoprotein ERAD pathway
    term:
      id: GO:1904382
      label: mannose trimming involved in glycoprotein ERAD pathway
    modifier: DECREASED
  downstream:
  - target: Altered Plasma and Cellular High-Mannose N-Glycan Profile
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Stepwise ratio analysis for plasma N-linked polymannose species showed a reduction of M7:M8 that is significant in affected individuals, consistent with EDEM3’s being the key enzyme in trimming M8B to M7 on secreted glycoproteins (Table S3)."
      explanation: >-
        The plasma glycan ratios in patients reflect the missing M8B-to-M7
        trimming step.
  - target: Impaired Glycoprotein ER-Associated Degradation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred for patients. Mannose trimming generates the glycan signal that
      targets misfolded glycoproteins for ERAD, and loss of EDEM1 and EDEM3
      together delays ERAD in cultured cells, but degradation of ERAD substrates
      has not been measured in EDEM3-CDG patient cells.
    evidence:
    - reference: PMID:34698634
      reference_title: "Purified EDEM3 or EDEM1 alone produces determinant oligosaccharide structures from M8B in mammalian glycoprotein ERAD."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Accordingly, degradation of human ATF6α, a transmembrane-type gpERAD substrate, and mCD3-δ-ΔTM-HA, a soluble gpERAD substrate, was markedly delayed in EDEM1, 3-DKO cells"
      explanation: >-
        Loss of EDEM1 and EDEM3 together delays degradation of glycoprotein
        ERAD substrates. Indirect because the cells lack both paralogs and are
        not patient cells.
  - target: Neurodevelopmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The link from the glycan defect to the neurodevelopmental phenotype rests
      on genetic association only. The intervening cellular steps are unknown,
      no neural model of EDEM3 deficiency exists, and the authors state that
      the mechanism remains to be determined.
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "In conclusion, we show that bi-allelic EDEM3 variants cause EDEM3-CDG, a CDG with non-specific developmental delay and/or intellectual disability."
      explanation: >-
        Establishes that EDEM3 loss causes the developmental phenotype without
        identifying the mechanism.
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Further functional studies are necessary to determine the precise pathophysiological mechanism of EDEM3-CDG."
      explanation: >-
        The authors' own statement that the mechanism is unknown, which is
        why this edge is typed as having unknown intermediates.
  - target: Blunted PERK-Mediated Unfolded Protein Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link. The authors connect the Glc1Man5GlcNAc2 accumulation seen
      in patient fibroblasts to an impaired unfolded protein response, and
      offer two readings of the blunted PERK induction: an impaired response,
      or an increased capacity to eliminate misfolded proteins. Neither has
      been tested.
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "G1M5 accumulation is a marker for an impaired UPR"
      explanation: >-
        The authors' rationale for testing the UPR, based on the trimming
        defect observed in patient cells.
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "suggesting that the UPR is impaired in EDEM3-CDG or that these cell lines have an increased capacity to eliminate misfolded proteins"
      explanation: >-
        The authors' interpretation, which leaves the causal direction open.
  evidence:
  - reference: PMID:34698634
    reference_title: "Purified EDEM3 or EDEM1 alone produces determinant oligosaccharide structures from M8B in mammalian glycoprotein ERAD."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, EDEM3 is a major α1,2-mannosidase for the second step from M8B."
    explanation: >-
      Purified-enzyme assays identify EDEM3 as the main enzyme for the step
      lost in patients.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2."
    explanation: >-
      A second trimming defect, at Man5GlcNAc2, in patient fibroblasts.
  - reference: PMID:16431915
    reference_title: "EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of EDEM3 also greatly stimulates mannose trimming not only from misfolded alpha1-AT null (Hong Kong) but also from total glycoproteins"
    explanation: >-
      EDEM3 trims total cellular glycoproteins, not only ERAD substrates,
      which explains why its loss changes the global N-glycan profile.
- name: Altered Plasma and Cellular High-Mannose N-Glycan Profile
  biological_scale: ORGANISM
  description: >-
    Secreted and cellular glycoproteins carry fewer trimmed high-mannose
    glycans. Patient plasma shows reduced Man3-Man7 species with normal or
    mildly raised Man8 and Man9, giving reduced Man5:Man9, Man6:Man9, Man7:Man9
    and Man3:Man4 ratios and a raised Man9:Man3 ratio. Transferrin
    glycosylation, the standard CDG screen, is normal.
  biological_processes:
  - preferred_term: N-glycan processing
    term:
      id: GO:0006491
      label: N-glycan processing
    modifier: ABNORMAL
  downstream:
  - target: Abnormal High-Mannose N-Glycan Level
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "M9:M3 was increased in all 12 affected individuals."
      explanation: >-
        The glycan profile change is the measured laboratory abnormality.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The N-glycan profiles from affected individuals showed decreased levels of low mannose N-glycan species M3–M7 (Figure 3C) with preserved normal M8 and M9 or sometimes mildly increased abundance of M9 as compared to control subjects."
    explanation: >-
      Plasma N-glycan profiling in all 12 affected individuals.
- name: Impaired Glycoprotein ER-Associated Degradation
  biological_scale: CELLULAR
  description: >-
    Trimmed high-mannose glycans are the signal recognised by the lectins that
    deliver misfolded glycoproteins to ERAD. EDEM3 overexpression accelerates
    ERAD of misfolded glycoproteins, and combined EDEM1 and EDEM3 loss delays
    it. Slower clearance of misfolded glycoproteins is therefore the expected
    consequence of EDEM3 loss, but it has not been measured in patient cells.
  biological_processes:
  - preferred_term: ERAD pathway
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:16431915
    reference_title: "EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "EDEM3 accelerates glycoprotein ERAD in transfected HEK293 cells, as shown by increased degradation of misfolded alpha1-antitrypsin variant (null (Hong Kong)) and of TCRalpha."
    explanation: >-
      EDEM3 promotes ERAD of misfolded glycoproteins.
- name: Blunted PERK-Mediated Unfolded Protein Response
  biological_scale: CELLULAR
  description: >-
    Lymphoblastoid cells from affected individuals induce PERK (EIF2AK3) mRNA
    less than control cells after tunicamycin (measured by quantitative PCR
    only); ATF6 and IRE1 changes
    were not significant (three patient and three control lines). In contrast,
    EDEM3 knockout in hepatoma cells activates ER stress and apoptosis, so the
    direction of the stress response appears to depend on the cell type.
  biological_processes:
  - preferred_term: PERK-mediated unfolded protein response
    term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    modifier: DECREASED
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Affected individuals’ mRNA from family 1 showed significantly decreased induction of PERK expression when compared to controls (p = 0.020), whereas ATF6 and IRE1 did not change significantly (p = 0.423 and p = 0.091, respectively)."
    explanation: >-
      Blunted PERK induction in patient lymphoblastoid cells.
  - reference: PMID:39838427
    reference_title: "The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "In turn, significant UPR activation and apoptosis occur in EDEM3 knockout cells."
    explanation: >-
      In EDEM3 knockout hepatoma cells, EDEM3 loss activates rather than
      blunts ER stress signalling. The cells are a cancer line, not patient cells, so this may
      reflect cell context rather than contradict the patient finding.
phenotypes:
- category: Neurological
  name: Neurodevelopmental Delay
  description: >-
    Developmental delay and/or intellectual disability in all reported
    individuals, described as neurodevelopmental delay. Brain MRI in three
    families showed no structural abnormality or myelination defect.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
    explanation: >-
      Developmental delay or intellectual disability in 12 of 12.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging (MRI) of affected individuals from families 2, 3, and 5 did not detect structural abnormalities or myelination defects."
    explanation: >-
      Normal brain MRI where performed.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Reported only in a combined count with developmental delay
    ("developmental delay and/or intellectual disability", 12 of 12), so the
    number with intellectual disability is not known and no frequency is
    given.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
    explanation: >-
      Intellectual disability is part of the combined 12-of-12 count.
- category: Neurological
  name: Delayed Speech and Language Development
  description: >-
    Speech delay in all reported individuals.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1)."
    explanation: >-
      Speech delay in 12 of 12.
- category: Neurological
  name: Hypotonia
  description: >-
    Hypotonia in half of the reported individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia was present in six out of 12 persons."
    explanation: >-
      Hypotonia in 6 of 12.
- category: Craniofacial
  name: Underdeveloped Nasal Alae
  description: >-
    Hypoplastic alae nasi, the most frequent facial feature (9 of 12).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Hypoplastic alae nasi in 9 of 12.
- category: Craniofacial
  name: Thin Upper Lip
  description: >-
    Thin upper lip in 9 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Thin upper lip in 9 of 12.
- category: Craniofacial
  name: Increased Nasal Height
  description: >-
    Increased nasal height in 8 of 12, recorded under the HPO term Long nose.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Increased nasal height
    term:
      id: HP:0003189
      label: Long nose
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Increased nasal height in 8 of 12.
- category: Craniofacial
  name: Narrow Palpebral Fissures
  description: >-
    Narrow palpebral fissures in 6 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Narrow palpebral fissure
    term:
      id: HP:0045025
      label: Narrow palpebral fissure
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Narrow palpebral fissures in 6 of 12.
- category: Craniofacial
  name: Epicanthus
  description: >-
    Epicanthal folds in 6 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Epicanthal folds in 6 of 12.
- category: Craniofacial
  name: Bulbous Nasal Tip
  description: >-
    Bulbous nasal tip in 6 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Bulbous nasal tip in 6 of 12.
- category: Craniofacial
  name: Short Philtrum
  description: >-
    Short philtrum in 6 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Short philtrum in 6 of 12.
- category: Craniofacial
  name: Retrognathia
  description: >-
    Retrognathia in 6 of 12.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features, such as narrow palpebral fissures (6/12), epicanthal folds (6/12), increased nasal height (8/12), bulbous nasal tip (6/12), hypoplastic alae nasi (9/12), short philtrum (6/12), thin upper lip (9/12), and retrognathia (6/12) were also found in half or more of the affected individuals."
    explanation: >-
      Retrognathia in 6 of 12.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  description: >-
    Gastroesophageal reflux in 3 of 12.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
    explanation: >-
      Reflux in 3 of 12.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Early feeding difficulties requiring nasogastric tube feeding in 2 of 12,
    one of whom later needed a gastrostomy.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
    explanation: >-
      Early feeding difficulty in 2 of 12.
- category: Metabolism/Laboratory
  name: Abnormal High-Mannose N-Glycan Level
  description: >-
    Abnormal plasma high-mannose N-glycan profile with a raised Man9:Man3 ratio
    in every affected individual; the diagnostic laboratory finding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal high-mannose N-glycan level
    term:
      id: HP:0410356
      label: Abnormal high-mannose N-glycan level
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "M9:M3 was increased in all 12 affected individuals."
    explanation: >-
      Raised Man9:Man3 ratio in 12 of 12.
biochemical:
- name: Plasma N-linked Man9:Man3 ratio
  presence: INCREASED
  notes: >-
    Semiquantitative plasma N-glycan profiling. The Man9:Man3 ratio was raised
    in all 12 affected individuals and the authors propose it as the most
    sensitive marker; Man6:Man9 best separated affected individuals from
    obligate heterozygous parents. No LOINC code exists for this ratio.
  reference_ranges:
  - lower_bound: 1.16
    upper_bound: 2.92
    unit: "{ratio}"
    population: controls, method as published
    notes: >-
      Normal range reported alongside the one affected individual whose
      Man5:Man9 and Man6:Man9 ratios were normal; that individual's Man9:Man3
      ratio was 3.30.
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One of the 12 EDEM3-CDG-affected individuals showed normal plasma of M5:M9 and M6:M9 ratios but also showed the lowest plasma N-linked M3:M4 ratio at 0.27 (normal 0.39–0.56) and a significantly increased M9:M3 ratio at 3.30 (normal 1.16–2.92) in this cohort."
      explanation: >-
        States the normal Man9:Man3 range used by the assay.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Instead, M9:M3 ratio is increased in all 12 affected individuals, providing a more sensitive diagnostic biomarker than M8 or M9 abundance in plasma."
    explanation: >-
      The Man9:Man3 ratio as the most sensitive plasma marker.
- name: Plasma N-linked Man3:Man4 ratio
  presence: DECREASED
  notes: >-
    Reduced in all 12 affected individuals. A reduced Man3:Man4 ratio had not
    been reported in any other CDG; type I CDGs instead raise Man3 and Man4.
    No LOINC code exists for this ratio.
  reference_ranges:
  - lower_bound: 0.39
    upper_bound: 0.56
    unit: "{ratio}"
    population: controls, method as published
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One of the 12 EDEM3-CDG-affected individuals showed normal plasma of M5:M9 and M6:M9 ratios but also showed the lowest plasma N-linked M3:M4 ratio at 0.27 (normal 0.39–0.56) and a significantly increased M9:M3 ratio at 3.30 (normal 1.16–2.92) in this cohort."
      explanation: >-
        States the normal Man3:Man4 range used by the assay.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, M3:M4 ratio was also reduced in all 12 affected individuals tested, consistent with a possible role of EDEM3 in trimming M5 to shorter polymannose glycans, as suggested by the pulse chase data."
    explanation: >-
      Reduced Man3:Man4 ratio in 12 of 12.
genetic:
- name: EDEM3
  gene_term:
    preferred_term: EDEM3
    term:
      id: hgnc:16787
      label: EDEM3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic EDEM3 variants cause EDEM3-CDG. Most are protein-truncating and
    shown to cause loss of function; one family carries two missense variants
    in the GH47 mannosidase domain whose plasma glycan profile matches the
    truncating cases, but whose effect on the protein was not tested.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3"
    explanation: >-
      Gene discovery by exome sequencing and GeneMatcher across seven
      families.
variants:
- name: EDEM3 c.1859del
  description: >-
    Frameshift deletion p.(Ile620Thrfs*7) (NM_025191.3), homozygous in two
    Portuguese Romani families that share a 3.16 Mb homozygous haplotype around
    EDEM3; one heterozygote was found among 96 Portuguese Romani controls,
    suggesting a founder allele.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In affected individuals from families 1 and 2, a bi-allelic frameshift deletion, c.1859del (p.Ile620Thrfs∗7), was identified in EDEM3 (GenBank: NM_025191.3; Figure 1)."
    explanation: >-
      Identifies the variant and its transcript.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because families 1 and 2 are of Portuguese Romani origin, this suggests a possible founder effect."
    explanation: >-
      Possible founder origin.
- name: Other EDEM3 protein-truncating variants
  description: >-
    Families 3 to 6 carry c.2001dup p.(Ala668Serfs*9) with c.1369del
    p.(Arg457Glufs*28); homozygous c.940A>T p.(Arg314*) by maternal
    uniparental isodisomy; c.853+1G>T with c.1407T>A p.(Tyr469*); and
    homozygous c.1382_1385del p.(Phe461Serfs*23) (NM_025191.3).
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, two frameshift variants, c.2001dup (p.Ala668Serfs∗9) and c.1369del (p.Arg457Glufs∗28), were identified in family 3."
    explanation: >-
      Family 3 genotype.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family 5, a canonical splice site donor variant, c.853+1G>T, and a nonsense variant, c.1407T>A (p.Tyr469∗), were identified, and in family 6, a bi-allelic frameshift deletion, c.1382_1385del (p.Phe461Serfs∗23) was identified."
    explanation: >-
      Family 5 and 6 genotypes; the family 4 variant is cited under
      inheritance.
- name: EDEM3 p.Asp61Gly and p.Asp456Asn
  description: >-
    The only missense genotype reported: compound heterozygous c.182A>G
    p.(Asp61Gly) and c.1366G>A p.(Asp456Asn), both in the GH47 mannosidase
    domain. The individual has the same plasma N-glycan profile as those with
    truncating variants.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, in family 7, the compound heterozygous changes c.182A>G (p.Asp61Gly) and c.1366G>A (p.Asp456Asn) were identified."
    explanation: >-
      Identifies the missense genotype.
differential_diagnoses:
- name: Type I CDG with raised Man3 and Man4 (PMM2-, MPI-, ALG3- and ALG9-CDG)
  description: >-
    Type I CDGs raise plasma Man3 and Man4 and usually give an abnormal
    transferrin pattern, whereas EDEM3-CDG lowers Man3, lowers the Man3:Man4
    ratio and leaves transferrin normal.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increases of M3 and M4 abundances have been reported as important diagnostic biomarkers for type I CDG subtypes, including PMM2-CDG, MPI-CDG, ALG3-CDG, and ALG9-CDG."
    explanation: >-
      The opposite direction of the Man3 and Man4 change separates these
      disorders from EDEM3-CDG.
- name: Nonsyndromic intellectual disability
  description: >-
    The clinical picture (developmental delay, speech delay, mild dysmorphism,
    normal MRI) is non-specific; exome sequencing and plasma N-glycan profiling
    distinguish EDEM3-CDG.
diagnosis:
- name: Plasma N-glycan profiling
  description: >-
    Semiquantitative plasma N-glycan analysis shows the characteristic ratios
    (raised Man9:Man3; reduced Man3:Man4, Man5:Man9, Man6:Man9 and Man7:Man9).
    It can confirm variants of uncertain significance found by exome
    sequencing. The standard transferrin isoform screen for CDG is normal and
    does not detect the disorder.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing."
    explanation: >-
      Plasma N-glycan profiling as a clinically available confirmatory test.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, human transferrin was normally glycosylated in the common clinical screening test for CDG in the three affected individuals from family 3."
    explanation: >-
      The routine transferrin screen misses EDEM3-CDG.
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, the combination of high M9:M3 and low M3:M4 ratios might also provide diagnostic clues for EDEM3-CDG when M5:M9 and M6:M9 ratios are normal."
    explanation: >-
      Ratios to use when the commoner markers are normal.
- name: Exome sequencing
  description: >-
    All reported individuals were identified by exome sequencing and gene
    matching.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families"
    explanation: >-
      Route to diagnosis in the published cohort.
treatments:
- name: Gastrostomy Tube Feeding
  description: >-
    No disease-specific treatment exists. Early feeding difficulties were
    managed with nasogastric tube feeding, and one individual needed a
    percutaneous endoscopic gastrostomy.
  treatment_term:
    preferred_term: percutaneous endoscopic gastrostomy
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."
    explanation: >-
      Tube feeding and gastrostomy in the published cohort.
animal_models:
- name: Edem3 knockout mouse
  species: Mouse
  genotype: Edem3 -/-
  publication: PMID:34143952
  description: >-
    Edem3 knockout mice have no obvious phenotype but show reduced brain and
    body weight, skewed genotype ratios, and plasma and brain N-glycan changes
    that overlap with, but differ from, those in patients.
  modeled_mechanisms:
  - target: Altered Plasma and Cellular High-Mannose N-Glycan Profile
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Plasma shows reduced Man5:Man9, Man6:Man9 and Man7:Man9 ratios, as in
      patients, and brain shows reduced Man5:Man9 and Man6:Man9. Mouse plasma
      and brain also show raised Man8 and Man9, which only some patients have.
    limitations: >-
      The mouse does not reproduce the reduced Man3:Man4 ratio, its most
      significant change is in the Man6:Man7 ratio rather than the human
      Man7:Man8 ratio, and it has no obvious neurodevelopmental phenotype.
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Similar to affected individuals, plasma from mice showed decreased ratios of M5:M9, M6:M9, and M7:M9 (p < 0.02; Figure S5B)."
      explanation: >-
        The knockout mouse reproduces the main plasma glycan ratios.
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the plasma from Edem3 KO mice, M3:M4 ratio is not decreased (Figures S5B and S5D)."
      explanation: >-
        One human biomarker the mouse does not reproduce.
  evidence:
  - reference: PMID:34143952
    reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although Edem3 KO mice did not present with any obvious phenotype, subtle changes have been noted, such as reduced weight of brains and body and largely skewed ratios of homozygous KO pups versus heterozygous and wild-type pups."
    explanation: >-
      The whole-animal phenotype of the knockout.
experimental_models:
- name: EDEM3-CDG patient fibroblasts with EDEM3 complementation
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Skin fibroblasts from affected individuals in families 1 and 3, studied by
    [2-3H]mannose pulse-chase N-glycan analysis before and after
    re-expression of wild-type EDEM3.
  publication: PMID:34143952
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Deficient ER Mannose Trimming
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Patient fibroblasts fail to trim M8B and M5 during the chase.
    limitations: >-
      Fibroblasts are not neural cells, so the model says nothing about the
      neurodevelopmental phenotype.
    evidence:
    - reference: PMID:34143952
      reference_title: "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "After 2 h of chase, the peaks for M7 and M4 did not appear in the cells of affected individuals (Figure 3B), indicating that the 1,2-alpha mannose residues were not removed from the M8B and M5 N-glycans during the chase, which is consistent with the absence of the biological function of EDEM3 (Figure 3A)."
      explanation: >-
        The trimming defect measured directly in patient cells.
discussions:
- discussion_id: edem3_cdg_neurodevelopmental_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Deficient ER Mannose Trimming
  - phenotypes#Neurodevelopmental Delay
  prompt: >-
    How does loss of EDEM3 mannose trimming cause developmental delay and
    intellectual disability when brain MRI is normal?
  rationale: >-
    Every mechanistic study of EDEM3 deficiency has used fibroblasts,
    lymphoblastoid cells, plasma or cancer cell lines. No neural cell or
    organoid model exists, and the knockout mouse has no obvious neurological
    phenotype, so the causal edges from the glycan defect to the developmental
    phenotypes rest on genetic association alone. Measuring ERAD substrate
    clearance and ER stress in patient-derived neurons would test whether
    slower ERAD, altered stress signalling, or a change in the glycosylation of
    specific neural glycoproteins is responsible.
- discussion_id: edem3_cdg_upr_direction
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Blunted PERK-Mediated Unfolded Protein Response
  prompt: >-
    Does EDEM3 loss blunt or activate the unfolded protein response?
  rationale: >-
    Patient lymphoblastoid cells show blunted PERK induction under tunicamycin,
    which the authors read either as an impaired response or as increased
    capacity to clear misfolded protein. EDEM3 knockout hepatoma cells instead
    show ER stress and apoptosis. The comparison uses three patient cell lines
    and a cancer cell line, so the direction in the tissues that matter is
    unknown.
- discussion_id: edem3_cdg_mouse_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Altered Plasma and Cellular High-Mannose N-Glycan Profile
  prompt: >-
    Why does the Edem3 knockout mouse reproduce most of the human glycan
    defect but not the neurodevelopmental phenotype or the reduced Man3:Man4
    ratio?
  rationale: >-
    The mouse shares the reduced Man5:Man9, Man6:Man9 and Man7:Man9 ratios but
    not the reduced Man3:Man4 ratio, and its largest change is at a different
    trimming step, which the authors attribute to a difference in substrate
    specificity between human and mouse EDEM3. It shows only reduced brain and
    body weight. Whether the missing neurological phenotype reflects species
    differences in EDEM3 substrates, compensation by EDEM1, or insufficiently
    detailed behavioural testing is untested.
notes: >-
  The entry name follows the gene-prefixed naming used for other CDG entries
  (for example DHRSX-Congenital_Disorder_of_Glycosylation); the MONDO label is
  used verbatim in disease_term.

  The human clinical evidence is a single series of 12 individuals from seven
  families (PMID:34143952), so every phenotype frequency is an n=12 figure. No
  later case reports are known, and no GeneReviews chapter covers EDEM3-CDG.

  The congenital_disorder_of_glycosylation module is not used as a conformance
  target. Its shared lesion is protein hypoglycosylation after defective
  lipid-linked oligosaccharide assembly or Golgi processing; EDEM3-CDG instead
  impairs ER mannose trimming, and transferrin glycosylation is normal.

  EDEM3 variants also influence plasma triglycerides (a common missense
  variant, p.Pro746Ser, lowers them by about 5%), but fasting triglycerides
  were normal in the EDEM3-CDG individuals tested, so triglycerides are not
  curated as a feature of the disease.
📚

References & Deep Research

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: EDEM3-Congenital_Disorder_of_Glycosylation · 2026-09-28T16:38:28Z · View source

New entry for EDEM3-CDG (CDG type 2v, MONDO:0030423, gene EDEM3), claimed in issue #13088. Deep research was requested from falcon; no Edison key was configured, so the run used dr_fallback and the report was produced by claude_code (research/EDEM3-Congenital_Disorder_of_Glycosylation-deep-research-claude_code.md; frontmatter records fell_back and requested_provider falcon). Report reference validation: 10/10 identifiers resolved and 29/29 quotes valid. The four term-validation mislabels were table-cell text beside correct CURIEs, not wrong bindings. preflight-dr returned WARN because the report cites the EDEM3 gene MIM (610214) alongside the phenotype MIM (619493) that MONDO cross-references; EDEM3 is the dominant gene in the report (43 mentions), so the report is about the right disease. The human clinical evidence is a single series (PMID:34143952, 12 individuals, 7 families); a PubMed search found no later case reports and check-genereviews --online returned NO_CHAPTER. Biochemistry is from PMID:34698634, 16431915 and 39838427 (hepatoma cells, used only as a contrasting REFUTE item on the direction of the ER stress response). The congenital_disorder_of_glycosylation module was not used as a conformance target because its shared lesion is protein hypoglycosylation, whereas EDEM3-CDG is a defect in ER mannose trimming with normal transferrin glycosylation. A fresh-context red-team review before the PR (7 important, 9 minor, no critical findings) led to these changes: the glycan phenotype was rebound from HP:0012355 (abnormal mannosylation, i.e. adding mannose) to HP:0410356 Abnormal high-mannose N-glycan level; the glycan-profile node process was changed from GO:0006487 protein N-linked glycosylation to GO:0006491 N-glycan processing; the unsupported ERAD-to-blunted-PERK edge was replaced by an indirect edge from the trimming node citing the authors' Glc1Man5 rationale; the trimming-to-phenotype edges were reduced to one edge to HP:0012758 Neurodevelopmental delay (replacing HP:0001263) carrying the authors' statement that the mechanism is undetermined; the intellectual-disability frequency was removed because the paper reports only a combined count; fibroblast cell_types were removed from the trimming node as an assay system; the knockout-hepatoma REFUTE item now quotes the knockout sentence with directness INDIRECT; the mouse-model description, Glc1Man5 hedge, missense loss-of-function wording, biomarker presence values, the remaining truncating variants and the normal-MRI evidence were added or corrected; and session narration was removed from notes. The reviewer's suggestions to use supports: PARTIAL were not taken because that value has been retired from the schema. Validation: just validate 57/57 snippets; check-entity-refs, check-causal-targets, check-duplicate-keys, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens and check-coarse-phenotypes all OK. Stub stubs/Congenital_Disorder_Of_Glycosylation_Type_2v.yaml deleted.

Claude Code ▸
EDEM3-Congenital Disorder of Glycosylation (EDEM3-CDG; CDG2V): Research Report
claude-haiku-4-5-20251001, claude-opus-5-5 7 citations 2026-09-28T12:10:56.550062

EDEM3-Congenital Disorder of Glycosylation (EDEM3-CDG; CDG2V): Research Report

Prepared: 2026-09-28 · Target: MONDO:0030423 · Category: Mendelian (autosomal recessive)

How to read this report. Six full-text or abstract records were read from the local references_cache/: PMID:34143952, 16431915, 29784879, 34698634, 35500441 and 39838427. Text in quotation marks from those PMIDs is copied exactly and can be used as a snippet. Everything else comes from web or PubMed-summary retrieval and is paraphrased; it has to be fetched with just fetch-reference before it can back a snippet. I list ontology identifiers as leads only. The repo requires every CURIE to be looked up (runoak or the term caches) before it is written into YAML, and I have marked the ones I could not source in this session.

Main limitation. The whole human clinical literature is one paper: Polla et al., 2021, Am J Hum Genet (PMID:34143952), describing 12 patients from 7 families. A PubMed search for "EDEM3" (54 hits as of today) turned up no later case series or case report. Every phenotype frequency below is therefore an n=12 figure.

1. Disease Information

Overview. EDEM3-CDG is an autosomal recessive congenital disorder of glycosylation. It is caused by biallelic loss-of-function variants in EDEM3, which encodes an ER-lumenal class I (GH47) α1,2-mannosidase that trims mannose in glycoprotein ER-associated degradation (gpERAD). The clinical picture is non-specific developmental delay or intellectual disability with speech delay, variable hypotonia and mild facial dysmorphism.

"The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms." (PMID:34143952)

"We propose to call this deficiency EDEM3-CDG." (PMID:34143952)

Identifiers (from the MONDO record via OLS, retrieved today):

Resource ID
MONDO MONDO:0030423 "congenital disorder of glycosylation, type 2v" (cached in cache/mondo/terms.csv)
OMIM (phenotype) 619493
OMIM (gene) 610214 (EDEM3)
Orphanet ORPHA:695783
DOID DOID:0051050
GARD 0025557
MedGen / UMLS 1794181 / C5561971
ICD-10 / ICD-11 No disease-specific code. It would fall under the CDG group code (ICD-10 E77.8 / ICD-11 5C51.1 group level), which I have not verified.
MeSH No specific heading; indexed under "Congenital Disorders of Glycosylation".

Synonyms: EDEM3-CDG; CDG2V; CDG-IIv; congenital disorder of glycosylation type IIv.

Nature of the data: aggregated case-level data from one exome/GeneMatcher-assembled cohort. There is no registry-level or EHR data. The FCDGC natural-history study (NCT04199000) enrolls CDG patients generally and may include EDEM3-CDG.

2. Etiology

  • Cause: biallelic germline EDEM3 variants, mostly protein-truncating.

    "we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3." (PMID:34143952)

  • Genetic risk factors:
  • Consanguinity and founder effect in the Portuguese Romani population, where c.1859del was found in 1/96 controls. > "Because families 1 and 2 are of Portuguese Romani origin, this suggests a possible founder effect." (PMID:34143952)
  • Uniparental isodisomy (family 4). > "In family 4, a bi-allelic nonsense variant, c.940A>T (p.Arg314∗), was found, resulting from maternal uniparental isodisomy of chromosome 1." (PMID:34143952)
  • Environmental risk, protective or GxE factors: none reported. Not applicable to a monogenic recessive enzyme deficiency.
  • Related common-variant biology (not disease risk): the low-frequency missense variant rs78444298 (p.Pro746Ser, protease-associated domain, MAF ~1.5%) is associated with about 5% lower plasma triglycerides.

    "A low-frequency EDEM3 missense variant in the protease-associated domain (rs78444298, p.Pro746Ser, minor allele frequency ∼1.5%) was associated with an approximately 5% decrease in triglyceride levels." (PMID:34143952)

  • The mechanism (EDEM3 loss → higher LRP1 → faster VLDL uptake) is from Xu et al., iScience 2020, PMID:32213464, which needs fetching.
  • EDEM3-CDG patients nevertheless had normal fasting triglycerides: > "In our subjects for whom fasting triglyceride levels are available (Table S1), all triglyceride measurements were within the normal range." (PMID:34143952)

3. Phenotypes

Frequencies are from PMID:34143952 (n=12). Onset is infantile or early childhood. Severity is mild to moderate and course appears static. Quality-of-life data do not exist.

Phenotype Freq. Suggested HPO (verify before use)
Developmental delay and/or intellectual disability 12/12 Global developmental delay HP:0001263; Intellectual disability HP:0001249
Speech delay 12/12 Delayed speech and language development HP:0000750
Hypotonia 6/12 Hypotonia HP:0001252
Hypoplastic alae nasi 9/12 Hypoplasia of the ala nasi (look up the CURIE)
Thin upper lip 9/12 Thin upper lip vermilion HP:0000219
Increased nasal height 8/12 Long nose / "increased nasal height" (look up)
Narrow palpebral fissures 6/12 Narrow palpebral fissure HP:0045025
Epicanthal folds 6/12 Epicanthus HP:0000286
Bulbous nasal tip 6/12 Bulbous nose HP:0000414
Short philtrum 6/12 Short philtrum HP:0000322
Retrognathia 6/12 Retrognathia HP:0000278
Gastroesophageal reflux 3/12 Gastroesophageal reflux HP:0002020
Early feeding difficulty requiring NG tube (1 of these 2 needed PEG) 2/12 Feeding difficulties HP:0011968
Normal brain MRI (families 2, 3, 5) 3 families tested Negative finding; do not assert a brain anomaly
Laboratory: abnormal plasma N-glycan profile (↑M9:M3, ↓M3:M4/M5:M9/M6:M9/M7:M9) 12/12 Abnormal protein N-linked glycosylation (look up); keep as biochemical biomarker
Laboratory: normal transferrin isoelectric focusing 3/3 tested (family 3) Negative finding

Supporting quotes (PMID:34143952):

"All affected individuals presented with developmental delay and/or intellectual disability (ID) and speech delay (Table S1). Hypotonia was present in six out of 12 persons."

"Additionally, gastroesophageal reflux was observed in three persons, and two individuals had early feeding difficulties requiring a nasogastric tube; of these, one individual needed a percutaneous endoscopic gastrostomy placement."

"Brain magnetic resonance imaging (MRI) of affected individuals from families 2, 3, and 5 did not detect structural abnormalities or myelination defects."

Additional features listed by CDG Hub (secondary source summarizing Table S1; each needs a primary-source check against the Polla supplement before curation): anosmia, apnea, delayed bone age, muscle atrophy, Poland sequence (one case), astigmatism, strabismus, failure to thrive, hyperactivity, anxiety and attention deficit.

4. Genetic / Molecular Information

Gene: EDEM3, located at 1q25.3. - HGNC:16787. Write it as hgnc:16787 in YAML, and confirm with just validate-terms. - NCBI Gene 80267 and UniProt Q9BZQ6. Both are from memory; verify them. - OMIM 610214. - Transcript NM_025191.3.

Protein: a 931-aa soluble ER-lumenal protein (mouse). It has an N-terminal GH47 α-mannosidase homology domain and a C-terminal protease-associated (PA) domain.

"EDEM3 consists of 931 amino acids and has all the signature motifs of Class I alpha-mannosidases (glycosyl hydrolase family 47) in its N-terminal domain and a protease-associated motif in its C-terminal region." (PMID:16431915)

Reported pathogenic variants (PMID:34143952; NM_025191.3). All were germline, with carrier parents. None has an ACMG classification in the paper; check ClinVar.

Family Genotype Type
1, 2 (Portuguese Romani) c.1859del p.(Ile620Thrfs*7), homozygous frameshift, NMD
3 c.2001dup p.(Ala668Serfs9) / c.1369del p.(Arg457Glufs28) frameshift
4 c.940A>T p.(Arg314*), homozygous by maternal UPD1 nonsense
5 c.853+1G>T / c.1407T>A p.(Tyr469*) splice donor / nonsense
6 c.1382_1385del p.(Phe461Serfs*23), homozygous frameshift
7 c.182A>G p.(Asp61Gly) / c.1366G>A p.(Asp456Asn) missense, both in the GH47 domain
  • Allele frequency: p.Asp61Gly is in 6/218,508 gnomAD alleles (rs777353823). p.Asp456Asn is absent from gnomAD.
  • Functional consequence: loss of function via nonsense-mediated decay and absent protein.

    "These demonstrated the absence of EDEM3 in individual IV-4 (family 1) and individual II-1 (family 3) consistent with loss of function of EDEM3 (Figure 3C)." (PMID:34143952)

  • Modifier genes: none established.
  • EDEM1 is a candidate functional backup, but it is not upregulated in patient cells: "EDEM1 levels were at 97% of normal levels (p = 0.9373) in fibroblast cell lines from affected individuals" (PMID:34143952).
  • TXNL4/ERp46 (ERp46 = TXNDC5) is required for EDEM3 activity (PMID:29784879). It is a plausible modifier, but this is unproven.
  • Epigenetic and chromosomal findings: none, apart from the UPD1 mechanism above.

5. Environmental Information

Not applicable. No toxins, lifestyle factors or infectious triggers are described. Tunicamycin is used only as an experimental ER-stress inducer. This section should be left empty rather than filled.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic truncating or missense EDEM3 variants lead to NMD of mRNA (about 17–18% residual) and absent EDEM3 protein. [Demonstrated: patient LCLs and fibroblasts, PMID:34143952]
  2. Loss of ER α1,2-mannosidase activity (GH47; needs a Cys82–Cys441 disulfide and is activated by ERp46) leads to failure to trim Man8GlcNAc2 isomer B to Man7/6/5. [Demonstrated: patient fibroblasts, patient plasma and Edem3-KO mouse plasma/brain (PMID:34143952); biochemistry (PMID:34698634, 29784879, 16431915)]
  3. Branch 2a, global N-glycome change (secreted and cellular glycoproteins): lower M3–M7, relatively preserved or raised M8/M9, ↑M9:M3 and ↓M3:M4. This is the diagnostic biomarker. [Demonstrated]
  4. Branch 2b, M5 → M4 trimming deficit with Glc1Man5 accumulation. The authors speculate that lipid-linked oligosaccharide (LLO) synthesis is impaired. [Observation demonstrated; LLO mechanism speculative]
  5. Lack of the α1,6-mannose-exposing glycan degron (M7A/M6/M5) leads to reduced recognition by OS-9/XTP3-B and slower gpERAD of misfolded glycoproteins. [Inferred for patients. Demonstrated in EDEM1/3 double-KO HCT116 cells (PMID:34698634); patient-cell ERAD-substrate kinetics not measured]
  6. Altered ER proteostasis and unfolded protein response (UPR): patient LCLs show blunted induction of PERK (EIF2AK3) by tunicamycin. [Demonstrated in vitro, n=3 vs n=3; direction is ambiguous — "impaired UPR" or "increased capacity to eliminate misfolded proteins"]
  7. Branch 4b (contrasting model): EDEM3-KO HepaRG hepatic cells show increased BiP/PERK/p-eIF2α, rising apoptosis and loss of viability with passage (PMID:39838427, a cancer cell line). The UPR direction therefore appears to depend on cell context.
  8. Neurodevelopmental dysfunction leads to DD/ID, speech delay and hypotonia, and dysmorphism arises through an undetermined craniofacial developmental route. [Not demonstrated. No neural cell or organoid model of EDEM3-CDG exists; MRI is normal]

    "Further functional studies are necessary to determine the precise pathophysiological mechanism of EDEM3-CDG." (PMID:34143952)

Key supporting quotes

  • Enzymatic step:

    "Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity." (PMID:34143952)

  • M5 trimming:

    "In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2." (PMID:34143952)

  • UPR:

    "Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response." (PMID:34143952)

  • EDEM3 as the main second-step enzyme:

    "Thus, EDEM3 is a major α1,2-mannosidase for the second step from M8B." (PMID:34698634, IN_VITRO)

  • Disulfide requirement:

    "Results showed that the mutations C160A and C529A of EDEM1 as well as C82A and C441A of EDEM3 indeed inactivated EDEM1 and EDEM3, respectively, in gpERAD" (PMID:34698634)

  • ERp46 partner:

    "the mannose-trimming activity of EDEM3 toward the model misfolded substrate, the glycoprotein T-cell receptor α locus (TCRα), was reconstituted only when ERp46 had established a covalent interaction with EDEM3." (PMID:29784879)

  • ERAD enhancement:

    "EDEM3 accelerates glycoprotein ERAD in transfected HEK293 cells, as shown by increased degradation of misfolded alpha1-antitrypsin variant (null (Hong Kong)) and of TCRalpha." (PMID:16431915)

  • Trimming beyond misfolded proteins:

    "Overexpression of EDEM3 also greatly stimulates mannose trimming not only from misfolded alpha1-AT null (Hong Kong) but also from total glycoproteins" (PMID:16431915)

  • M9 substrate (in vitro):

    "EDEM3 can convert an asparagine-linked M9 glycan to M8 and M7 glycans in contrast to glycine-linked M9 glycan, and the activity is enhanced in the presence of ERp46" (PMID:35500441)

  • Loss in hepatic cells:

    "Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death." (PMID:39838427, IN_VITRO, HCC context)

Ontology suggestions (all require lookup)

  • GO biological process:
  • ERAD pathway GO:0036503
  • protein alpha-1,2-demannosylation GO:0036508
  • protein N-linked glycosylation GO:0006487
  • response to endoplasmic reticulum stress GO:0034976
  • PERK-mediated unfolded protein response GO:0036499
  • ER mannose trimming involved in glycoprotein ERAD pathway (check whether a specific term exists)
  • GO molecular function: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity GO:0004571.
  • GO cellular component: endoplasmic reticulum lumen GO:0005788.
  • CL: fibroblast CL:0000057 (skin fibroblasts studied); B cell–derived lymphoblastoid lines (bind to B cell, CL:0000236, with a note); neuron CL:0000540 (inferred target tissue only).
  • Biological scale: step 1 MOLECULAR; step 2 MOLECULAR; step 3 CELLULAR; step 4 CELLULAR; step 5 ORGANISM.
  • Candidate modules: check just list-modules for an ERAD/UPR or glycosylation module before creating any conforms_to.

7. Anatomical Structures Affected

  • Organ/system: central nervous system (functional, with no structural MRI lesion), craniofacial region and GI tract (reflux, feeding).
  • Subcellular: ER lumen, where EDEM3 localizes with PDI:

    "showing the expected EDEM3 localization within the ER compartment, as revealed by significant overlapping with the ER marker, PDI" (PMID:39838427)

  • UBERON suggestions (verify): brain UBERON:0000955, face UBERON:0001456, esophagus UBERON:0001043.
  • Lateralization: not applicable; the facial features are symmetric. The single Poland sequence case is unilateral by definition and unverified.

8. Temporal Development

  • Onset: congenital or infantile. Feeding difficulty appears in infancy, and delays are recognized in early childhood.
  • Course: apparently static neurodevelopmental disorder. No regression is reported. The oldest reported patient was 33 years old (CDG Hub).
  • No staging, no remission, no longitudinal natural-history data. The critical period is early childhood, for developmental therapy.

9. Inheritance and Population

  • Inheritance: autosomal recessive (HP:0000007), with carrier parents confirmed by Sanger sequencing:

    "The unaffected parents were all heterozygous carriers." (PMID:34143952)

  • Penetrance and expressivity: apparently complete for DD/ID. Dysmorphism and hypotonia vary (about 50%).
  • Founder effect: c.1859del in the Portuguese Romani population (1/96 control carrier; shared 3.16 Mb homozygous haplotype).
  • Prevalence: unknown. There are 12 reported cases. Use measure_type: CASES_IN_LITERATURE with prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED.
  • Sex ratio, anticipation, mosaicism: not reported, not applicable and not reported, respectively.
  • Carrier frequency: not estimated. gnomAD pLoF counts could be queried.

10. Diagnostics

  • Genetic: exome or genome sequencing is how every case was found (exome + GeneMatcher). EDEM3 is included on some CDG panels. Chromosomal microarray and SNP array can reveal UPD1 or runs of homozygosity.
  • Biochemical (key): semiquantitative plasma N-glycan profiling (MALDI/LC-MS).

    "M9:M3 was increased in all 12 affected individuals." (PMID:34143952)

"M6:M9 ratio provided the highest discrimination between tested obligate heterozygotes (parents, n = 4) and affected individuals (n = 12; Table S3)." (PMID:34143952)

"Therefore, the combination of high M9:M3 and low M3:M4 ratios might also provide diagnostic clues for EDEM3-CDG when M5:M9 and M6:M9 ratios are normal." (PMID:34143952) - Reference ratios reported: M3:M4 normal 0.39–0.56; M9:M3 normal 1.16–2.92. - The standard CDG screen misses it: "Of note, human transferrin was normally glycosylated in the common clinical screening test for CDG in the three affected individuals from family 3." (PMID:34143952) - Variant validation: "The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing." (PMID:34143952) - Research assays: fibroblast [2-³H]mannose pulse-chase glycan analysis; EDEM3 immunoblot; qPCR. - Imaging: brain MRI is normal, which usefully separates it from many CDGs with cerebellar hypoplasia (e.g., PMM2-CDG). - Differential diagnosis: - Other type II/ERAD-related CDGs with normal transferrin: MAN1B1-CDG (which has a transferrin abnormality), MOGS-CDG, and PMM2-/ALG-CDG (distinguished by ↑M3/M4). - Non-specific ID syndromes. - Screening: no newborn screening. Carrier and prenatal testing are possible once familial variants are known. Targeted carrier testing is a consideration in the Portuguese Romani community.

11. Outcome / Prognosis

  • Survival, mortality and QoL data: none.
  • Survival into adulthood is documented (age 33).
  • Morbidity comes from ID, speech impairment and feeding problems; one patient needed a gastrostomy.
  • No prognostic biomarkers.

12. Treatment

There is no disease-specific therapy; care is supportive and multidisciplinary (CDG Hub, FCDGC). NCIT candidates below come from the CLAUDE.md list; confirm each by lookup.

Intervention NCIT (verify) Modality
Physical therapy NCIT:C15302 BEHAVIORAL
Speech-language therapy NCIT:C159273 BEHAVIORAL
Occupational therapy NCIT:C121351 BEHAVIORAL
Feeding support: NG tube / gastrostomy (1 case PEG) Supportive Care NCIT:C15747 (a gastrostomy procedure term needs lookup) SURGERY / OTHER
Reflux management Pharmacotherapy NCIT:C15986 (agent unspecified in the source) —
Genetic counseling NCIT:C15240 —
  • Experimental: NCT04199000, the FCDGC natural-history study. It is an observational CDG study (dietary interventions are explored generally) and not EDEM3-specific. Fetch it before citing.
  • No gene, RNA or targeted therapy exists.
  • Caution on pharmacology: kifunensine inhibits ER α1,2-mannosidases, so it would phenocopy the defect rather than treat it. EDEM3 inhibition has been proposed for hypertriglyceridemia (PMID:32213464) and cancer (PMID:39838427). That therapeutic vector runs opposite to this disease.

13. Prevention

  • Primary prevention is limited to genetic counseling, cascade carrier testing, and prenatal or preimplantation diagnosis for known familial variants.
  • Tertiary prevention covers early developmental intervention and feeding and reflux management.
  • No vaccination, public-health or environmental measures apply.

14. Other Species / Natural Disease

  • No naturally occurring animal disease has been reported (OMIA not checked in this session).
  • Orthologs: mouse Edem3; yeast HTM1/MNL1, whose activity likewise needs a PDI partner (Pdi1p), paralleling ERp46 (PMID:29784879); C. elegans edem-3.
  • The mechanism is conserved across eukaryotes:

    "This mechanism is conserved among eukaryotes, and mannose trimming from N-glycans is crucial for the degradation of glycoproteins by ER-associated degradation (ERAD)" (PMID:29784879)

  • Not zoonotic.

15. Model Organisms and Experimental Models

Model Findings Fidelity / limitations
Edem3 knockout mouse (PMID:34143952, MODEL_ORGANISM) Plasma and brain show ↑M8/M9 and ↓M5:M9 and M6:M9 ratios. There is no obvious phenotype; brain and body weight are reduced and genotype ratios are skewed. PARTIALLY_RECAPITULATES the glycan node. It does not model the neurodevelopmental phenotype. Species difference: the mouse does not reproduce the ↓M3:M4 ratio, and its most significant change is ↑M6:M7 rather than human ↓M7:M8. This is a HUMAN_MODEL_MISMATCH discussion candidate.
Hepatic Edem3 knockdown mouse (PMID:32213464; fetch) Plasma TG ↓, hepatic LRP1 ↑ Lipid biology; not relevant to CDG phenotypes
Patient fibroblasts and EBV-LCLs (PMID:34143952, IN_VITRO) NMD, absent protein, glycan defect, blunted PERK induction. Complementation with WT EDEM3 was performed (Fig. 3C–D). Strongest disease-relevant cellular model; not neural
EDEM1/3 double-KO HCT116 (PMID:34698634) M8B accumulation, delayed degradation of ATF6α and mCD3-δ Cancer cell line; double KO, not an EDEM3-only knockout
EDEM3-KO HepaRG (PMID:39838427) ↑BiP/PERK/p-eIF2α, apoptosis via p53/BAX, cell death at high passage Context is HCC/HBV; contradicts the direction of UPR in patient LCLs
C. elegans edem mutants (Ghenea et al. 2022, PLoS Genet, PMID:35192599; fetch) EDEM-2 acts on basal ERAD, EDEM-1/3 under stress; EDEM loss activates protective stress responses Invertebrate; no neurodevelopmental readout

Model gap: there is no iPSC-derived neuronal or organoid model of EDEM3-CDG.

Evidence-source summary for curation

PMID Type Use
34143952 HUMAN_CLINICAL (+ IN_VITRO + MODEL_ORGANISM sentences; split them by sentence) Disease definition, phenotypes, variants, biomarker, UPR, mouse
16431915 IN_VITRO (abstract only) EDEM3 GH47 mannosidase, ERAD enhancement
29784879 IN_VITRO ERp46 activation, Cys83/Cys442 disulfide
34698634 IN_VITRO EDEM3 as main M8B→M7/M6/M5 enzyme; EDEM1/3 DKO cells
35500441 IN_VITRO (abstract only) Asn-linked M9 substrate, ERp46 enhancement
39838427 IN_VITRO (cancer context; use cautiously) ER localization; KO → ER stress and apoptosis in hepatic cells
32213464, 35192599, 25092655, NCT04199000 Not cached Fetch with just fetch-reference before quoting

Gaps for the entry: - No GeneReviews chapter (confirm with just check-genereviews). - No natural-history, prevalence, prognosis or treatment data. - The neural mechanism is unmodeled. - The direction of the UPR change is unresolved: blunted in patient LCLs, activated in KO hepatic cells. This is a good KNOWLEDGE_GAP discussion.

Sources: - Local references_cache/ records: PMID_34143952, PMID_16431915, PMID_29784879, PMID_34698634, PMID_35500441, PMID_39838427 - CDG Hub – EDEM3-CDG (CDG-IIv) - FCDGC – EDEM3-CDG - OLS – MONDO:0030423 - EDEM3 Modulates Plasma Triglyceride Level through LRP1 (PMC7093811 / PMID:32213464) - Exome-wide association study of plasma lipids, Nat Genet 2017 - CDG state of the art 2022, Orphanet J Rare Dis - PubMed E-utilities search for "EDEM3"

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 29
Quoted claims found in source 29
Quoted claims not found in source 0
References weighed for topical relevance 10
On topic 8
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 36
Resolved 34
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 10
Terms named correctly 5
Terms named as a different term 4
Terms whose name is worth a second look 1

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:

  • DOID:0051050 (1 mention) - the report calls it "DOID"; DOID calls it congenital disorder of glycosylation type IIv
  • CL:0000540 (1 mention) - the report calls it "inferred target tissue only"; CL calls it neuron
  • NCIT:C15747 (1 mention) - the report calls it "a gastrostomy procedure term needs lookup"; NCIT calls it Supportive Care
  • NCIT:C15986 (1 mention) - the report calls it "agent unspecified in the source"; NCIT calls it Pharmacotherapy

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:

  • CL:0000057 (1 mention) - the report calls it "skin fibroblasts studied"; CL calls it fibroblast

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.