COG7-congenital disorder of glycosylation

Mendelian MONDO:0012118 Pathograph 35 Show in embeddings browser congenital disorder of glycosylation type II developmental anomaly of metabolic origin defect in conserved oligomeric Golgi complex

COG7-congenital disorder of glycosylation is a rare autosomal recessive congenital disorder of glycosylation caused by biallelic COG7 variants. COG7 deficiency impairs conserved oligomeric Golgi complex integrity, disrupts Golgi trafficking, and causes combined N- and O-glycosylation defects with severe infantile multisystem disease that can include progressive microcephaly, hypotonia, growth failure, gastrointestinal pseudo-obstruction, ventricular septal defect, wrinkled skin, adducted thumbs, and recurrent hyperthermia.

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1
Inheritance
9
Pathophys.
21
Phenotypes
1
Gaps
35
Pathograph
1
Genes
2
Medical Actions
1
Trials
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
The initial COG7-CDG report described affected siblings, and the disorder is modeled as an autosomal recessive COG-complex deficiency.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:15107842 SUPPORT Human Clinical
"Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex."
The sibling report and causal COG7 mutation support a familial Mendelian disorder; the inheritance mode is captured by the MONDO/OMIM disease concept and Falcon report.
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Discussions and Knowledge Gaps

1
By what route does a Golgi tethering and glycosylation defect produce recurrent hemophagocytic lymphohistiocytosis?
KNOWLEDGE GAP OPEN gap_cog7_glycosylation_immune_dysregulation
Attached to
pathophysiology#Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis pathophysiology#Combined N- and O-glycosylation Defect
The clinical association is now documented - recurrent HLH in three COG6/COG7 patients and unexplained recurrent fever in about 40% of published COG-deficiency patients - but no mechanism connects the two. HLH is classically driven by defective cytotoxic granule exocytosis in NK and CD8 T cells, and several of the proteins in that pathway are glycosylated and traffic through the Golgi, which makes a hypoglycosylation route plausible; nothing in the reported series tests it. Nor is it known whether the flares are infection-triggered secondary HLH in an infection-susceptible host, which would be a different disease model with different implications for prophylaxis. The authors state the link as a suggestion, and this entry curates it no more strongly than that.
Proposed experiments
NK-cell degranulation and cytotoxic-granule trafficking in COG deficiency
exp_cog7_nk_cytotoxicity_and_granule_trafficking
Measure CD107a degranulation, perforin and granzyme B content, and cytotoxic killing in NK and CD8 T cells from COG6/COG7-deficient patients against matched controls, alongside glycoproteomic profiling of the granule-exocytosis machinery. A degranulation defect tracking with hypoglycosylation would establish the primary-HLH route; normal degranulation would point to an infection-triggered secondary mechanism.
Prospective inflammatory-flare registry across COG subtypes
exp_cog_deficiency_flare_registry
Capture febrile episodes prospectively across COG1-COG8 patients with paired ferritin, soluble CD25, triglycerides, fibrinogen, and infectious workup, to establish which COG subtypes carry the risk, what fraction of flares meet HLH criteria, and whether corticosteroid prophylaxis changes the neurological trajectory that this series reported.
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Pathophysiology

9
COG7 Loss Destabilizes the Conserved Oligomeric Golgi Complex
COG7 variants impair integrity of the conserved oligomeric Golgi complex, disturbing intra-Golgi trafficking and the localization of glycosylation machinery.
COG7 hgnc:18622 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COG7 (hgnc:18622). hgnc:18622 is a gene from the HUGO Gene Nomenclature Committee.
Golgi vesicle transport GO:0048193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi vesicle transport (GO:0048193). GO:0048193 is a biological process from the Gene Ontology. ⚠ ABNORMAL intra-Golgi vesicle-mediated transport GO:0006891 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intra-Golgi vesicle-mediated transport (GO:0006891). GO:0006891 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Golgi apparatus GO:0005794 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Golgi apparatus (GO:0005794). GO:0005794 is an anatomical location from the Gene Ontology.
Downstream
Mislocalized Golgi Glycosylation Machinery Loss of COG-complex integrity disrupts Golgi trafficking and enzyme compartmentalization, mislocalizing glycosylation machinery.
Show evidence (1 reference)
PMID:15107842 SUPPORT In Vitro
"The mutation impairs integrity of the COG complex and alters Golgi trafficking, resulting in disruption of multiple glycosylation pathways."
This directly supports the upstream COG-complex and Golgi-trafficking defect.
Mislocalized Golgi Glycosylation Machinery
Disturbed anterograde and retrograde Golgi trafficking mislocalizes glycosylation enzymes, producing defective glycoprotein maturation.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
N-glycan processing GO:0006491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased N-glycan processing (GO:0006491). GO:0006491 is a biological process from the Gene Ontology. ↓ DECREASED Golgi vesicle transport GO:0048193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi vesicle transport (GO:0048193). GO:0048193 is a biological process from the Gene Ontology. ⚠ ABNORMAL intra-Golgi vesicle-mediated transport GO:0006891 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intra-Golgi vesicle-mediated transport (GO:0006891). GO:0006891 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Golgi apparatus GO:0005794 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Golgi apparatus (GO:0005794). GO:0005794 is an anatomical location from the Gene Ontology.
Downstream
Combined N- and O-glycosylation Defect Mislocalized Golgi enzymes impair maturation of both N-linked and O-linked glycoproteins.
Show evidence (2 references)
PMID:17904886 SUPPORT Other
"If the balance is disturbed, the glycosylation machinery is mislocalized, which can cause Congenital Disorders of Glycosylation type II (CDG-II), as illustrated by the identification of congenital defects in the Conserved Oligomeric Golgi (COG) complex in humans."
The review links disturbed vesicular balance to mislocalized glycosylation machinery in COG-related CDG-II.
PMID:17904886 SUPPORT Other
"We collected findings from different COG deficient cell types, such as CHO, yeast and human fibroblasts to hypothesize about structure and function of the COG complex"
This supports fibroblasts as one human cellular context used to study COG complex deficiency.
Combined N- and O-glycosylation Defect
COG7-CDG produces a type II CDG biochemical pattern with defective N-glycosylation and O-glycosylation.
N-glycan processing GO:0006491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased N-glycan processing (GO:0006491). GO:0006491 is a biological process from the Gene Ontology. ↓ DECREASED protein O-linked glycosylation GO:0006493 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein O-linked glycosylation (GO:0006493). GO:0006493 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis COG-complex deficiency is associated with recurrent hyperinflammatory febrile episodes that can meet HLH criteria, linking the Golgi glycosylation defect to immune dysregulation.
Neurodevelopmental and growth involvement The combined Golgi glycosylation defect is associated with progressive microcephaly, hypotonia, growth retardation, and failure to thrive in reported COG7-CDG patients.
Gastrointestinal dysmotility and feeding involvement COG7-CDG patients can have feeding problems from gastrointestinal pseudo-obstruction, contributing to failure to thrive.
Cardiac and thermoregulatory involvement The COG7-CDG multisystem phenotype includes cardiac anomalies and episodes of extreme hyperthermia.
Skin involvement Wrinkled skin is reported as part of the COG7-CDG phenotype.
Congenital limb involvement COG7-CDG patients can have adducted thumbs as a congenital limb manifestation.
Abnormal Glycosylation Deficient N- and O-glycosylation produces abnormal glycoprotein glycosylation profiles.
Type II Transferrin Isoform Profile The N-glycosylation component of the combined Golgi defect is reflected by a type II transferrin isoform profile.
Type II-like serum transferrin isoelectric focusing pattern Defective N-glycan processing is reflected by a type II-like sialotransferrin isoelectric focusing pattern.
Hyposialylated apolipoprotein C-III isoforms Defective O-glycosylation is reflected by increased hyposialylated apolipoprotein C-III isoforms.
Decreased total plasma sialic acid Global Golgi glycosylation disruption is reflected by markedly decreased total plasma sialic acid.
Increased plasma lysosomal enzyme activities The multiple Golgi glycosylation and trafficking defect is accompanied by increased plasma lysosomal enzyme activities.
Recurrent Infections Orphanet records recurrent infections as part of the multisystem COG7-CDG phenotype spectrum.
Abnormal facial shape Severe multisystem COG7-CDG can include dysmorphic facial appearance as part of the congenital presentation.
Severe Liver Disease Multisystem glycoprotein biosynthesis defects contribute to severe infantile liver disease.
Fatal Infantile Course The severe multiple Golgi glycosylation defect produced an early lethal infantile presentation in the original affected siblings.
Show evidence (2 references)
PMID:17904886 SUPPORT Other
"COG defects are a novel group of CDG-II with deficient N- as well as O-glycosylation."
This supports combined N- and O-glycosylation defects as the downstream biochemical consequence.
PMID:17356545 SUPPORT Human Clinical
"A combined disorder in the biosynthesis of N- and O-linked glycosylation with hyposialylation was detected."
This later human series directly supports the combined N- and O-glycosylation defect with hyposialylation in COG7-CDG.
Neurodevelopmental and growth involvement
COG7-CDG multisystem disease includes growth retardation, progressive severe microcephaly, hypotonia, and failure to thrive.
Downstream
Progressive microcephaly Progressive severe microcephaly is part of the characteristic COG7-CDG phenotype.
Hypotonia Hypotonia is reported among characteristic neurologic findings.
Growth delay Growth retardation is reported in affected COG7-CDG patients.
Failure to thrive Failure to thrive is reported in affected COG7-CDG patients.
Seizure Orphanet records seizure as a frequent neurologic phenotype of COG7-CDG.
Brain Atrophy Orphanet records brain atrophy as a very frequent neurologic structural phenotype of COG7-CDG.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The later COG7 series directly reports neurodevelopmental and growth manifestations in affected patients.
Gastrointestinal dysmotility and feeding involvement
COG7-CDG patients can have feeding problems caused by gastrointestinal pseudo-obstruction.
Downstream
Feeding difficulties Feeding problems are reported in COG7-CDG.
Intestinal pseudo-obstruction Feeding problems are attributed to gastrointestinal pseudo-obstruction in the reported COG7-CDG patients.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series reports feeding problems by gastrointestinal pseudo-obstruction.
Cardiac and thermoregulatory involvement
COG7-CDG includes cardiac anomalies and episodes of extreme hyperthermia in reported patients.
Downstream
Ventricular septal defect Ventricular septal defect is named in the paper title as a consistent COG7-CDG phenotype.
Recurrent hyperthermia Episodes of extreme hyperthermia are reported in COG7-CDG.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports cardiac anomalies and episodes of extreme hyperthermia.
Skin involvement
Wrinkled skin is reported among characteristic COG7-CDG findings.
Downstream
Cutis laxa Wrinkled skin is represented using the HPO cutis laxa term, whose definition includes wrinkled skin.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports wrinkled skin.
Congenital limb involvement
Adducted thumbs are reported as part of the COG7-CDG phenotype.
Downstream
Adducted thumb Adducted thumbs are reported in COG7-CDG.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports adducted thumbs.
Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
COG6- and COG7-deficient patients experience recurrent, poorly tolerated febrile episodes with biological features of hemophagocytic lymphohistiocytosis. In the reported series these flares were followed in two of three patients by neurological deterioration and new-onset epilepsy, so the inflammatory arm is not merely intercurrent illness but a driver of the neurological course. A systematic review found unexplained recurrent fever in roughly 40% of published COG-deficiency patients, with only one further fully documented HLH case, so the syndrome is probably underdiagnosed rather than rare.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:42269412 SUPPORT Human Clinical
"All three patients experienced recurrent febrile episodes associated with biological features of HLH."
Directly reports the recurrent HLH-associated febrile episodes this node represents in COG6/COG7 deficiency.
PMID:42269412 SUPPORT Human Clinical
"In two cases, these episodes were followed by neurological deterioration and onset of epilepsy."
Supports the neurological consequence that makes this arm clinically important rather than incidental.
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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 COG7-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

21
Cardiovascular 1
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia."
The paper title specifically names VSD as part of the consistent phenotype; the abstract body also reports cardiac anomalies.
Digestive 2
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports feeding problems.
Intestinal pseudo-obstruction HP:0004389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal pseudo-obstruction, annotated with Intestinal pseudo-obstruction (HP:0004389). HP:0004389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports feeding problems by gastrointestinal pseudo-obstruction.
Head and Neck 2
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
The clinical and biochemical report explicitly describes affected siblings as dysmorphic, which is modeled with the broad HPO facial-shape term because the abstract does not provide a more specific gestalt.
Progressive microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive severe microcephaly, annotated with Microcephaly (HP:0000252), qualified as course progressive; severity severe. HP:0000252 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Severity: SEVERE
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports progressive severe microcephaly in affected COG7-CDG patients.
Immune 1
Recurrent Infections VERY_FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79333 SUPPORT Other
"HP:0002719 | Recurrent infections | Very frequent (99-80%)"
Orphanet records recurrent infections as a very frequent phenotype of COG7-CDG.
Integument 1
Cutis laxa HP:0000973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wrinkled skin, annotated with Cutis laxa (HP:0000973). HP:0000973 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The COG7 clinical series reports wrinkled skin; HP:0000973 is used as the closest HPO term because its definition includes wrinkled skin.
Metabolism 3
Recurrent hyperthermia Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Episodes of extreme hyperthermia, annotated with Fever (HP:0001945), qualified as temporality recurrent. HP:0001945 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports episodes of extreme hyperthermia.
Recurrent unexplained fever FREQUENT Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954). HP:0001954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42269412 SUPPORT Human Clinical
"The literature review identified recurrent, unexplained, and poorly tolerated febrile episodes in approximately 40% of reported patients."
A systematic review of published COG-deficiency patients puts recurrent unexplained fever at roughly 40%, supporting the FREQUENT band.
Elevated Hepatic Transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79333 SUPPORT Other
"HP:0002910 | Elevated circulating hepatic transaminase concentration | Very frequent (99-80%)"
Orphanet records elevated circulating hepatic transaminase concentration as a very frequent phenotype of COG7-CDG.
Musculoskeletal 1
Hypotonia 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:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports hypotonia.
Nervous System 1
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79333 SUPPORT Other
"HP:0001250 | Seizure | Frequent (79-30%)"
Orphanet records seizure as a frequent phenotype of COG7-CDG.
Growth 2
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports growth retardation.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports failure to thrive.
Other 7
Abnormal Glycosylation HP:0012345 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal glycosylation (HP:0012345). HP:0012345 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16151902 SUPPORT Human Clinical
"Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern."
Serum transferrin IEF directly supports abnormal N-glycosylation.
PMID:16151902 SUPPORT Human Clinical
"O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms."
Apolipoprotein C-III IEF directly supports abnormal O-glycosylation.
Hemophagocytic lymphohistiocytosis Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytosis (HP:0012156), qualified as temporality recurrent. HP:0012156 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:42269412 SUPPORT Human Clinical
"We describe three patients with COG6 or COG7 deficiency presenting recurrent episodes of hemophagocytic lymphohistiocytosis (HLH)."
Directly reports recurrent HLH in COG7-deficient patients.
Adducted thumb HP:0001181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adducted thumb (HP:0001181). HP:0001181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17356545 SUPPORT Human Clinical
"The siblings and an unrelated single child of consanguineous parents presented with growth retardation, progressive, severe microcephaly, hypotonia, adducted thumbs, feeding problems by gastrointestinal pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin and episodes of..."
The clinical series directly reports adducted thumbs.
Severe Liver Disease Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Sequelae: Elevated Hepatic Transaminases Fatal Infantile Course
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
This directly supports severe liver disease and early lethality in affected siblings.
Type II Transferrin Isoform Profile VERY_FREQUENT HP:0012301 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type II transferrin isoform profile (HP:0012301). HP:0012301 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79333 SUPPORT Other
"HP:0012301 | Type II transferrin isoform profile | Very frequent (99-80%)"
Orphanet records type II transferrin isoform profile as a very frequent phenotype of COG7-CDG.
Brain Atrophy VERY_FREQUENT HP:0012444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain atrophy (HP:0012444). HP:0012444 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79333 SUPPORT Other
"HP:0012444 | Brain atrophy | Very frequent (99-80%)"
Orphanet records brain atrophy as a very frequent phenotype of COG7-CDG.
Fatal Infantile Course
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
The sibling report supports an early fatal clinical course in severe COG7-CDG.
🧬

Genetic Associations

1
COG7 pathogenic variants (Causal)
Gene: COG7 hgnc:18622 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COG7 (hgnc:18622). hgnc:18622 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:15107842 SUPPORT Human Clinical
"Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex."
This establishes COG7 as the causal gene for the disorder.
💊

Medical Actions

2
Supportive and Symptomatic Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No COG7-specific disease-modifying treatment is established; current care is supportive and directed to organ complications, while CDG-wide therapeutic discovery remains an unmet need.
Show evidence (1 reference)
PMID:37858231 SUPPORT Other
"However, much remains to be understood, with targeted therapies' discovery and approval being the most urgent unmet need."
The review supports the absence of established targeted CDG therapies; management of COG7-CDG therefore remains supportive and symptom-directed.
Early or prophylactic corticosteroid therapy for febrile episodes
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Corticosteroid treatment started early in, or prophylactically before, a febrile episode. In the reported COG6/COG7 series this appeared to reduce both the severity of inflammatory flares and their neurological impact. This is an observation in three patients, not a trial result, and the authors frame it as a recommendation for early recognition and preventive anti-inflammatory strategy rather than an established regimen.
Mechanism Target:
INHIBITS Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis — Suppresses the hyperinflammatory flare rather than correcting the underlying Golgi glycosylation defect.
Show evidence (1 reference)
PMID:42269412 SUPPORT Human Clinical
"Early or prophylactic corticosteroid therapy during febrile episodes appeared to mitigate both the severity and neurological impact of inflammatory flares."
Uncontrolled observation in three patients; supports the direction of effect but not its magnitude, hence PARTIAL.
Show evidence (1 reference)
PMID:42269412 SUPPORT Human Clinical
"Early recognition and preventive anti-inflammatory strategies are recommended."
The authors' explicit management recommendation for COG deficiency.
🔬

Biochemical Markers

4
Type II-like serum transferrin isoelectric focusing pattern (ABNORMAL)
Context: Type II-like transferrin IEF reflects abnormal Golgi-stage N-glycan processing.
Pathograph Readouts
Readout Of Combined N- and O-glycosylation Defect Positive Diagnostic
A type II-like serum sialotransferrin pattern reports the N-glycan processing component of the combined Golgi glycosylation defect.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern."
Serum sialotransferrin isoelectric focusing directly demonstrates the type II-like glycosylation abnormality.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern."
This directly supports the diagnostic transferrin IEF abnormality.
Hyposialylated apolipoprotein C-III isoforms (INCREASED)
Context: Apolipoprotein C-III IEF can reveal O-glycosylation defects in COG7-CDG.
Pathograph Readouts
Readout Of Combined N- and O-glycosylation Defect Positive Diagnostic
Increased hyposialylated apolipoprotein C-III isoforms report the O-glycosylation component of the combined Golgi glycosylation defect.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms."
Apolipoprotein C-III isoelectric focusing directly reports abnormal O-glycosylation.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms."
This directly supports abnormal apolipoprotein C-III isoforms as an O-glycosylation biomarker.
Increased plasma lysosomal enzyme activities (INCREASED)
Context: Elevated lysosomal enzyme activities in plasma are a reported biochemical abnormality in the original COG7-CDG siblings.
Pathograph Readouts
Readout Of Combined N- and O-glycosylation Defect Positive Diagnostic
Increased plasma lysosomal enzyme activities are a reported accompanying biochemical abnormality of the multiple Golgi glycosylation defect.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"Increased activities of lysosomal enzymes in plasma were found"
The abnormality is reported in COG7-CDG siblings with the multiple Golgi glycosylation defect, but the abstract does not define the exact mechanistic intermediate.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"Increased activities of lysosomal enzymes in plasma were found"
The abstract directly reports increased plasma lysosomal enzyme activities.
Decreased total plasma sialic acid (DECREASED)
Context: Reduced total sialic acid in plasma is a directly reported biochemical abnormality in COG7-CDG.
Pathograph Readouts
Readout Of Combined N- and O-glycosylation Defect Negative Diagnostic
Decreased total plasma sialic acid reports defective glycoprotein sialylation in the combined Golgi glycosylation defect.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"total sialic acid in plasma was strongly decreased"
Markedly decreased total plasma sialic acid is a direct biochemical readout of the reported COG7-CDG glycosylation disturbance.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"total sialic acid in plasma was strongly decreased"
The abstract directly reports markedly decreased total plasma sialic acid.
🔬

Diagnosis

2
Serum transferrin and apolipoprotein C-III isoelectric focusing
A type II-like serum sialotransferrin pattern and hyposialylated apolipoprotein C-III isoforms support a combined N- and O-glycosylation defect.
Results: Type II-like transferrin IEF with hyposialylated apolipoprotein C-III isoforms supports COG7-CDG evaluation.
Show evidence (1 reference)
PMID:16151902 SUPPORT Human Clinical
"This report on patients with a new variant of CDG, due to a multiple Golgi defect, emphasizes in addition to sialotransferrins the importance of analysis of a serum O-linked glycoprotein, e.g. apolipoprotein C-III, in unclassified CDG-X cases."
The abstract recommends adding O-linked glycoprotein analysis to sialotransferrin testing for unclassified CDG cases.
Molecular testing for COG7
Sequencing or targeted molecular testing can confirm pathogenic COG7 variants in a compatible CDG-II biochemical and clinical presentation.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic COG7 variants confirm the molecular diagnosis.
Show evidence (1 reference)
PMID:15107842 SUPPORT Human Clinical
"Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex."
Molecular identification of the COG7 mutation supports genetic testing as diagnostic confirmation.
🔬

Clinical Trials

1
NCT04199000 RECRUITING
CDG-wide observational natural-history study that may include genetically confirmed rare CDG subtypes such as COG7-CDG.
Show evidence (1 reference)
clinicaltrials:NCT04199000 SUPPORT Human Clinical
"The purpose of this research is to study the natural history of congenital disorders of glycosylation and its causes and treatments."
The trial is CDG-wide rather than COG7-specific, so it partially supports relevance to COG7-CDG.
{ }

Source YAML

click to show 
name: COG7-congenital disorder of glycosylation
creation_date: "2026-05-09T12:45:18Z"
description: >-
  COG7-congenital disorder of glycosylation is a rare autosomal recessive
  congenital disorder of glycosylation caused by biallelic COG7 variants.
  COG7 deficiency impairs conserved oligomeric Golgi complex integrity,
  disrupts Golgi trafficking, and causes combined N- and O-glycosylation
  defects with severe infantile multisystem disease that can include
  progressive microcephaly, hypotonia, growth failure, gastrointestinal
  pseudo-obstruction, ventricular septal defect, wrinkled skin, adducted
  thumbs, and recurrent hyperthermia.
category: Mendelian
disease_term:
  preferred_term: COG7-congenital disorder of glycosylation
  term:
    id: MONDO:0012118
    label: COG7-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type II
- developmental anomaly of metabolic origin
- defect in conserved oligomeric Golgi complex
synonyms:
- COG7-CDG
- COG-7 deficiency
- CDG type IIe
- CDG-IIe
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The initial COG7-CDG report described affected siblings, and the disorder is
    modeled as an autosomal recessive COG-complex deficiency.
  evidence:
  - reference: PMID:15107842
    reference_title: Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two siblings with a fatal form of CDG caused by a
      mutation in the gene encoding COG-7, a subunit of the conserved
      oligomeric Golgi (COG) complex.
    explanation: >-
      The sibling report and causal COG7 mutation support a familial Mendelian
      disorder; the inheritance mode is captured by the MONDO/OMIM disease
      concept and Falcon report.
pathophysiology:
- name: COG7 Loss Destabilizes the Conserved Oligomeric Golgi Complex
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    COG7 variants impair integrity of the conserved oligomeric Golgi complex,
    disturbing intra-Golgi trafficking and the localization of glycosylation
    machinery.
  genes:
  - preferred_term: COG7
    term:
      id: hgnc:18622
      label: COG7
  biological_processes:
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: intra-Golgi vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0006891
      label: intra-Golgi vesicle-mediated transport
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:15107842
    reference_title: Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutation impairs integrity of the COG complex and alters Golgi
      trafficking, resulting in disruption of multiple glycosylation pathways.
    explanation: >-
      This directly supports the upstream COG-complex and Golgi-trafficking
      defect.
  downstream:
  - target: Mislocalized Golgi Glycosylation Machinery
    description: >-
      Loss of COG-complex integrity disrupts Golgi trafficking and enzyme
      compartmentalization, mislocalizing glycosylation machinery.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15107842
      reference_title: Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mutation impairs integrity of the COG complex and alters Golgi
        trafficking, resulting in disruption of multiple glycosylation
        pathways.
      explanation: >-
        The causal COG7 mutation directly links impaired COG-complex integrity
        with altered Golgi trafficking and downstream glycosylation disruption.
    - reference: PMID:17904886
      reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        If the balance is disturbed, the glycosylation machinery is
        mislocalized, which can cause Congenital Disorders of Glycosylation type
        II (CDG-II), as illustrated by the identification of congenital defects
        in the Conserved Oligomeric Golgi (COG) complex in humans.
      explanation: >-
        The review explicitly connects COG-complex defects with mislocalized
        glycosylation machinery.
- name: Mislocalized Golgi Glycosylation Machinery
  description: >-
    Disturbed anterograde and retrograde Golgi trafficking mislocalizes
    glycosylation enzymes, producing defective glycoprotein maturation.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: N-glycan processing
    modifier: DECREASED
    term:
      id: GO:0006491
      label: N-glycan processing
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: intra-Golgi vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0006891
      label: intra-Golgi vesicle-mediated transport
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:17904886
    reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the balance is disturbed, the glycosylation machinery is mislocalized,
      which can cause Congenital Disorders of Glycosylation type II (CDG-II), as
      illustrated by the identification of congenital defects in the Conserved
      Oligomeric Golgi (COG) complex in humans.
    explanation: >-
      The review links disturbed vesicular balance to mislocalized
      glycosylation machinery in COG-related CDG-II.
  - reference: PMID:17904886
    reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We collected findings from different COG deficient cell types, such as CHO, yeast and human fibroblasts to hypothesize about structure and function of the COG complex"
    explanation: >-
      This supports fibroblasts as one human cellular context used to study COG
      complex deficiency.
  downstream:
  - target: Combined N- and O-glycosylation Defect
    description: >-
      Mislocalized Golgi enzymes impair maturation of both N-linked and
      O-linked glycoproteins.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17904886
      reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        If the balance is disturbed, the glycosylation machinery is
        mislocalized, which can cause Congenital Disorders of Glycosylation type
        II (CDG-II), as illustrated by the identification of congenital defects
        in the Conserved Oligomeric Golgi (COG) complex in humans.
      explanation: >-
        The review connects disturbed Golgi trafficking balance and
        mislocalized glycosylation machinery to COG-related CDG-II.
    - reference: PMID:17904886
      reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        COG defects are a novel group of CDG-II with deficient N- as well as
        O-glycosylation.
      explanation: >-
        The same review specifically supports combined N- and O-glycosylation
        deficiency in COG defects.
- name: Combined N- and O-glycosylation Defect
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    COG7-CDG produces a type II CDG biochemical pattern with defective
    N-glycosylation and O-glycosylation.
  biological_processes:
  - preferred_term: N-glycan processing
    modifier: DECREASED
    term:
      id: GO:0006491
      label: N-glycan processing
  - preferred_term: protein O-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
    modifier: ABNORMAL
  - preferred_term: O-glycan
    term:
      id: CHEBI:59521
      label: O-glycan
    modifier: ABNORMAL
  - preferred_term: sialic acid
    term:
      id: CHEBI:26667
      label: sialic acid
    modifier: DECREASED
  evidence:
  - reference: PMID:17904886
    reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      COG defects are a novel group of CDG-II with deficient N- as well as
      O-glycosylation.
    explanation: >-
      This supports combined N- and O-glycosylation defects as the downstream
      biochemical consequence.
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A combined disorder in the biosynthesis of N- and O-linked glycosylation
      with hyposialylation was detected.
    explanation: >-
      This later human series directly supports the combined N- and
      O-glycosylation defect with hyposialylation in COG7-CDG.
  downstream:
  - target: Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
    description: >-
      COG-complex deficiency is associated with recurrent hyperinflammatory
      febrile episodes that can meet HLH criteria, linking the Golgi
      glycosylation defect to immune dysregulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42269412
      reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings suggest a link between glycosylation defects and immune
        dysregulation.
      explanation: >-
        The case series and systematic review propose the glycosylation-defect
        to immune-dysregulation link this edge represents, while stating it as
        a suggested rather than demonstrated mechanism.
  - target: Neurodevelopmental and growth involvement
    description: >-
      The combined Golgi glycosylation defect is associated with progressive
      microcephaly, hypotonia, growth retardation, and failure to thrive in
      reported COG7-CDG patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The COG7 clinical series directly reports neurodevelopmental and growth
        manifestations in affected patients with the combined glycosylation
        disorder.
  - target: Gastrointestinal dysmotility and feeding involvement
    description: >-
      COG7-CDG patients can have feeding problems from gastrointestinal
      pseudo-obstruction, contributing to failure to thrive.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The same clinical series reports feeding problems by gastrointestinal
        pseudo-obstruction and failure to thrive in COG7-CDG.
  - target: Cardiac and thermoregulatory involvement
    description: >-
      The COG7-CDG multisystem phenotype includes cardiac anomalies and
      episodes of extreme hyperthermia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports cardiac anomalies and extreme
        hyperthermia episodes in COG7-CDG.
  - target: Skin involvement
    description: Wrinkled skin is reported as part of the COG7-CDG phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        Wrinkled skin is directly reported in the same COG7-CDG clinical
        series.
  - target: Congenital limb involvement
    description: >-
      COG7-CDG patients can have adducted thumbs as a congenital limb
      manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        Adducted thumbs are directly reported among the characteristic clinical
        findings in the COG7-CDG series.
  - target: Abnormal Glycosylation
    description: >-
      Deficient N- and O-glycosylation produces abnormal glycoprotein
      glycosylation profiles.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17904886
      reference_title: Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        COG defects are a novel group of CDG-II with deficient N- as well as
        O-glycosylation.
      explanation: >-
        The review directly supports abnormal glycosylation as the biochemical
        manifestation of deficient N- and O-glycosylation in COG defects.
  - target: Type II Transferrin Isoform Profile
    description: >-
      The N-glycosylation component of the combined Golgi defect is reflected by
      a type II transferrin isoform profile.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:79333
      reference_title: "COG7-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012301 | Type II transferrin isoform profile | Very frequent (99-80%)"
      explanation: Orphanet records the type II transferrin profile as a very frequent COG7-CDG biochemical phenotype.
  - target: Type II-like serum transferrin isoelectric focusing pattern
    description: >-
      Defective N-glycan processing is reflected by a type II-like
      sialotransferrin isoelectric focusing pattern.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isoelectric focusing of serum sialotransferrins showed a type 2-like
        CDG pattern.
      explanation: >-
        Serum sialotransferrin IEF is a direct biochemical readout of the
        N-glycosylation component of the combined glycosylation defect.
  - target: Hyposialylated apolipoprotein C-III isoforms
    description: >-
      Defective O-glycosylation is reflected by increased hyposialylated
      apolipoprotein C-III isoforms.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        O-Glycosylation was investigated by isoelectric focusing of
        apolipoprotein C-III, which showed increased fractions of hyposialylated
        isoforms.
      explanation: >-
        Apolipoprotein C-III IEF directly reports the O-glycosylation arm of
        the combined biochemical defect.
  - target: Decreased total plasma sialic acid
    description: >-
      Global Golgi glycosylation disruption is reflected by markedly decreased
      total plasma sialic acid.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "total sialic acid in plasma was strongly decreased"
      explanation: >-
        Decreased total plasma sialic acid is a directly reported biochemical
        consequence in affected siblings with the multiple Golgi glycosylation
        defect.
  - target: Increased plasma lysosomal enzyme activities
    description: >-
      The multiple Golgi glycosylation and trafficking defect is accompanied by
      increased plasma lysosomal enzyme activities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Increased activities of lysosomal enzymes in plasma were found"
      explanation: >-
        Increased plasma lysosomal enzyme activities are reported in affected
        siblings with the multiple Golgi glycosylation defect, but the abstract
        does not define the exact intermediate mechanism.
  - target: Recurrent Infections
    description: >-
      Orphanet records recurrent infections as part of the multisystem COG7-CDG
      phenotype spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:79333
      reference_title: "COG7-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002719 | Recurrent infections | Very frequent (99-80%)"
      explanation: Orphanet records recurrent infections as a very frequent COG7-CDG phenotype.
  - target: Abnormal facial shape
    description: >-
      Severe multisystem COG7-CDG can include dysmorphic facial appearance as
      part of the congenital presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
      explanation: >-
        The sibling report directly documents dysmorphism in COG7-CDG; the
        broad HPO facial-shape term is used because no more specific facial
        gestalt is given in the abstract.
  - target: Severe Liver Disease
    description: >-
      Multisystem glycoprotein biosynthesis defects contribute to severe
      infantile liver disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report on two dysmorphic siblings with severe liver disease who died
        at the age of a few weeks.
      explanation: >-
        Human sibling cases with COG7-related combined glycosylation defects
        directly support severe infantile liver disease as a clinical
        consequence.
  - target: Fatal Infantile Course
    description: >-
      The severe multiple Golgi glycosylation defect produced an early lethal
      infantile presentation in the original affected siblings.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
      explanation: >-
        The clinical report links COG7-CDG with severe liver disease and death
        in the first weeks of life.
- name: Neurodevelopmental and growth involvement
  description: >-
    COG7-CDG multisystem disease includes growth retardation, progressive
    severe microcephaly, hypotonia, and failure to thrive.
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The later COG7 series directly reports neurodevelopmental and growth
      manifestations in affected patients.
  downstream:
  - target: Progressive microcephaly
    description: >-
      Progressive severe microcephaly is part of the characteristic COG7-CDG
      phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports progressive severe microcephaly.
  - target: Hypotonia
    description: Hypotonia is reported among characteristic neurologic findings.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The COG7 series directly reports hypotonia.
  - target: Growth delay
    description: Growth retardation is reported in affected COG7-CDG patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports growth retardation.
  - target: Failure to thrive
    description: Failure to thrive is reported in affected COG7-CDG patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports failure to thrive.
  - target: Seizure
    description: >-
      Orphanet records seizure as a frequent neurologic phenotype of COG7-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:79333
      reference_title: "COG7-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
      explanation: Orphanet records seizure as a frequent COG7-CDG phenotype.
  - target: Brain Atrophy
    description: >-
      Orphanet records brain atrophy as a very frequent neurologic structural
      phenotype of COG7-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:79333
      reference_title: "COG7-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012444 | Brain atrophy | Very frequent (99-80%)"
      explanation: Orphanet records brain atrophy as a very frequent COG7-CDG phenotype.
- name: Gastrointestinal dysmotility and feeding involvement
  description: >-
    COG7-CDG patients can have feeding problems caused by gastrointestinal
    pseudo-obstruction.
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The clinical series reports feeding problems by gastrointestinal
      pseudo-obstruction.
  downstream:
  - target: Feeding difficulties
    description: Feeding problems are reported in COG7-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports feeding problems.
  - target: Intestinal pseudo-obstruction
    description: >-
      Feeding problems are attributed to gastrointestinal pseudo-obstruction in
      the reported COG7-CDG patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The COG7 series directly reports gastrointestinal pseudo-obstruction.
- name: Cardiac and thermoregulatory involvement
  description: >-
    COG7-CDG includes cardiac anomalies and episodes of extreme hyperthermia in
    reported patients.
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The clinical series directly reports cardiac anomalies and episodes of
      extreme hyperthermia.
  downstream:
  - target: Ventricular septal defect
    description: >-
      Ventricular septal defect is named in the paper title as a consistent
      COG7-CDG phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A common mutation in the COG7 gene with a consistent phenotype
        including microcephaly, adducted thumbs, growth retardation, VSD and
        episodes of hyperthermia.
      explanation: >-
        The title specifically names VSD as part of the consistent phenotype.
  - target: Recurrent hyperthermia
    description: Episodes of extreme hyperthermia are reported in COG7-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The clinical series directly reports episodes of extreme hyperthermia.
- name: Skin involvement
  description: Wrinkled skin is reported among characteristic COG7-CDG findings.
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports wrinkled skin.
  downstream:
  - target: Cutis laxa
    description: >-
      Wrinkled skin is represented using the HPO cutis laxa term, whose
      definition includes wrinkled skin.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: >-
        The COG7 series directly reports wrinkled skin; HP:0000973 is the
        closest HPO match because its definition includes wrinkled skin.
- name: Congenital limb involvement
  description: Adducted thumbs are reported as part of the COG7-CDG phenotype.
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports adducted thumbs.
  downstream:
  - target: Adducted thumb
    description: Adducted thumbs are reported in COG7-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17356545
      reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The siblings and an unrelated single child of consanguineous parents
        presented with growth retardation, progressive, severe microcephaly,
        hypotonia, adducted thumbs, feeding problems by gastrointestinal
        pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
        and episodes of extreme hyperthermia.
      explanation: The clinical series directly reports adducted thumbs.
- name: Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
  biological_scale: ORGANISM
  description: >-
    COG6- and COG7-deficient patients experience recurrent, poorly tolerated
    febrile episodes with biological features of hemophagocytic
    lymphohistiocytosis. In the reported series these flares were followed in
    two of three patients by neurological deterioration and new-onset epilepsy,
    so the inflammatory arm is not merely intercurrent illness but a driver of
    the neurological course. A systematic review found unexplained recurrent
    fever in roughly 40% of published COG-deficiency patients, with only one
    further fully documented HLH case, so the syndrome is probably
    underdiagnosed rather than rare.
  role: consequence
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: macrophage activation
    modifier: INCREASED
    term:
      id: GO:0042116
      label: macrophage activation
  evidence:
  - reference: PMID:42269412
    reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients experienced recurrent febrile episodes associated with
      biological features of HLH.
    explanation: >-
      Directly reports the recurrent HLH-associated febrile episodes this node
      represents in COG6/COG7 deficiency.
  - reference: PMID:42269412
    reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two cases, these episodes were followed by neurological deterioration
      and onset of epilepsy.
    explanation: >-
      Supports the neurological consequence that makes this arm clinically
      important rather than incidental.
phenotypes:
- name: Abnormal Glycosylation
  category: Biochemical
  description: >-
    Serum transferrin isoelectric focusing and apolipoprotein C-III
    isoelectric focusing show abnormal N-linked and O-linked glycosylation.
  phenotype_term:
    preferred_term: Abnormal glycosylation
    term:
      id: HP:0012345
      label: Abnormal glycosylation
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern."
    explanation: >-
      Serum transferrin IEF directly supports abnormal N-glycosylation.
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms."
    explanation: >-
      Apolipoprotein C-III IEF directly supports abnormal O-glycosylation.
- name: Abnormal facial shape
  category: Clinical
  description: >-
    Dysmorphic appearance was reported in the original affected siblings with
    severe infantile COG7-CDG; no more specific facial gestalt is available in
    the cached abstract.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks."
    explanation: >-
      The clinical and biochemical report explicitly describes affected
      siblings as dysmorphic, which is modeled with the broad HPO facial-shape
      term because the abstract does not provide a more specific gestalt.
- name: Progressive microcephaly
  category: Neurological
  description: >-
    Progressive severe microcephaly is part of the recurrent COG7-CDG clinical
    presentation.
  phenotype_term:
    preferred_term: Progressive severe microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
    severity: SEVERE
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The clinical series directly reports progressive severe microcephaly in
      affected COG7-CDG patients.
- name: Hypotonia
  category: Neurological
  description: Hypotonia is reported among characteristic COG7-CDG findings.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports hypotonia.
- name: Growth delay
  category: Growth
  description: Growth retardation is reported in COG7-CDG patients.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports growth retardation.
- name: Failure to thrive
  category: Growth
  description: Failure to thrive is reported in affected COG7-CDG patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports failure to thrive.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding problems are reported in COG7-CDG and were attributed to
    gastrointestinal pseudo-obstruction in the clinical series.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports feeding problems.
- name: Intestinal pseudo-obstruction
  category: Gastrointestinal
  description: >-
    Gastrointestinal pseudo-obstruction is reported as the cause of feeding
    problems in affected COG7-CDG patients.
  phenotype_term:
    preferred_term: Gastrointestinal pseudo-obstruction
    term:
      id: HP:0004389
      label: Intestinal pseudo-obstruction
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The clinical series directly reports feeding problems by gastrointestinal
      pseudo-obstruction.
- name: Ventricular septal defect
  category: Cardiac
  description: >-
    Ventricular septal defect is named as part of the consistent COG7-CDG
    phenotype.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common mutation in the COG7 gene with a consistent phenotype including
      microcephaly, adducted thumbs, growth retardation, VSD and episodes of
      hyperthermia.
    explanation: >-
      The paper title specifically names VSD as part of the consistent
      phenotype; the abstract body also reports cardiac anomalies.
- name: Recurrent hyperthermia
  category: Clinical
  description: Episodes of extreme hyperthermia are reported in COG7-CDG.
  phenotype_term:
    preferred_term: Episodes of extreme hyperthermia
    term:
      id: HP:0001945
      label: Fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports episodes of extreme hyperthermia.
- name: Hemophagocytic lymphohistiocytosis
  category: Immunologic
  description: >-
    Recurrent episodes meeting the biological criteria for hemophagocytic
    lymphohistiocytosis, reported in COG6- and COG7-deficient patients.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
    temporality: RECURRENT
  reports_on:
  - target: Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      HLH biology is the diagnostic readout of the hyperinflammatory node.
  evidence:
  - reference: PMID:42269412
    reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe three patients with COG6 or COG7 deficiency presenting
      recurrent episodes of hemophagocytic lymphohistiocytosis (HLH).
    explanation: >-
      Directly reports recurrent HLH in COG7-deficient patients.
- name: Recurrent unexplained fever
  category: Immunologic
  description: >-
    Recurrent, unexplained, and poorly tolerated febrile episodes, distinct from
    the extreme-hyperthermia episodes of the original COG7 series in that they
    carry an inflammatory signature rather than a thermoregulatory one.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:42269412
    reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The literature review identified recurrent, unexplained, and poorly
      tolerated febrile episodes in approximately 40% of reported patients.
    explanation: >-
      A systematic review of published COG-deficiency patients puts recurrent
      unexplained fever at roughly 40%, supporting the FREQUENT band.
- name: Cutis laxa
  category: Dermatologic
  description: >-
    Wrinkled skin is reported in COG7-CDG and is represented with the HPO cutis
    laxa term because its definition includes wrinkled skin.
  phenotype_term:
    preferred_term: Wrinkled skin
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: >-
      The COG7 clinical series reports wrinkled skin; HP:0000973 is used as
      the closest HPO term because its definition includes wrinkled skin.
- name: Adducted thumb
  category: Musculoskeletal
  description: Adducted thumbs are reported in affected COG7-CDG patients.
  phenotype_term:
    preferred_term: Adducted thumb
    term:
      id: HP:0001181
      label: Adducted thumb
  evidence:
  - reference: PMID:17356545
    reference_title: A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The siblings and an unrelated single child of consanguineous parents
      presented with growth retardation, progressive, severe microcephaly,
      hypotonia, adducted thumbs, feeding problems by gastrointestinal
      pseudo-obstruction, failure to thrive, cardiac anomalies, wrinkled skin
      and episodes of extreme hyperthermia.
    explanation: The clinical series directly reports adducted thumbs.
- name: Severe Liver Disease
  category: Hepatic
  description: >-
    Severe infantile liver disease was reported in the original clinical and
    biochemical description of COG7 deficiency.
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two dysmorphic siblings with severe liver disease who died
      at the age of a few weeks.
    explanation: >-
      This directly supports severe liver disease and early lethality in
      affected siblings.
  sequelae:
  - target: Elevated Hepatic Transaminases
    description: Hepatocyte injury in severe liver disease releases hepatic transaminases into the circulation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:79333
      reference_title: "COG7-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002910 | Elevated circulating hepatic transaminase concentration | Very frequent (99-80%)"
      explanation: Orphanet supports elevated circulating hepatic transaminases as a very frequent hepatic manifestation of COG7-CDG.
  - target: Fatal Infantile Course
    description: >-
      Severe liver disease in the reported affected siblings was associated
      with death within the first weeks of life.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report on two dysmorphic siblings with severe liver disease who died
        at the age of a few weeks.
      explanation: >-
        The same sibling report links severe liver disease with death during
        early infancy.
- name: Seizure
  category: Neurological
  frequency: FREQUENT
  description: >
    Seizures are recorded as a frequent neurological phenotype of COG7-CDG in
    Orphanet.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:79333
    reference_title: "COG7-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
    explanation: Orphanet records seizure as a frequent phenotype of COG7-CDG.
- name: Recurrent Infections
  category: Immunological
  frequency: VERY_FREQUENT
  description: >
    Recurrent infections are recorded as a very frequent phenotype of COG7-CDG
    in Orphanet.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: ORPHA:79333
    reference_title: "COG7-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002719 | Recurrent infections | Very frequent (99-80%)"
    explanation: Orphanet records recurrent infections as a very frequent phenotype of COG7-CDG.
- name: Elevated Hepatic Transaminases
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >
    Elevated circulating hepatic transaminase concentration is recorded as a
    very frequent biochemical phenotype of COG7-CDG in Orphanet.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: ORPHA:79333
    reference_title: "COG7-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002910 | Elevated circulating hepatic transaminase concentration | Very frequent (99-80%)"
    explanation: Orphanet records elevated circulating hepatic transaminase concentration as a very frequent phenotype of COG7-CDG.
- name: Type II Transferrin Isoform Profile
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >
    Type II transferrin isoform profile is recorded as a very frequent
    biochemical phenotype of COG7-CDG in Orphanet.
  phenotype_term:
    preferred_term: Type II transferrin isoform profile
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  evidence:
  - reference: ORPHA:79333
    reference_title: "COG7-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012301 | Type II transferrin isoform profile | Very frequent (99-80%)"
    explanation: Orphanet records type II transferrin isoform profile as a very frequent phenotype of COG7-CDG.
- name: Brain Atrophy
  category: Neurological
  frequency: VERY_FREQUENT
  description: >
    Brain atrophy is recorded as a very frequent neurological phenotype of
    COG7-CDG in Orphanet.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: ORPHA:79333
    reference_title: "COG7-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012444 | Brain atrophy | Very frequent (99-80%)"
    explanation: Orphanet records brain atrophy as a very frequent phenotype of COG7-CDG.
- name: Fatal Infantile Course
  category: Clinical
  description: >-
    The earliest reported affected siblings died within the first weeks of life.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two dysmorphic siblings with severe liver disease who died
      at the age of a few weeks.
    explanation: >-
      The sibling report supports an early fatal clinical course in severe
      COG7-CDG.
genetic:
- name: COG7 pathogenic variants
  association: Causal
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: COG7
    term:
      id: hgnc:18622
      label: COG7
  evidence:
  - reference: PMID:15107842
    reference_title: Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two siblings with a fatal form of CDG caused by a
      mutation in the gene encoding COG-7, a subunit of the conserved
      oligomeric Golgi (COG) complex.
    explanation: >-
      This establishes COG7 as the causal gene for the disorder.
biochemical:
- name: Type II-like serum transferrin isoelectric focusing pattern
  presence: ABNORMAL
  context: >-
    Type II-like transferrin IEF reflects abnormal Golgi-stage N-glycan
    processing.
  readouts:
  - target: Combined N- and O-glycosylation Defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A type II-like serum sialotransferrin pattern reports the N-glycan
      processing component of the combined Golgi glycosylation defect.
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isoelectric focusing of serum sialotransferrins showed a type 2-like
        CDG pattern.
      explanation: >-
        Serum sialotransferrin isoelectric focusing directly demonstrates the
        type II-like glycosylation abnormality.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG
      pattern.
    explanation: >-
      This directly supports the diagnostic transferrin IEF abnormality.
- name: Hyposialylated apolipoprotein C-III isoforms
  presence: INCREASED
  context: >-
    Apolipoprotein C-III IEF can reveal O-glycosylation defects in COG7-CDG.
  readouts:
  - target: Combined N- and O-glycosylation Defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased hyposialylated apolipoprotein C-III isoforms report the
      O-glycosylation component of the combined Golgi glycosylation defect.
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        O-Glycosylation was investigated by isoelectric focusing of
        apolipoprotein C-III, which showed increased fractions of
        hyposialylated isoforms.
      explanation: >-
        Apolipoprotein C-III isoelectric focusing directly reports abnormal
        O-glycosylation.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      O-Glycosylation was investigated by isoelectric focusing of apolipoprotein
      C-III, which showed increased fractions of hyposialylated isoforms.
    explanation: >-
      This directly supports abnormal apolipoprotein C-III isoforms as an
      O-glycosylation biomarker.
- name: Increased plasma lysosomal enzyme activities
  presence: INCREASED
  context: >-
    Elevated lysosomal enzyme activities in plasma are a reported biochemical
    abnormality in the original COG7-CDG siblings.
  readouts:
  - target: Combined N- and O-glycosylation Defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased plasma lysosomal enzyme activities are a reported accompanying
      biochemical abnormality of the multiple Golgi glycosylation defect.
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Increased activities of lysosomal enzymes in plasma were found"
      explanation: >-
        The abnormality is reported in COG7-CDG siblings with the multiple
        Golgi glycosylation defect, but the abstract does not define the exact
        mechanistic intermediate.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased activities of lysosomal enzymes in plasma were found"
    explanation: >-
      The abstract directly reports increased plasma lysosomal enzyme activities.
- name: Decreased total plasma sialic acid
  biomarker_term:
    preferred_term: sialic acid
    term:
      id: CHEBI:26667
      label: sialic acid
  presence: DECREASED
  context: >-
    Reduced total sialic acid in plasma is a directly reported biochemical
    abnormality in COG7-CDG.
  readouts:
  - target: Combined N- and O-glycosylation Defect
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Decreased total plasma sialic acid reports defective glycoprotein
      sialylation in the combined Golgi glycosylation defect.
    evidence:
    - reference: PMID:16151902
      reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "total sialic acid in plasma was strongly decreased"
      explanation: >-
        Markedly decreased total plasma sialic acid is a direct biochemical
        readout of the reported COG7-CDG glycosylation disturbance.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "total sialic acid in plasma was strongly decreased"
    explanation: >-
      The abstract directly reports markedly decreased total plasma sialic acid.
diagnosis:
- name: Serum transferrin and apolipoprotein C-III isoelectric focusing
  description: >-
    A type II-like serum sialotransferrin pattern and hyposialylated
    apolipoprotein C-III isoforms support a combined N- and O-glycosylation
    defect.
  results: Type II-like transferrin IEF with hyposialylated apolipoprotein C-III isoforms supports COG7-CDG evaluation.
  evidence:
  - reference: PMID:16151902
    reference_title: Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report on patients with a new variant of CDG, due to a multiple
      Golgi defect, emphasizes in addition to sialotransferrins the importance
      of analysis of a serum O-linked glycoprotein, e.g. apolipoprotein C-III,
      in unclassified CDG-X cases.
    explanation: >-
      The abstract recommends adding O-linked glycoprotein analysis to
      sialotransferrin testing for unclassified CDG cases.
- name: Molecular testing for COG7
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Sequencing or targeted molecular testing can confirm pathogenic COG7
    variants in a compatible CDG-II biochemical and clinical presentation.
  results: Biallelic pathogenic COG7 variants confirm the molecular diagnosis.
  evidence:
  - reference: PMID:15107842
    reference_title: Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two siblings with a fatal form of CDG caused by a
      mutation in the gene encoding COG-7, a subunit of the conserved
      oligomeric Golgi (COG) complex.
    explanation: >-
      Molecular identification of the COG7 mutation supports genetic testing as
      diagnostic confirmation.
treatments:
- name: Supportive and Symptomatic Care
  description: >-
    No COG7-specific disease-modifying treatment is established; current care
    is supportive and directed to organ complications, while CDG-wide
    therapeutic discovery remains an unmet need.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37858231
    reference_title: "Congenital disorders of glycosylation (CDG): state of the art in 2022."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, much remains to be understood, with targeted therapies'
      discovery and approval being the most urgent unmet need.
    explanation: >-
      The review supports the absence of established targeted CDG therapies;
      management of COG7-CDG therefore remains supportive and symptom-directed.
- name: Early or prophylactic corticosteroid therapy for febrile episodes
  description: >-
    Corticosteroid treatment started early in, or prophylactically before, a
    febrile episode. In the reported COG6/COG7 series this appeared to reduce
    both the severity of inflammatory flares and their neurological impact.
    This is an observation in three patients, not a trial result, and the
    authors frame it as a recommendation for early recognition and preventive
    anti-inflammatory strategy rather than an established regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
    treatment_effect: INHIBITS
    description: >-
      Suppresses the hyperinflammatory flare rather than correcting the
      underlying Golgi glycosylation defect.
    evidence:
    - reference: PMID:42269412
      reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Early or prophylactic corticosteroid therapy during febrile episodes
        appeared to mitigate both the severity and neurological impact of
        inflammatory flares.
      explanation: >-
        Uncontrolled observation in three patients; supports the direction of
        effect but not its magnitude, hence PARTIAL.
  evidence:
  - reference: PMID:42269412
    reference_title: "Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early recognition and preventive anti-inflammatory strategies are
      recommended.
    explanation: >-
      The authors' explicit management recommendation for COG deficiency.
clinical_trials:
- name: NCT04199000
  status: RECRUITING
  description: >-
    CDG-wide observational natural-history study that may include genetically
    confirmed rare CDG subtypes such as COG7-CDG.
  evidence:
  - reference: clinicaltrials:NCT04199000
    reference_title: Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this research is to study the natural history of
      congenital disorders of glycosylation and its causes and treatments.
    explanation: >-
      The trial is CDG-wide rather than COG7-specific, so it partially supports
      relevance to COG7-CDG.
discussions:
- discussion_id: gap_cog7_glycosylation_immune_dysregulation
  prompt: >-
    By what route does a Golgi tethering and glycosylation defect produce
    recurrent hemophagocytic lymphohistiocytosis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Hyperinflammatory episodes and hemophagocytic lymphohistiocytosis
  - pathophysiology#Combined N- and O-glycosylation Defect
  rationale: >-
    The clinical association is now documented - recurrent HLH in three
    COG6/COG7 patients and unexplained recurrent fever in about 40% of
    published COG-deficiency patients - but no mechanism connects the two. HLH
    is classically driven by defective cytotoxic granule exocytosis in NK and
    CD8 T cells, and several of the proteins in that pathway are glycosylated
    and traffic through the Golgi, which makes a hypoglycosylation route
    plausible; nothing in the reported series tests it. Nor is it known whether
    the flares are infection-triggered secondary HLH in an
    infection-susceptible host, which would be a different disease model with
    different implications for prophylaxis. The authors state the link as a
    suggestion, and this entry curates it no more strongly than that.
  proposed_experiments:
  - experiment_id: exp_cog7_nk_cytotoxicity_and_granule_trafficking
    name: NK-cell degranulation and cytotoxic-granule trafficking in COG deficiency
    description: >-
      Measure CD107a degranulation, perforin and granzyme B content, and
      cytotoxic killing in NK and CD8 T cells from COG6/COG7-deficient patients
      against matched controls, alongside glycoproteomic profiling of the
      granule-exocytosis machinery. A degranulation defect tracking with
      hypoglycosylation would establish the primary-HLH route; normal
      degranulation would point to an infection-triggered secondary mechanism.
  - experiment_id: exp_cog_deficiency_flare_registry
    name: Prospective inflammatory-flare registry across COG subtypes
    description: >-
      Capture febrile episodes prospectively across COG1-COG8 patients with
      paired ferritin, soluble CD25, triglycerides, fibrinogen, and infectious
      workup, to establish which COG subtypes carry the risk, what fraction of
      flares meet HLH criteria, and whether corticosteroid prophylaxis changes
      the neurological trajectory that this series reported.
notes: >-
  Falcon deep research completed on 2026-05-09. The YAML intentionally uses
  only claims with PMID or ClinicalTrials.gov cache-backed snippets. Broader
  report findings on seizures, infections, cardiac insufficiency, founder
  effects, and endocrine findings were not modeled unless supported by fetched
  abstract text.
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
COG7–Congenital Disorder of Glycosylation (COG7-CDG) — Comprehensive Research Report
Edison Scientific Literature 29 citations 2026-05-09T09:03:50.707690

COG7–Congenital Disorder of Glycosylation (COG7-CDG) — Comprehensive Research Report

Target disease

Name: COG7-congenital disorder of glycosylation (COG7-CDG) (spaapen2005clinicalandbiochemical pages 3-6, francisco2023congenitaldisordersof pages 4-6)
Category: Mendelian (autosomal recessive) (wu2004mutationofthe pages 3-4, zeevaert2008deficienciesinsubunits pages 2-3)
Known identifier in retrieved sources: MIM/OMIM 608779 (unsal2026endocrineimplicationsof pages 15-16, francisco2023congenitaldisordersof pages 4-6)
MONDO ID: Not identified in retrieved sources (no MONDO cross-reference present in the documents retrieved for this run).

1. Disease information

Overview (current understanding)

COG7-CDG is a severe, typically neonatal-onset congenital disorder of glycosylation caused by loss of function of COG7, a subunit of the conserved oligomeric Golgi (COG) complex, leading to impaired Golgi trafficking and combined N- and O-glycosylation defects (wu2004mutationofthe pages 2-3, francisco2023congenitaldisordersof pages 2-4).

Synonyms / alternative names

  • COG-7 deficiency (spaapen2005clinicalandbiochemical pages 3-6)
  • CDG type IIe / CDG-IIe (historical subtype naming; noted as proposed nomenclature in early COG7-deficiency literature) (spaapen2005clinicalandbiochemical pages 3-6)

Key identifiers (from available evidence)

  • OMIM/MIM: 608779 (unsal2026endocrineimplicationsof pages 15-16, francisco2023congenitaldisordersof pages 4-6)

Not found in retrieved texts for this run: Orphanet number, ICD-10/ICD-11 code, MeSH disease heading, MONDO ID.

Evidence provenance

Most disease-specific information available here is aggregated from published case reports/series and reviews, rather than EHR-derived cohorts (e.g., index families and a 6-patient founder series) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

2. Etiology

Disease causal factors

Primary cause: biallelic pathogenic variants in COG7 impair COG complex integrity and Golgi trafficking, producing broad glycosylation abnormalities (wu2004mutationofthe pages 2-3, wu2004mutationofthe pages 3-4).

Inheritance: autosomal recessive; multiple affected families are consanguineous and show homozygosity for the recurrent splice variant (wu2004mutationofthe pages 3-4, zeevaert2008deficienciesinsubunits pages 3-5).

Risk factors

  • Genetic: COG7 loss-of-function variants; a recurrent splice variant is associated with multiple families (zeevaert2008deficienciesinsubunits pages 3-5).
  • Environmental: Not established/expected as a primary driver in this Mendelian disorder; no gene–environment interaction evidence was identified in retrieved sources.

Protective factors

No genetic or environmental protective factors were identified in retrieved sources.

3. Phenotypes (clinical spectrum)

Typical onset, course, and severity

COG7-CDG is classically a rapidly progressive neonatal multisystem disorder with early lethality (weeks to months) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

Key clinical manifestations (human)

Case reports and a North African founder series describe a consistent phenotype including: * Growth impairment / prenatal growth retardation (HPO suggestion: HP:0001511 Intrauterine growth restriction) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5) * Progressive microcephaly (HP:0000252 Microcephaly) (unsal2026endocrineimplicationsof pages 15-16, zeevaert2008deficienciesinsubunits pages 3-5) * Dysmorphic features (e.g., micrognathia; low-set/dysplastic ears; loose/wrinkled skin reported) (HP:0000347 Micrognathia; HP:0000369 Low-set ears; HP:0000974 Hyperelastic skin / cutis laxa-like features) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5) * Generalized hypotonia (HP:0001252 Hypotonia) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5) * Severe encephalopathy / seizures / epilepsy (HP:0001298 Encephalopathy; HP:0001250 Seizures) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5) * Cholestatic liver disease / hepatopathy (HP:0001396 Cholestasis; HP:0001402 Hepatomegaly) (spaapen2005clinicalandbiochemical pages 3-6, zeevaert2008deficienciesinsubunits pages 3-5) * Recurrent infections (HP:0002719 Recurrent infections) (wu2004mutationofthe pages 1-2) * Cardiac defects including ASD/VSD (HP:0001631 Atrial septal defect; HP:0001629 Ventricular septal defect) (zeevaert2008deficienciesinsubunits pages 3-5) * Episodes of hyperthermia (HP:0001945 Fever / hyperthermia episodes) (zeevaert2008deficienciesinsubunits pages 3-5) * Hand anomalies including adducted thumbs/overlapping fingers/ulnar deviation/contractures (HP:0001184 Adducted thumbs; HP:0009484 Ulnar deviation of the hand) (unsal2026endocrineimplicationsof pages 15-16)

Frequency information (available)

  • A founder series reported 6 patients from 4 families (North Africa) with a shared homozygous splice variant and highly similar severe phenotype (zeevaert2008deficienciesinsubunits pages 3-5).
  • Reported laboratory abnormality frequencies include elevated CK in 4/6 and transaminase elevation in 6/6 (zeevaert2008deficienciesinsubunits pages 3-5).

Quality of life impact

Direct QoL instrument results specific to COG7-CDG were not found; however, the reported severe neonatal encephalopathy, cholestatic liver disease, seizures, and early death imply profound impairment (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

4. Genetic / molecular information

Causal gene

  • COG7 (component of the conserved oligomeric Golgi complex) (unsal2026endocrineimplicationsof pages 15-16, wu2004mutationofthe pages 2-3)

Pathogenic variants (human)

A recurrent homozygous splice variant is prominent: * IVS1+4A>C (also reported as c.169+4A>C) → aberrant splicing with a 19-bp deletion in mRNA and marked reduction/absence of COG7 protein (wu2004mutationofthe pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5).

Functional consequence: loss of COG7 destabilizes the COG complex, disrupts Golgi trafficking, reduces nucleotide-sugar transport into the Golgi, and reduces glycosyltransferase activities, producing combined N- and O-glycosylation defects (wu2004mutationofthe pages 2-3, wu2004mutationofthe pages 4-6).

Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic mechanisms, or chromosomal abnormalities specific to COG7-CDG were identified in retrieved sources.

5. Environmental information

COG7-CDG is a monogenic disorder; non-genetic environmental contributors or infectious triggers were not reported in the retrieved evidence.

6. Mechanism / pathophysiology

Mechanistic causal chain (gene → cell biology → biochemical signature → clinical phenotype)

  1. COG7 deficiency reduces/abolishes COG7 protein and destabilizes the COG complex (wu2004mutationofthe pages 2-3).
  2. This impairs ER–Golgi and intra-Golgi trafficking (e.g., slowed trafficking of a Golgi sialyltransferase reporter ST-GFP) (wu2004mutationofthe pages 2-3, wu2004mutationofthe pages 3-4).
  3. Disrupted Golgi homeostasis leads to defective glycosylation enzyme function/localization, including reduced activities of O-glycan Core1GalT and ST3Gal-I and impaired nucleotide-sugar transport into the Golgi (~30% of normal in patient fibroblasts) (wu2004mutationofthe pages 2-3).
  4. The net result is combined N- and O-hypoglycosylation, especially hyposialylation/galactosylation defects, measurable in plasma glycoproteins (transferrin, apoC-III) and reflected in systemic multi-organ disease (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6).

Key cellular/biochemical findings (selected quantitative data)

  • Golgi nucleotide-sugar transport ~30% of normal for CMP-sialic acid/UDP-galactose in one patient’s fibroblasts (wu2004mutationofthe pages 2-3).
  • Glycosyltransferase activities reduced (Core1GalT and ST3Gal-I reductions reported) (wu2004mutationofthe pages 2-3).
  • Total serum sialic acid reduced two- to fivefold in the index family, with transferrin glycoforms distributed across 0–4 sialic acids (wu2004mutationofthe pages 1-2, wu2004mutationofthe pages 2-3).

Ontology suggestions

GO Biological Process (examples): * Golgi organization; vesicle tethering / retrograde vesicle-mediated transport, Golgi to ER; protein glycosylation; protein sialylation (mechanistically implied by trafficking and sialylation defects) (wu2004mutationofthe pages 2-3, francisco2023congenitaldisordersof pages 2-4).

Cell types (CL, examples): * Fibroblast (patient-derived dermal fibroblasts are the key experimental system) (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 1-3).
* Hepatocyte; neuron (inferred from dominant liver and CNS involvement described clinically; direct cellular profiling not found) (zeevaert2008deficienciesinsubunits pages 3-5, francisco2023congenitaldisordersof pages 1-2).

7. Anatomical structures affected

Based on multisystem involvement reported: * Brain/CNS (encephalopathy, seizures; cerebral/cerebellar atrophy described in summaries) (UBERON examples: UBERON:0000955 brain; UBERON:0002037 cerebellum) (unsal2026endocrineimplicationsof pages 15-16, zeevaert2008deficienciesinsubunits pages 3-5). * Liver (cholestasis, elevated transaminases, hepatopathy) (UBERON:0002107 liver) (spaapen2005clinicalandbiochemical pages 3-6, zeevaert2008deficienciesinsubunits pages 3-5). * Heart (ASD/VSD; cardiac insufficiency) (UBERON:0000948 heart) (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5). * Immune/host defense (recurrent infections) (wu2004mutationofthe pages 1-2).

Subcellular localization central to pathogenesis: Golgi apparatus (GO cellular component: Golgi apparatus) (wu2004mutationofthe pages 2-3).

8. Temporal development

  • Onset: congenital/neonatal (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).
  • Course: rapidly progressive, multi-organ deterioration (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).
  • Duration: typically weeks to months in classic cases (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

9. Inheritance and population

Inheritance

Autosomal recessive, frequently in consanguineous families (zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5).

Epidemiology (available data)

Population prevalence/incidence estimates were not identified in retrieved evidence.

Variant distribution / founder effect

A cohort described 6 patients (2 Tunisia, 4 Morocco) all homozygous for IVS1+4A>C / c.169+4A>C, and haplotyping suggested a shared ancestral haplotype consistent with a founder effect in North Africa (zeevaert2008deficienciesinsubunits pages 3-5).

Case fatality / prognosis statistics

Deaths were reported between 5 weeks and 9 months in the 6-patient series (zeevaert2008deficienciesinsubunits pages 3-5); the index sibling pair died at 5 and 10 weeks (wu2004mutationofthe pages 1-2).

10. Diagnostics

Core clinical laboratory tests / biomarkers

1) Serum transferrin isoforms (IEF) * Abnormal type II / type 2-like CDG pattern is a key screening biomarker for processing/trafficking CDGs (wu2004mutationofthe pages 1-2, spaapen2005clinicalandbiochemical pages 3-6).
* Visual evidence: transferrin IEF patterns from affected siblings are shown in Spaapen et al. 2005 (spaapen2005clinicalandbiochemical media a32196a0, spaapen2005clinicalandbiochemical media 9596aac9).

2) Apolipoprotein C-III isoforms (IEF) * ApoC-III IEF demonstrates O-glycan hyposialylation, supporting combined N- and O-glycosylation involvement (spaapen2005clinicalandbiochemical pages 3-6).
* Visual evidence: apoC-III IEF figure in Spaapen et al. 2005 (spaapen2005clinicalandbiochemical media a32196a0, spaapen2005clinicalandbiochemical media 9596aac9).

3) Sialic acid quantitation (blood/urine) * Low total plasma sialic acid reported in affected siblings (e.g., 321 and 599 µmol/L vs reference range) and increased urinary free sialic acid in one patient (spaapen2005clinicalandbiochemical pages 3-6).

4) Supportive labs * Elevated transaminases (200–890 U/L in the 6-patient series) and elevated CK in 4/6 (zeevaert2008deficienciesinsubunits pages 3-5).

Genetic testing

Disease confirmation is via molecular detection of biallelic COG7 pathogenic variants (e.g., IVS1+4A>C) (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6).

Current diagnostic practice trends (2023–2024 emphasis)

A 2023 state-of-the-art review highlights that while transferrin IEF historically underpinned CDG screening, genomic sequencing (WES/WGS) is now “very powerful” and may be the only route when biochemical biomarkers are absent (francisco2023congenitaldisordersof pages 4-6). The same review notes expanding glycomics biomarkers (e.g., ESI-QTOF-MS glycan profiling; additional glycoprotein biomarkers) (francisco2023congenitaldisordersof pages 4-6).

Differential diagnosis

Not systematically enumerated in retrieved texts; however, differential diagnosis typically includes other Golgi/trafficking CDG and other causes of neonatal cholestasis/encephalopathy with abnormal transferrin IEF (supported generally by the CDG classification context) (francisco2023congenitaldisordersof pages 2-4, paprocka2021congenitaldisordersof pages 2-4).

11. Outcome / prognosis

COG7-CDG is most often lethal in early infancy in the classic phenotype, with fatality occurring as early as 5–10 weeks in initial siblings and by 9 months in the founder series (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

Prognostic biomarkers specific to COG7-CDG were not identified; severity is largely defined clinically and by multi-organ involvement (zeevaert2008deficienciesinsubunits pages 3-5).

12. Treatment

Disease-specific therapy

No COG7-CDG-specific disease-modifying therapy was identified in the retrieved evidence.

General CDG treatment landscape (expert consensus from authoritative reviews)

A 2023 Orphanet Journal of Rare Diseases review states the urgency of developing targeted therapies and indicates that CDG patients often require ongoing management for multi-organ complications (francisco2023congenitaldisordersof pages 1-2). The review also states CDG treatment remains almost entirely symptomatic/supportive, with mannose supplementation for MPI-CDG as a key established exception (francisco2023congenitaldisordersof pages 2-4).

Supportive care (real-world implementations; inferred from phenotype)

Given the presentation, standard practice typically includes: * seizure management (anti-seizure medications) (general CDG neurology management context) (paprocka2021congenitaldisordersof pages 2-4) * nutritional support / failure-to-thrive management * management of cholestasis and hepatic dysfunction * infection prevention and treatment * cardiology management for structural defects/heart failure These are consistent with the reported multi-organ involvement and severe neonatal course, though explicit COG7-CDG management protocols were not found in retrieved sources (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 3-5).

Clinical trials / registries relevant to CDG (and applicability to COG7-CDG)

  • NCT04199000 (“Clinical and Basic Investigations Into Congenital Disorders of Glycosylation”), observational natural history study; start date 2019-10-08; recruiting; estimated enrollment 500. Key aims include measuring progression/severity using the Nijmegen CDG rating scale and collecting patient-reported outcomes (PROMIS) and biospecimens for biomarkers (NCT04199000 chunk 1). The record requires a genetically/enzymatically/molecularly confirmed CDG diagnosis, making it plausibly inclusive of rare CDG subtypes even if COG7 is not explicitly listed among keywords in the excerpt (NCT04199000 chunk 1).

MAXO suggestions (supportive)

  • MAXO:0000758 anticonvulsant therapy (for seizures; generalized CDG epilepsy management context) (paprocka2021congenitaldisordersof pages 2-4)
  • MAXO:0000472 nutritional support / feeding support
  • MAXO:0000464 supportive care
    (These MAXO mappings are suggested conceptually; explicit MAXO-coded statements were not present in the retrieved texts.)

13. Prevention

Primary prevention is not applicable in the usual sense for a recessive Mendelian disorder; the principal prevention strategies are genetic counseling and carrier/prenatal testing in at-risk families (implied by AR inheritance and founder effect) (zeevaert2008deficienciesinsubunits pages 3-5).

14. Other species / natural disease

No naturally occurring veterinary disease analogs specifically tied to COG7 were identified in retrieved sources.

15. Model organisms and experimental systems

Cellular models (human)

Patient-derived dermal fibroblasts are the principal model system; mechanistic assays include: * trafficking assays (ST-GFP fluorescence recovery/photobleaching approaches) * nucleotide-sugar transport assays into Golgi * glycosyltransferase activity assays * lectin binding/neuraminidase treatment Importantly, complementation with wild-type COG7 cDNA rescues trafficking and glycosylation defects, supporting causality (wu2004mutationofthe pages 2-3, wu2004mutationofthe pages 4-6).

Comparative models

COG biology and phenotypes are also studied in CHO cell mutants (ldlB/ldlC), yeast, and animal models including Drosophila and C. elegans (general COG modeling context) (zeevaert2008deficienciesinsubunits pages 2-3).

Recent developments and latest research emphasis (2023–2024)

Field-level advances relevant to COG7-CDG

A 2023 “state of the art” review highlights rapid progress driven by multi-omics and expanding gene discovery, and explicitly notes the unmet need for targeted therapies: “targeted therapies’ discovery and approval being the most urgent unmet need.” (published Oct 2023; URL: https://doi.org/10.1186/s13023-023-02879-z) (francisco2023congenitaldisordersof pages 1-2). The same review reports substantial expansion of known CDG genes/phenotypes (163 genes; 193 phenotypes) and emphasizes genomic sequencing as a key diagnostic route (francisco2023congenitaldisordersof pages 1-2, francisco2023congenitaldisordersof pages 4-6).

For trafficking-related CDG classification, the review places vesicular transport defects (including COG defects) within an “other (including multiple)” category (francisco2023congenitaldisordersof pages 2-4).

Key structured summary table

Category Structured fact Evidence / key references
Disease name / synonyms COG7-congenital disorder of glycosylation (COG7-CDG); older nomenclature includes CDG type IIe / CDG-IIe and COG-7 deficiency (spaapen2005clinicalandbiochemical pages 3-6) Spaapen et al., 2005, J Inherit Metab Dis, DOI: https://doi.org/10.1007/s10545-005-0015-z (spaapen2005clinicalandbiochemical pages 3-6)
Identifier(s) MIM/OMIM: 608779 reported for COG7-CDG in recent review tables (unsal2026endocrineimplicationsof pages 15-16, francisco2023congenitaldisordersof pages 4-6) Ünsal & Özön, 2026, DOI: https://doi.org/10.4274/jcrpe.galenos.2025.2024-10-7; Francisco et al., 2023, DOI: https://doi.org/10.1186/s13023-023-02879-z (unsal2026endocrineimplicationsof pages 15-16, francisco2023congenitaldisordersof pages 4-6)
Disease class Trafficking-related / Golgi homeostasis CDG affecting combined N- and O-glycosylation through COG complex dysfunction (wu2004mutationofthe pages 2-3, francisco2023congenitaldisordersof pages 2-4) Wu et al., 2004, Nat Med, DOI: https://doi.org/10.1038/nm1041; Francisco et al., 2023, DOI: https://doi.org/10.1186/s13023-023-02879-z (wu2004mutationofthe pages 2-3, francisco2023congenitaldisordersof pages 2-4)
Inheritance Autosomal recessive; reported in affected siblings and multiple consanguineous families (wu2004mutationofthe pages 3-4, zeevaert2008deficienciesinsubunits pages 2-3) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (wu2004mutationofthe pages 3-4, zeevaert2008deficienciesinsubunits pages 2-3)
Key pathogenic variant Recurrent homozygous splice variant IVS1+4A>C, also reported as c.169+4A>C, causing aberrant splicing with a 19-bp deletion in mRNA and marked reduction/absence of COG7 protein (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6, zeevaert2008deficienciesinsubunits pages 3-5) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Spaapen et al., 2005, DOI: https://doi.org/10.1007/s10545-005-0015-z; Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6, zeevaert2008deficienciesinsubunits pages 3-5)
Molecular consequence COG7 loss destabilizes COG complex integrity and impairs Golgi trafficking, with slowed ER-to-Golgi/Golgi transport and broad glycosylation abnormalities (wu2004mutationofthe pages 3-4, wu2004mutationofthe pages 2-3) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041 (wu2004mutationofthe pages 3-4, wu2004mutationofthe pages 2-3)
Core clinical features Severe neonatal multisystem disease: prenatal growth retardation/IUGR, microcephaly, dysmorphic facial features, loose/wrinkled skin, hypotonia, seizures/epilepsy, cholestatic liver disease/hepatopathy, recurrent infections, cardiac insufficiency, cerebellar/brain abnormalities (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5)
Recognizable phenotype clues Frequently highlighted pattern: microcephaly, growth impairment, adducted thumbs/hand anomalies, ventricular septal defect (VSD), and episodes of hyperthermia (zeevaert2008deficienciesinsubunits pages 3-5) Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (zeevaert2008deficienciesinsubunits pages 3-5)
Additional neurodevelopmental / structural findings Reported features include global developmental delay, cerebral/cerebellar atrophy, hypoplasia of the corpus callosum, delayed myelination, and skeletal/hand abnormalities (unsal2026endocrineimplicationsof pages 15-16) Ünsal & Özön, 2026, DOI: https://doi.org/10.4274/jcrpe.galenos.2025.2024-10-7 (unsal2026endocrineimplicationsof pages 15-16)
Transferrin IEF biomarker Abnormal serum transferrin isoelectric focusing (IEF) showing a type II / type 2-like CDG pattern; one report described an approximately equal distribution of transferrin glycoforms with 0–4 sialic acids (wu2004mutationofthe pages 1-2, wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6, spaapen2005clinicalandbiochemical media a32196a0) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Spaapen et al., 2005, DOI: https://doi.org/10.1007/s10545-005-0015-z (wu2004mutationofthe pages 1-2, wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6, spaapen2005clinicalandbiochemical media a32196a0)
ApoC-III IEF biomarker Aberrant apolipoprotein C-III IEF demonstrating hyposialylation of O-linked glycans (spaapen2005clinicalandbiochemical pages 3-6, spaapen2005clinicalandbiochemical media a32196a0) Spaapen et al., 2005, DOI: https://doi.org/10.1007/s10545-005-0015-z (spaapen2005clinicalandbiochemical pages 3-6, spaapen2005clinicalandbiochemical media a32196a0)
Sialic acid abnormalities Low total plasma sialic acid reported: 321 µmol/L and 599 µmol/L in two siblings (reference 1620–2940 µmol/L); two- to fivefold reduction in total serum sialic acid also described; urinary free sialic acid increased in one patient (182 µmol/mmol creatinine) (wu2004mutationofthe pages 1-2, spaapen2005clinicalandbiochemical pages 3-6) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Spaapen et al., 2005, DOI: https://doi.org/10.1007/s10545-005-0015-z (wu2004mutationofthe pages 1-2, spaapen2005clinicalandbiochemical pages 3-6)
Other biochemical / cellular findings Partial N-glycan sialylation defect, decreased O-glycan sialylation, increased RCA-I lectin binding, elevated CMP-sialic acid (2–3×), reduced Golgi nucleotide-sugar transport (~30% of normal), and reduced Core1GalT (~40%) and ST3Gal-I (~62%) activities (wu2004mutationofthe pages 2-3) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041 (wu2004mutationofthe pages 2-3)
Liver / muscle laboratory abnormalities Markedly elevated transaminases in all six patients (200–890 U/L, normal <40) and elevated CK in 4/6 patients (zeevaert2008deficienciesinsubunits pages 3-5) Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (zeevaert2008deficienciesinsubunits pages 3-5)
Prognosis Usually rapidly progressive and lethal in infancy; reported deaths occurred from 5 weeks to 9 months; initial sibling report described death at 5 and 10 weeks (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5) Wu et al., 2004, DOI: https://doi.org/10.1038/nm1041; Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (wu2004mutationofthe pages 1-2, zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5)
Notable populations / founder effect Early series identified 6 patients from 4 families, all with consanguinity and originating from North Africa (2 Tunisia, 4 Morocco); shared haplotype suggested a founder effect / shared ancestral haplotype for c.169+4A>C (zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5) Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (zeevaert2008deficienciesinsubunits pages 2-3, zeevaert2008deficienciesinsubunits pages 3-5)
Frequency data available In one screened cohort of 35 CDG-IIx cases, 5/35 (~14%) had a COG-subunit defect; COG7 was described as the most frequent COG-related defect in that series (zeevaert2008deficienciesinsubunits pages 2-3) Zeevaert et al., 2008, DOI: https://doi.org/10.1016/j.ymgme.2007.08.118 (zeevaert2008deficienciesinsubunits pages 2-3)
Diagnostic practice notes Recent CDG reviews indicate a shift from reliance on transferrin IEF alone toward WES/WGS and broader biochemical glycomics; however, transferrin IEF remains an important first-line screen for many N-glycosylation defects (francisco2023congenitaldisordersof pages 4-6, paprocka2021congenitaldisordersof pages 2-4) Francisco et al., 2023, DOI: https://doi.org/10.1186/s13023-023-02879-z; Paprocka et al., 2021, DOI: https://doi.org/10.3390/brainsci11010088 (francisco2023congenitaldisordersof pages 4-6, paprocka2021congenitaldisordersof pages 2-4)
Key references Wu et al., 2004 (Nature Medicine; discovery of lethal COG7 disorder; DOI: https://doi.org/10.1038/nm1041); Spaapen et al., 2005 (clinical/biochemical siblings report; DOI: https://doi.org/10.1007/s10545-005-0015-z); Zeevaert et al., 2008 (6-patient/founder-effect cohort; DOI: https://doi.org/10.1016/j.ymgme.2007.08.118); Francisco et al., 2023 (state-of-the-art CDG review; DOI: https://doi.org/10.1186/s13023-023-02879-z) PMID not available in gathered evidence; URLs/DOIs supported by context (wu2004mutationofthe pages 2-3, spaapen2005clinicalandbiochemical pages 3-6, zeevaert2008deficienciesinsubunits pages 3-5, francisco2023congenitaldisordersof pages 4-6)

Table: This table compiles the core structured facts for COG7-congenital disorder of glycosylation, including identifiers, inheritance, recurrent pathogenic variant, clinical and laboratory hallmarks, prognosis, and population observations. It is designed as a concise evidence-backed summary for knowledge-base curation.

Key diagnostic figure evidence (visual)

Transferrin IEF (type II-like pattern) and apoC-III IEF (O-glycan hyposialylation) in COG7 deficiency are shown in Spaapen et al. 2005 (spaapen2005clinicalandbiochemical media a32196a0, spaapen2005clinicalandbiochemical media 9596aac9).

Evidence gaps / not available in retrieved sources

  • MONDO, Orphanet, ICD-10/ICD-11, and MeSH identifiers for COG7-CDG were not found in retrieved texts during this run.
  • Population prevalence/incidence and long-term survivorship data beyond infancy were not identified.
  • No COG7-specific interventional trials were identified; available trial evidence is CDG-wide natural history/registry infrastructure.

References

  1. (spaapen2005clinicalandbiochemical pages 3-6): L. J. M. Spaapen, J. A. Bakker, S. B. van der Meer, H. J. Sijstermans, R. A. Steet, R. A. Wevers, and J. Jaeken. Clinical and biochemical presentation of siblings with cog-7 deficiency, a lethal multiple o- and n-glycosylation disorder. Journal of Inherited Metabolic Disease, 28:707-714, Sep 2005. URL: https://doi.org/10.1007/s10545-005-0015-z, doi:10.1007/s10545-005-0015-z. This article has 73 citations and is from a peer-reviewed journal.

  2. (francisco2023congenitaldisordersof pages 4-6): Rita Francisco, Sandra Brasil, Joana Poejo, Jaak Jaeken, Carlota Pascoal, Paula A. Videira, and Vanessa dos Reis Ferreira. Congenital disorders of glycosylation (cdg): state of the art in 2022. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02879-z, doi:10.1186/s13023-023-02879-z. This article has 71 citations and is from a peer-reviewed journal.

  3. (wu2004mutationofthe pages 3-4): Xiaohua Wu, Richard A Steet, Ognian Bohorov, Jaap Bakker, John Newell, Monty Krieger, Leo Spaapen, Stuart Kornfeld, and Hudson H Freeze. Mutation of the cog complex subunit gene cog7 causes a lethal congenital disorder. Nature Medicine, 10:518-523, Apr 2004. URL: https://doi.org/10.1038/nm1041, doi:10.1038/nm1041. This article has 360 citations and is from a highest quality peer-reviewed journal.

  4. (zeevaert2008deficienciesinsubunits pages 2-3): Renate Zeevaert, François Foulquier, Jaak Jaeken, and Gert Matthijs. Deficiencies in subunits of the conserved oligomeric golgi (cog) complex define a novel group of congenital disorders of glycosylation. Molecular genetics and metabolism, 93 1:15-21, Jan 2008. URL: https://doi.org/10.1016/j.ymgme.2007.08.118, doi:10.1016/j.ymgme.2007.08.118. This article has 126 citations and is from a peer-reviewed journal.

  5. (unsal2026endocrineimplicationsof pages 15-16): Yağmur Ünsal and Zeynep Alev Özön. Endocrine implications of congenital disorders of glycosylation. Journal of clinical research in pediatric endocrinology, Feb 2026. URL: https://doi.org/10.4274/jcrpe.galenos.2025.2024-10-7, doi:10.4274/jcrpe.galenos.2025.2024-10-7. This article has 2 citations.

  6. (wu2004mutationofthe pages 2-3): Xiaohua Wu, Richard A Steet, Ognian Bohorov, Jaap Bakker, John Newell, Monty Krieger, Leo Spaapen, Stuart Kornfeld, and Hudson H Freeze. Mutation of the cog complex subunit gene cog7 causes a lethal congenital disorder. Nature Medicine, 10:518-523, Apr 2004. URL: https://doi.org/10.1038/nm1041, doi:10.1038/nm1041. This article has 360 citations and is from a highest quality peer-reviewed journal.

  7. (francisco2023congenitaldisordersof pages 2-4): Rita Francisco, Sandra Brasil, Joana Poejo, Jaak Jaeken, Carlota Pascoal, Paula A. Videira, and Vanessa dos Reis Ferreira. Congenital disorders of glycosylation (cdg): state of the art in 2022. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02879-z, doi:10.1186/s13023-023-02879-z. This article has 71 citations and is from a peer-reviewed journal.

  8. (wu2004mutationofthe pages 1-2): Xiaohua Wu, Richard A Steet, Ognian Bohorov, Jaap Bakker, John Newell, Monty Krieger, Leo Spaapen, Stuart Kornfeld, and Hudson H Freeze. Mutation of the cog complex subunit gene cog7 causes a lethal congenital disorder. Nature Medicine, 10:518-523, Apr 2004. URL: https://doi.org/10.1038/nm1041, doi:10.1038/nm1041. This article has 360 citations and is from a highest quality peer-reviewed journal.

  9. (zeevaert2008deficienciesinsubunits pages 3-5): Renate Zeevaert, François Foulquier, Jaak Jaeken, and Gert Matthijs. Deficiencies in subunits of the conserved oligomeric golgi (cog) complex define a novel group of congenital disorders of glycosylation. Molecular genetics and metabolism, 93 1:15-21, Jan 2008. URL: https://doi.org/10.1016/j.ymgme.2007.08.118, doi:10.1016/j.ymgme.2007.08.118. This article has 126 citations and is from a peer-reviewed journal.

  10. (wu2004mutationofthe pages 4-6): Xiaohua Wu, Richard A Steet, Ognian Bohorov, Jaap Bakker, John Newell, Monty Krieger, Leo Spaapen, Stuart Kornfeld, and Hudson H Freeze. Mutation of the cog complex subunit gene cog7 causes a lethal congenital disorder. Nature Medicine, 10:518-523, Apr 2004. URL: https://doi.org/10.1038/nm1041, doi:10.1038/nm1041. This article has 360 citations and is from a highest quality peer-reviewed journal.

  11. (spaapen2005clinicalandbiochemical pages 1-3): L. J. M. Spaapen, J. A. Bakker, S. B. van der Meer, H. J. Sijstermans, R. A. Steet, R. A. Wevers, and J. Jaeken. Clinical and biochemical presentation of siblings with cog-7 deficiency, a lethal multiple o- and n-glycosylation disorder. Journal of Inherited Metabolic Disease, 28:707-714, Sep 2005. URL: https://doi.org/10.1007/s10545-005-0015-z, doi:10.1007/s10545-005-0015-z. This article has 73 citations and is from a peer-reviewed journal.

  12. (francisco2023congenitaldisordersof pages 1-2): Rita Francisco, Sandra Brasil, Joana Poejo, Jaak Jaeken, Carlota Pascoal, Paula A. Videira, and Vanessa dos Reis Ferreira. Congenital disorders of glycosylation (cdg): state of the art in 2022. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02879-z, doi:10.1186/s13023-023-02879-z. This article has 71 citations and is from a peer-reviewed journal.

  13. (spaapen2005clinicalandbiochemical media a32196a0): L. J. M. Spaapen, J. A. Bakker, S. B. van der Meer, H. J. Sijstermans, R. A. Steet, R. A. Wevers, and J. Jaeken. Clinical and biochemical presentation of siblings with cog-7 deficiency, a lethal multiple o- and n-glycosylation disorder. Journal of Inherited Metabolic Disease, 28:707-714, Sep 2005. URL: https://doi.org/10.1007/s10545-005-0015-z, doi:10.1007/s10545-005-0015-z. This article has 73 citations and is from a peer-reviewed journal.

  14. (spaapen2005clinicalandbiochemical media 9596aac9): L. J. M. Spaapen, J. A. Bakker, S. B. van der Meer, H. J. Sijstermans, R. A. Steet, R. A. Wevers, and J. Jaeken. Clinical and biochemical presentation of siblings with cog-7 deficiency, a lethal multiple o- and n-glycosylation disorder. Journal of Inherited Metabolic Disease, 28:707-714, Sep 2005. URL: https://doi.org/10.1007/s10545-005-0015-z, doi:10.1007/s10545-005-0015-z. This article has 73 citations and is from a peer-reviewed journal.

  15. (paprocka2021congenitaldisordersof pages 2-4): Justyna Paprocka, Aleksandra Jezela-Stanek, Anna Tylki-Szymańska, and Stephanie Grunewald. Congenital disorders of glycosylation from a neurological perspective. Brain Sciences, 11:88, Jan 2021. URL: https://doi.org/10.3390/brainsci11010088, doi:10.3390/brainsci11010088. This article has 131 citations.

  16. (NCT04199000 chunk 1): Eva Morava-Kozicz. Clinical and Basic Investigations Into Congenital Disorders of Glycosylation. Icahn School of Medicine at Mount Sinai. 2019. ClinicalTrials.gov Identifier: NCT04199000