ALG9-congenital disorder of glycosylation

Mendelian MONDO:0012117 Pathograph 30 Show in embeddings browser congenital disorder of glycosylation type I disorder of protein N-glycosylation

ALG9-congenital disorder of glycosylation is a rare autosomal recessive disorder of protein N-linked glycosylation caused by biallelic ALG9 variants. ALG9 deficiency disrupts endoplasmic-reticulum lipid-linked oligosaccharide assembly, producing a type I congenital disorder of glycosylation pattern and a variable spectrum that includes neurodevelopmental impairment, seizures, hypotonia, hepatomegaly, renal cysts, pericardial effusion, and severe prenatal skeletal dysplasia in some affected fetuses.

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1
Inheritance
10
Pathophys.
17
Phenotypes
2
Hypotheses
30
Pathograph
1
Genes
1
Trials
9
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
ALG9-CDG is inherited as an autosomal recessive disorder, with reported affected individuals carrying homozygous ALG9 variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25966638 SUPPORT Human Clinical
"A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al."
The fetal ALG9 skeletal-dysplasia paper directly describes the syndrome as autosomal recessive.
PMID:28742265 SUPPORT Human Clinical
"All the patients had homozygous gene mutations."
The Saudi CDG cohort supports recessive disease by reporting homozygous mutations across affected patients, including ALG9-CDG cases.
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Mechanistic Hypotheses

2
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
canonical_alg9_cdg_model CANONICAL
Evidence balance 2 support
Biallelic ALG9 loss of function reduces ER alpha-1,2-mannosyltransferase activity, causing Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol intermediates to accumulate. Transfer of incomplete oligosaccharides to proteins produces protein hypoglycosylation and a type I transferrin pattern, followed by multisystem disease through incompletely resolved client-protein and tissue-specific intermediates.
Pathograph links
ALG9 alpha-1,2-mannosyltransferase deficiency -> Truncated lipid-linked oligosaccharide accumulation DIRECT Reduced ALG9 activity causes accumulation of incomplete DolPP-linked oligosaccharides.
Truncated lipid-linked oligosaccharide accumulation -> Protein hypoglycosylation INDIRECT KNOWN INTERMEDIATES Oligosaccharyltransferase-mediated transfer of the incomplete Man6GlcNAc2 and Man8GlcNAc2 precursors produces proteins bearing truncated N-glycans and the type I hypoglycosylation pattern. Intermediates: Transfer of incomplete lipid-linked oligosaccharides to nascent proteins.
Protein hypoglycosylation -> Multisystem glycoprotein dysfunction INDIRECT UNKNOWN INTERMEDIATES Widespread abnormal N-glycosylation is associated with neurologic, visceral, renal, cardiac, and skeletal manifestations, while the affected client proteins and tissue-specific intermediates remain unresolved.
Multisystem glycoprotein dysfunction -> Neurodevelopmental and brain involvement INDIRECT UNKNOWN INTERMEDIATES ALG9-CDG glycoprotein dysfunction is associated with developmental delay, hypotonia, seizures, microcephaly, and brain MRI abnormalities.
Multisystem glycoprotein dysfunction -> Growth, hepatic, and renal involvement INDIRECT UNKNOWN INTERMEDIATES Liveborn ALG9-CDG patients frequently show failure to thrive and hepatic or renal involvement.
Multisystem glycoprotein dysfunction -> Prenatal skeletal and hydrops involvement INDIRECT UNKNOWN INTERMEDIATES The severe prenatal ALG9-CDG spectrum includes lethal skeletal dysplasia and ALG9 has been reported among CDG genes associated with nonimmune hydrops fetalis.
Multisystem glycoprotein dysfunction -> Cardiac and pericardial involvement INDIRECT UNKNOWN INTERMEDIATES ALG9-CDG can include cardiovascular findings, particularly pericardial effusion in the reported infant case.
Multisystem glycoprotein dysfunction -> Dysmorphic involvement INDIRECT UNKNOWN INTERMEDIATES Multisystem ALG9-CDG includes dysmorphic findings such as inverted nipples, but the client proteins and developmental intermediates are unresolved.
Neurodevelopmental and brain involvement -> Global developmental delay INDIRECT UNKNOWN INTERMEDIATES Developmental delay is a reported liveborn ALG9-CDG manifestation.
Neurodevelopmental and brain involvement -> Hypotonia INDIRECT UNKNOWN INTERMEDIATES Hypotonia is a recurrent neurologic manifestation of ALG9-CDG.
Neurodevelopmental and brain involvement -> Seizure INDIRECT UNKNOWN INTERMEDIATES Seizures are part of the liveborn ALG9-CDG neurologic spectrum.
Neurodevelopmental and brain involvement -> Microcephaly INDIRECT UNKNOWN INTERMEDIATES Microcephaly is reported among liveborn ALG9-CDG patients.
Neurodevelopmental and brain involvement -> Progressive microcephaly INDIRECT UNKNOWN INTERMEDIATES Orphanet records progressive microcephaly as a frequent ALG9-CDG phenotype.
Neurodevelopmental and brain involvement -> Intellectual disability INDIRECT UNKNOWN INTERMEDIATES Intellectual disability is a very frequent neurodevelopmental manifestation in Orphanet's ALG9-CDG record.
Neurodevelopmental and brain involvement -> Delayed myelination INDIRECT UNKNOWN INTERMEDIATES Delayed myelination is a reported brain MRI finding in ALG9-CDG.
Neurodevelopmental and brain involvement -> Cerebral atrophy INDIRECT UNKNOWN INTERMEDIATES Cerebral volume loss is a reported brain MRI finding in ALG9-CDG.
Neurodevelopmental and brain involvement -> Cerebellar atrophy INDIRECT UNKNOWN INTERMEDIATES Cerebellar volume loss is a reported brain MRI finding in ALG9-CDG.
Growth, hepatic, and renal involvement -> Failure to thrive INDIRECT UNKNOWN INTERMEDIATES Failure to thrive is a recurrent liveborn ALG9-CDG feature.
Growth, hepatic, and renal involvement -> Hepatomegaly INDIRECT UNKNOWN INTERMEDIATES Hepatomegaly or hepatosplenomegaly is part of the visceral ALG9-CDG phenotype.
Growth, hepatic, and renal involvement -> Renal cyst INDIRECT UNKNOWN INTERMEDIATES Renal cysts or cystic renal disease are recurrent ALG9-CDG findings.
Prenatal skeletal and hydrops involvement -> Skeletal dysplasia INDIRECT UNKNOWN INTERMEDIATES Skeletal dysplasia is the defining severe prenatal ALG9-CDG phenotype.
Prenatal skeletal and hydrops involvement -> Hydrops fetalis INDIRECT UNKNOWN INTERMEDIATES ALG9 is reported among CDG genes associated with nonimmune hydrops fetalis.
Cardiac and pericardial involvement -> Pericardial effusion INDIRECT UNKNOWN INTERMEDIATES Pericardial effusion is the reported cardiovascular manifestation.
Cardiac and pericardial involvement -> Abnormal heart morphology INDIRECT UNKNOWN INTERMEDIATES Orphanet records abnormal heart morphology as a frequent cardiovascular phenotype in ALG9-CDG.
Dysmorphic involvement -> Inverted nipples INDIRECT UNKNOWN INTERMEDIATES Inverted nipples were reported as a dysmorphic ALG9-CDG finding.
Show evidence (2 references)
PMID:15148656 SUPPORT In Vitro
"Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors..."
Patient-derived biochemical studies directly support the enzyme defect, accumulated precursor species, and transfer of incomplete glycans that define the canonical model.
PMID:15945070 SUPPORT Human Clinical
"Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing."
The patient transferrin result supports protein hypoglycosylation as the central biochemical lesion downstream of the ALG9 precursor defect.
Emerging ER Glycoprotein Quality-Control and Degradation Model
emerging_er_quality_control_degradation_model EMERGING
Evidence balance 1 support
Glycoproteins bearing the truncated Man6GlcNAc2 and Man8GlcNAc2 structures can enter the ER glucosylation-deglucosylation quality-control cycle, while misfolded glycoproteins are degraded more rapidly in patient cells. This is a bounded cellular-response hypothesis: the in-vitro finding is established, but whether enhanced degradation materially contributes to human ALG9-CDG manifestations has not been demonstrated.
Pathograph links
Protein hypoglycosylation -> ER glycoprotein quality-control and enhanced degradation INDIRECT KNOWN INTERMEDIATES Glycoproteins bearing truncated Man6GlcNAc2 and Man8GlcNAc2 glycans enter the ER quality-control cycle, and patient cells show increased degradation of misfolded glycoproteins; clinical contribution is not established. Intermediates: Entry of truncated glycoproteins into the ER glucosylation-deglucosylation quality-control cycle before degradation of misfolded glycoproteins.
Show evidence (1 reference)
PMID:19451548 SUPPORT In Vitro
"We also showed that in comparison with control cells, patient's cells degraded misfolded glycoproteins at an increasing rate. The Man(8)GlcNAc(2) isomer C on the patient's glycoproteins was found to promote the degradation of misfolded glycoproteins."
The patient-cell experiment directly supports enhanced degradation of misfolded glycoproteins, without establishing its clinical contribution.
⚙

Pathophysiology

10
ALG9 alpha-1,2-mannosyltransferase deficiency
Pathogenic ALG9 variants impair an alpha-1,2-mannosyltransferase required for lipid-linked oligosaccharide assembly in the endoplasmic reticulum.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
ALG9 hgnc:15672 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG9 (hgnc:15672). hgnc:15672 is a gene from the HUGO Gene Nomenclature Committee.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
mannosyltransferase activity GO:0000030 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased mannosyltransferase activity (GO:0000030). GO:0000030 is a molecular function from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Truncated lipid-linked oligosaccharide accumulation Reduced ALG9 activity causes accumulation of incomplete DolPP-linked oligosaccharides. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (1 reference)
PMID:15148656 SUPPORT In Vitro
"Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors..."
The defining paper directly identifies ALG9 enzyme deficiency and the associated lipid-linked oligosaccharide accumulation in patient-derived biochemical studies.
Truncated lipid-linked oligosaccharide accumulation
The ALG9 enzymatic block causes the distinct precursor lesion: accumulation of DolPP-linked Man6GlcNAc2 and Man8GlcNAc2 intermediates before their transfer to nascent proteins.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Protein hypoglycosylation Oligosaccharyltransferase-mediated transfer of the incomplete Man6GlcNAc2 and Man8GlcNAc2 precursors produces proteins bearing truncated N-glycans and the type I hypoglycosylation pattern. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (1 reference)
PMID:15945070 SUPPORT In Vitro
"A defect in the ALG9 enzyme was suggested by the accumulation of the DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 in the patient's fibroblasts and confirmed by mutation analysis: the patient is homozygous for the ALG9 mutation p.Y286C."
Patient fibroblast data independently support the ALG9 biochemical block.
Protein hypoglycosylation
Transfer of incomplete ALG9-associated oligosaccharides produces proteins bearing truncated N-glycans. Serum transferrin isoelectric focusing detects the resulting type I protein-hypoglycosylation pattern.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model Emerging ER Glycoprotein Quality-Control and Degradation Model
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Multisystem glycoprotein dysfunction Widespread abnormal N-glycosylation is associated with neurologic, visceral, renal, cardiac, and skeletal manifestations, while the affected client proteins and tissue-specific intermediates remain unresolved. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
ER glycoprotein quality-control and enhanced degradation Glycoproteins bearing truncated Man6GlcNAc2 and Man8GlcNAc2 glycans enter the ER quality-control cycle, and patient cells show increased degradation of misfolded glycoproteins; clinical contribution is not established. Emerging ER Glycoprotein Quality-Control and Degradation Model
Show evidence (2 references)
PMID:15945070 SUPPORT Human Clinical
"Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing."
The confirmed patient transferrin pattern directly supports protein hypoglycosylation downstream of the precursor lesion.
PMID:19451548 SUPPORT In Vitro
"We demonstrated that lipid-linked Man(6)GlcNAc(2) and Man(8)GlcNAc(2) are transferred onto proteins with the same efficiency."
Patient-cell experiments directly demonstrate transfer of both truncated lipid-linked oligosaccharide species onto proteins.
ER glycoprotein quality-control and enhanced degradation
Truncated Man6GlcNAc2- and Man8GlcNAc2-bearing glycoproteins enter the ER folding-quality-control cycle, and misfolded glycoproteins are degraded at an increased rate in the studied patient's cells. The contribution of this response to human manifestations remains unknown.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:19451548 SUPPORT In Vitro
"We also showed that in comparison with control cells, patient's cells degraded misfolded glycoproteins at an increasing rate. The Man(8)GlcNAc(2) isomer C on the patient's glycoproteins was found to promote the degradation of misfolded glycoproteins."
The patient-cell study directly demonstrates enhanced degradation, while leaving its clinical importance unresolved.
Multisystem glycoprotein dysfunction
Defective N-glycosylation manifests as neurodevelopmental disease, congenital anomalies, renal cystic disease, pericardial effusion, and severe skeletal dysplasia in the most severe fetal presentations.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neurodevelopmental and brain involvement ALG9-CDG glycoprotein dysfunction is associated with developmental delay, hypotonia, seizures, microcephaly, and brain MRI abnormalities. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Growth, hepatic, and renal involvement Liveborn ALG9-CDG patients frequently show failure to thrive and hepatic or renal involvement. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Prenatal skeletal and hydrops involvement The severe prenatal ALG9-CDG spectrum includes lethal skeletal dysplasia and ALG9 has been reported among CDG genes associated with nonimmune hydrops fetalis. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Cardiac and pericardial involvement ALG9-CDG can include cardiovascular findings, particularly pericardial effusion in the reported infant case. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Dysmorphic involvement Multisystem ALG9-CDG includes dysmorphic findings such as inverted nipples, but the client proteins and developmental intermediates are unresolved. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (2 references)
PMID:28932688 SUPPORT Human Clinical
"Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia."
The review directly supports both the recurrent liveborn multisystem phenotype and the severe prenatal skeletal branch.
PMID:25966638 SUPPORT Human Clinical
"All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia."
The fetal skeletal-dysplasia paper summarizes recurrent liveborn ALG9-CDG manifestations and distinguishes them from the fetal skeletal phenotype.
Neurodevelopmental and brain involvement
Liveborn ALG9-CDG includes neurodevelopmental delay, hypotonia, seizures, microcephaly, delayed myelination, and cerebral/cerebellar volume loss.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Global developmental delay Developmental delay is a reported liveborn ALG9-CDG manifestation. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Hypotonia Hypotonia is a recurrent neurologic manifestation of ALG9-CDG. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Seizure Seizures are part of the liveborn ALG9-CDG neurologic spectrum. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Microcephaly Microcephaly is reported among liveborn ALG9-CDG patients. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Progressive microcephaly Orphanet records progressive microcephaly as a frequent ALG9-CDG phenotype. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Intellectual disability Intellectual disability is a very frequent neurodevelopmental manifestation in Orphanet's ALG9-CDG record. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Delayed myelination Delayed myelination is a reported brain MRI finding in ALG9-CDG. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Cerebral atrophy Cerebral volume loss is a reported brain MRI finding in ALG9-CDG. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Cerebellar atrophy Cerebellar volume loss is a reported brain MRI finding in ALG9-CDG. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (2 references)
PMID:15148656 SUPPORT Human Clinical
"The ALG9 defect found in the patient with CDG--who presented with developmental delay, hypotonia, seizures, and hepatomegaly--shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology."
The defining ALG9-CDG report links the glycosylation defect to developmental delay, hypotonia, and seizures.
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The second case report documents brain volume loss and delayed myelination on MRI.
Growth, hepatic, and renal involvement
ALG9-CDG liveborn presentations include failure to thrive, hepatic enlargement or cysts, and renal cystic disease.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Failure to thrive Failure to thrive is a recurrent liveborn ALG9-CDG feature. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Hepatomegaly Hepatomegaly or hepatosplenomegaly is part of the visceral ALG9-CDG phenotype. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Renal cyst Renal cysts or cystic renal disease are recurrent ALG9-CDG findings. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (2 references)
PMID:28932688 SUPPORT Human Clinical
"Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia."
The review summarizes failure to thrive with hepatic and/or renal cysts in the liveborn ALG9-CDG phenotype.
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second case report directly lists failure to thrive, cystic renal disease, and hepatosplenomegaly.
Prenatal skeletal and hydrops involvement
Severe prenatal ALG9-CDG can present with lethal skeletal dysplasia with visceral malformations, and ALG9 has been reported among CDG genes associated with nonimmune hydrops fetalis.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
skeletal system UBERON:0001434 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal system (UBERON:0001434). UBERON:0001434 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Skeletal dysplasia Skeletal dysplasia is the defining severe prenatal ALG9-CDG phenotype. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Hydrops fetalis ALG9 is reported among CDG genes associated with nonimmune hydrops fetalis. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (2 references)
PMID:25966638 SUPPORT Human Clinical
"Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype."
The fetal series supports lethal skeletal dysplasia as the severe prenatal end of the ALG9-CDG spectrum.
PMID:31420886 SUPPORT Human Clinical
"The genes reported for CDG with NIHF for 15 distinct families include: PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7% (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15)."
The systematic review identifies ALG9 among CDG genes reported with nonimmune hydrops fetalis.
Cardiac and pericardial involvement
ALG9-CDG can include cardiovascular findings, including pericardial effusion reported in an affected infant.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pericardial effusion Pericardial effusion is the reported cardiovascular manifestation. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Abnormal heart morphology Orphanet records abnormal heart morphology as a frequent cardiovascular phenotype in ALG9-CDG. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second case report directly lists pericardial effusion among ALG9-CDG features.
Dysmorphic involvement
Dysmorphic manifestations are part of the reported ALG9-CDG spectrum; inverted nipples were documented in an affected infant.
Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Downstream
Inverted nipples Inverted nipples were reported as a dysmorphic ALG9-CDG finding. Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The case report directly includes inverted nipples among the multisystem features of ALG9-CDG.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ALG9-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

17
Cardiovascular 1
Abnormal heart morphology FREQUENT HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79328 SUPPORT Other
"HP:0001627 | Abnormal heart morphology | Frequent (79-30%)"
Orphanet reports abnormal heart morphology as frequent.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15148656 SUPPORT Human Clinical
"The ALG9 defect found in the patient with CDG--who presented with developmental delay, hypotonia, seizures, and hepatomegaly--shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology."
The original ALG9-CDG case directly reports hepatomegaly.
ORPHA:79328 SUPPORT Other
"HP:0002240 | Hepatomegaly | Frequent (79-30%)"
Orphanet reports hepatomegaly as frequent.
Genitourinary 1
Renal cyst HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second reported infant had cystic renal disease.
Head and Neck 1
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25966638 SUPPORT Human Clinical
"All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia."
The fetal skeletal-dysplasia paper summarizes microcephaly among the previously reported liveborn ALG9-CDG patients.
Metabolism 1
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31420886 SUPPORT Human Clinical
"The genes reported for CDG with NIHF for 15 distinct families include: PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7% (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15)."
This review identifies ALG9 among CDG genes reported with nonimmune hydrops fetalis.
Musculoskeletal 2
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second case report directly lists hypotonia among the infant's features.
ORPHA:79328 SUPPORT Other
"HP:0001252 | Hypotonia | Frequent (79-30%)"
Orphanet reports hypotonia as frequent.
Skeletal dysplasia FREQUENT HP:0002652 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal dysplasia (HP:0002652). HP:0002652 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25966638 SUPPORT Human Clinical
"A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al."
The ALG9 fetal series directly supports skeletal dysplasia in the severe prenatal phenotype.
ORPHA:79328 SUPPORT Other
"HP:0002652 | Skeletal dysplasia | Frequent (79-30%)"
Orphanet reports skeletal dysplasia as frequent.
Nervous System 6
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15148656 SUPPORT Human Clinical
"The ALG9 defect found in the patient with CDG--who presented with developmental delay, hypotonia, seizures, and hepatomegaly--shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology."
The original ALG9-CDG report directly lists developmental delay in the affected patient.
ORPHA:79328 SUPPORT Other
"HP:0001263 | Global developmental delay | Very frequent (99-80%)"
Orphanet reports global developmental delay as very frequent.
Seizure VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28932688 SUPPORT Human Clinical
"She developed failure to thrive and seizures."
The ALG9-CDG review's additional case directly supports seizures as part of the phenotype.
ORPHA:79328 SUPPORT Other
"HP:0001250 | Seizure | Very frequent (99-80%)"
Orphanet reports seizure as very frequent.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79328 SUPPORT Other
"HP:0001249 | Intellectual disability | Very frequent (99-80%)"
Orphanet reports intellectual disability as very frequent.
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The second ALG9-CDG case report directly documents delayed myelination on brain MRI.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The second ALG9-CDG case report directly documents cerebral-hemisphere volume loss on MRI.
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The second ALG9-CDG case report directly documents cerebellar volume loss on MRI.
Growth 1
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:28932688 SUPPORT Human Clinical
"Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia."
The review identifies failure to thrive as a recurrent liveborn ALG9-CDG manifestation.
Other 3
Inverted nipples FREQUENT HP:0003186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inverted nipples (HP:0003186). HP:0003186 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second reported infant had inverted nipples.
ORPHA:79328 SUPPORT Other
"HP:0003186 | Inverted nipples | Frequent (79-30%)"
Orphanet reports inverted nipples as frequent.
Progressive microcephaly FREQUENT HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive microcephaly (HP:0000253). HP:0000253 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:79328 SUPPORT Other
"HP:0000253 | Progressive microcephaly | Frequent (79-30%)"
Orphanet reports progressive microcephaly as frequent.
Pericardial effusion FREQUENT HP:0001698 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pericardial effusion (HP:0001698). HP:0001698 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15945070 SUPPORT Human Clinical
"The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples."
The second reported infant had pericardial effusion.
ORPHA:79328 SUPPORT Other
"HP:0001698 | Pericardial effusion | Frequent (79-30%)"
Orphanet reports pericardial effusion as frequent.
🧬

Genetic Associations

1
ALG9 (Biallelic loss-of-function variants)
Gene: ALG9 hgnc:15672 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG9 (hgnc:15672). hgnc:15672 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:15148656 SUPPORT Human Clinical
"A homozygous point-mutation 1567G-->A (amino acid substitution E523K) was detected in the ALG9 gene."
The defining ALG9-CDG report identifies a homozygous ALG9 variant in the affected patient.
PMID:25966638 SUPPORT Human Clinical
"All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation."
The fetal series directly links homozygous ALG9 splice variants to the severe prenatal form.
🔬

Biochemical Markers

2
Type I carbohydrate-deficient transferrin pattern (ABNORMAL)
Context: ALG9-CDG produces a type I CDG transferrin pattern from impaired synthesis or transfer of lipid-linked oligosaccharide precursors.
Pathograph Readouts
Readout Of Protein hypoglycosylation Present Absent Diagnostic
A type I carbohydrate-deficient transferrin pattern directly reports hypoglycosylation of a serum glycoprotein; it is not ALG9-specific.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing."
The patient-level transferrin pattern is an indirect readout of the upstream lipid-linked-oligosaccharide defect and is not ALG9-specific.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing."
This is the reported biochemical diagnostic signature in a confirmed ALG9-CDG patient.
Accumulated DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 (ABNORMAL)
Context: Patient cells accumulate truncated lipid-linked oligosaccharides upstream of the ALG9-dependent mannosyltransferase steps.
Pathograph Readouts
Readout Of ALG9 alpha-1,2-mannosyltransferase deficiency Positive Diagnostic
Accumulation of DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 reports the ALG9-dependent mannosyltransferase block in lipid-linked oligosaccharide assembly.
Show evidence (1 reference)
PMID:15148656 SUPPORT In Vitro
"Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures"
The cultured-cell biochemical study directly links accumulation of the two truncated intermediates to ALG9 enzyme deficiency.
Show evidence (1 reference)
PMID:15148656 SUPPORT In Vitro
"Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors..."
The defining biochemical report directly describes the accumulated DolPP-linked oligosaccharide species.
🔬

Diagnosis

3
Serum transferrin isoelectric focusing
Transferrin isoelectric focusing is a nonspecific biochemical screen that can detect a type I CDG hypoglycosylation pattern but cannot distinguish ALG9-CDG from other type I congenital disorders of glycosylation.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: A type I CDG transferrin pattern that requires etiologic follow-up.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing."
This directly supports the type I transferrin pattern as a biochemical screening result; it does not establish the ALG9 subtype.
ALG9 molecular genetic testing
Molecular diagnosis requires two pathogenic or likely pathogenic ALG9 variants affecting opposite alleles (in trans), interpreted with the biochemical and clinical findings.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic or likely pathogenic ALG9 variants in trans.
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"A defect in the ALG9 enzyme was suggested by the accumulation of the DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 in the patient's fibroblasts and confirmed by mutation analysis: the patient is homozygous for the ALG9 mutation p.Y286C."
A confirmed affected individual was homozygous for an ALG9 variant, illustrating biallelic molecular confirmation.
Glycan profiling
Glycan profiling can corroborate an abnormal type I glycosylation pattern, but it is a biochemical characterization method and cannot by itself establish biallelic ALG9 etiology.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Abnormal glycan profile consistent with a type I glycosylation defect.
Show evidence (1 reference)
PMID:28932688 SUPPORT Human Clinical
"The metabolic work-up included analysis of a transferrin isoelectric focusing, which showed a type 1 pattern. This was confirmed by glycan profiling"
The case report supports glycan profiling as confirmation of the biochemical pattern, not as a method for identifying an ALG9 genotype.
🩻

Imaging Findings

3
Cerebral atrophy on MRI
Brain MRI in one reported infant showed cerebral-hemisphere volume loss.
Mri
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The case report directly documents cerebral volume loss on MRI.
Cerebellar atrophy on MRI
Brain MRI in one reported infant showed cerebellar volume loss.
Mri
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The case report directly documents cerebellar volume loss on MRI.
Delayed myelination on MRI
Brain MRI in one reported infant showed delayed myelination.
Mri
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:15945070 SUPPORT Human Clinical
"Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination."
The case report directly documents delayed myelination on MRI.
📈

Progression

1
Variable prenatal-to-infantile spectrum
Reported ALG9-CDG severity ranges from liveborn multisystem neurodevelopmental disease to lethal prenatal skeletal dysplasia with visceral malformations.
Show evidence (2 references)
PMID:25966638 SUPPORT Human Clinical
"Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype."
The fetal series defines the severe prenatal end of the ALG9-CDG spectrum.
PMID:28932688 SUPPORT Human Clinical
"Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia."
The ALG9-CDG review summarizes both liveborn and fetal-lethal disease presentations.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet reports a worldwide point prevalence below 1 per 1,000,000.
Show evidence (1 reference)
ORPHA:79328 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28122681,PMID:28932688"
Orphanet provides a disease-level worldwide point-prevalence class rather than a selected-cohort subtype fraction.
🔬

Clinical Trials

1
NCT04199000 RECRUITING
Recruiting CDG-wide observational natural-history research relevant to genetically, enzymatically, or molecularly confirmed CDG subtypes such as ALG9-CDG; it does not provide treatment-efficacy evidence.
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 study is observational and CDG-wide rather than ALG9-specific, so it only partially supports relevance to ALG9-CDG natural-history research.
{ }

Source YAML

click to show 
name: ALG9-congenital disorder of glycosylation
creation_date: "2026-05-11T16:30:19Z"
description: >-
  ALG9-congenital disorder of glycosylation is a rare autosomal recessive
  disorder of protein N-linked glycosylation caused by biallelic ALG9 variants.
  ALG9 deficiency disrupts endoplasmic-reticulum lipid-linked oligosaccharide
  assembly, producing a type I congenital disorder of glycosylation pattern and
  a variable spectrum that includes neurodevelopmental impairment, seizures,
  hypotonia, hepatomegaly, renal cysts, pericardial effusion, and severe
  prenatal skeletal dysplasia in some affected fetuses.
category: Mendelian
disease_term:
  preferred_term: ALG9-congenital disorder of glycosylation
  term:
    id: MONDO:0012117
    label: ALG9-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- ALG9-CDG
- CDG-IL
- congenital disorder of glycosylation type IL
references:
- reference: ORPHA:79328
  title: ALG9-CDG
- reference: PMID:15148656
  title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
- reference: PMID:15945070
  title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
- reference: PMID:19451548
  title: Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
- reference: PMID:25966638
  title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
- reference: PMID:28742265
  title: "Congenital disorders of glycosylation: The Saudi experience."
- reference: PMID:28932688
  title: "ALG9-CDG: New clinical case and review of the literature."
- reference: PMID:31420886
  title: "Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review."
- reference: clinicaltrials:NCT04199000
  title: Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ALG9-CDG is inherited as an autosomal recessive disorder, with reported
    affected individuals carrying homozygous ALG9 variants.
  evidence:
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A rare lethal autosomal recessive syndrome with skeletal dysplasia,
      polycystic kidneys and multiple malformations was first described by
      Gillessen-Kaesbach et al and subsequently by Nishimura et al.
    explanation: >-
      The fetal ALG9 skeletal-dysplasia paper directly describes the syndrome as
      autosomal recessive.
  - reference: PMID:28742265
    reference_title: "Congenital disorders of glycosylation: The Saudi experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients had homozygous gene mutations.
    explanation: >-
      The Saudi CDG cohort supports recessive disease by reporting homozygous
      mutations across affected patients, including ALG9-CDG cases.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet reports a worldwide point prevalence below 1 per 1,000,000.
  evidence:
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28122681,PMID:28932688"
    explanation: >-
      Orphanet provides a disease-level worldwide point-prevalence class rather
      than a selected-cohort subtype fraction.
progression:
- phase: Variable prenatal-to-infantile spectrum
  notes: >-
    Reported ALG9-CDG severity ranges from liveborn multisystem
    neurodevelopmental disease to lethal prenatal skeletal dysplasia with
    visceral malformations.
  evidence:
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study shows that some pathogenic variants in ALG9 can present as a
      lethal skeletal dysplasia with visceral malformations as the most severe
      phenotype.
    explanation: >-
      The fetal series defines the severe prenatal end of the ALG9-CDG spectrum.
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of these patients had a similar phenotype with failure to thrive,
      dysmorphic features, seizures, hepatic and/or renal cysts; the other three
      patients died in utero from a lethal skeletal dysplasia.
    explanation: >-
      The ALG9-CDG review summarizes both liveborn and fetal-lethal disease
      presentations.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_alg9_cdg_model
  hypothesis_label: Canonical ALG9-CDG Precursor Assembly and Protein Hypoglycosylation Model
  status: CANONICAL
  description: >-
    Biallelic ALG9 loss of function reduces ER alpha-1,2-mannosyltransferase
    activity, causing Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol
    intermediates to accumulate. Transfer of incomplete oligosaccharides to
    proteins produces protein hypoglycosylation and a type I transferrin pattern,
    followed by multisystem disease through incompletely resolved client-protein
    and tissue-specific intermediates.
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using this approach, we have found, in a patient with CDG, a deficiency of
      the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
      accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
      structures, which was paralleled by the transfer of incomplete
      oligosaccharides precursors to protein.
    explanation: >-
      Patient-derived biochemical studies directly support the enzyme defect,
      accumulated precursor species, and transfer of incomplete glycans that
      define the canonical model.
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum
      transferrin analyzed by isoelectric focusing.
    explanation: >-
      The patient transferrin result supports protein hypoglycosylation as the
      central biochemical lesion downstream of the ALG9 precursor defect.
- hypothesis_group_id: emerging_er_quality_control_degradation_model
  hypothesis_label: Emerging ER Glycoprotein Quality-Control and Degradation Model
  status: EMERGING
  description: >-
    Glycoproteins bearing the truncated Man6GlcNAc2 and Man8GlcNAc2 structures
    can enter the ER glucosylation-deglucosylation quality-control cycle, while
    misfolded glycoproteins are degraded more rapidly in patient cells. This is
    a bounded cellular-response hypothesis: the in-vitro finding is established,
    but whether enhanced degradation materially contributes to human ALG9-CDG
    manifestations has not been demonstrated.
  evidence:
  - reference: PMID:19451548
    reference_title: Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also showed that in comparison with control cells, patient's cells
      degraded misfolded glycoproteins at an increasing rate. The
      Man(8)GlcNAc(2) isomer C on the patient's glycoproteins was found to
      promote the degradation of misfolded glycoproteins.
    explanation: >-
      The patient-cell experiment directly supports enhanced degradation of
      misfolded glycoproteins, without establishing its clinical contribution.
pathophysiology:
- name: ALG9 alpha-1,2-mannosyltransferase deficiency
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    Pathogenic ALG9 variants impair an alpha-1,2-mannosyltransferase required
    for lipid-linked oligosaccharide assembly in the endoplasmic reticulum.
  genes:
  - preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  molecular_functions:
  - preferred_term: mannosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0000030
      label: mannosyltransferase activity
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using this approach, we have found, in a patient with CDG, a deficiency of
      the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
      accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
      structures, which was paralleled by the transfer of incomplete
      oligosaccharides precursors to protein.
    explanation: >-
      The defining paper directly identifies ALG9 enzyme deficiency and the
      associated lipid-linked oligosaccharide accumulation in patient-derived
      biochemical studies.
  downstream:
  - target: Truncated lipid-linked oligosaccharide accumulation
    description: >-
      Reduced ALG9 activity causes accumulation of incomplete
      DolPP-linked oligosaccharides.
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using this approach, we have found, in a patient with CDG, a deficiency
        of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
        accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
        structures, which was paralleled by the transfer of incomplete
        oligosaccharides precursors to protein.
      explanation: >-
        This is direct biochemical evidence that ALG9 deficiency causes
        accumulation of truncated lipid-linked oligosaccharides.
- name: Truncated lipid-linked oligosaccharide accumulation
  description: >-
    The ALG9 enzymatic block causes the distinct precursor lesion: accumulation
    of DolPP-linked Man6GlcNAc2 and Man8GlcNAc2 intermediates before their
    transfer to nascent proteins.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  chemical_entities:
  - preferred_term: N-glycan precursor
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A defect in the ALG9 enzyme was suggested by the accumulation of the
      DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 in the patient's fibroblasts and
      confirmed by mutation analysis: the patient is homozygous for the ALG9
      mutation p.Y286C.
    explanation: >-
      Patient fibroblast data independently support the ALG9 biochemical block.
  downstream:
  - target: Protein hypoglycosylation
    description: >-
      Oligosaccharyltransferase-mediated transfer of the incomplete Man6GlcNAc2
      and Man8GlcNAc2 precursors produces proteins bearing truncated N-glycans
      and the type I hypoglycosylation pattern.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Transfer of incomplete lipid-linked oligosaccharides to nascent proteins.
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using this approach, we have found, in a patient with CDG, a deficiency
        of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
        accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
        structures, which was paralleled by the transfer of incomplete
        oligosaccharides precursors to protein.
      explanation: >-
        Patient-derived biochemical studies directly connect accumulation of
        the incomplete precursors with their transfer to protein.
- name: Protein hypoglycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    Transfer of incomplete ALG9-associated oligosaccharides produces proteins
    bearing truncated N-glycans. Serum transferrin isoelectric focusing detects
    the resulting type I protein-hypoglycosylation pattern.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum
      transferrin analyzed by isoelectric focusing.
    explanation: >-
      The confirmed patient transferrin pattern directly supports protein
      hypoglycosylation downstream of the precursor lesion.
  - reference: PMID:19451548
    reference_title: Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrated that lipid-linked Man(6)GlcNAc(2) and Man(8)GlcNAc(2) are
      transferred onto proteins with the same efficiency.
    explanation: >-
      Patient-cell experiments directly demonstrate transfer of both truncated
      lipid-linked oligosaccharide species onto proteins.
  downstream:
  - target: Multisystem glycoprotein dysfunction
    description: >-
      Widespread abnormal N-glycosylation is associated with neurologic,
      visceral, renal, cardiac, and skeletal manifestations, while the affected
      client proteins and tissue-specific intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ALG9 defect found in the patient with CDG--who presented with
        developmental delay, hypotonia, seizures, and hepatomegaly--shows that
        efficient lipid-linked oligosaccharide synthesis is required for proper
        human development and physiology.
      explanation: >-
        The original report supports the clinical association between the ALG9
        glycosylation defect and multisystem developmental disease without
        resolving individual downstream intermediates.
  - target: ER glycoprotein quality-control and enhanced degradation
    description: >-
      Glycoproteins bearing truncated Man6GlcNAc2 and Man8GlcNAc2 glycans enter
      the ER quality-control cycle, and patient cells show increased degradation
      of misfolded glycoproteins; clinical contribution is not established.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Entry of truncated glycoproteins into the ER glucosylation-deglucosylation quality-control cycle before degradation of misfolded glycoproteins.
    hypothesis_groups:
    - emerging_er_quality_control_degradation_model
    evidence:
    - reference: PMID:19451548
      reference_title: Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In addition, glycoproteins bearing these Man(6)GlcNAc(2) and
        Man(8)GlcNAc(2) structures efficiently entered in the
        glucosylation/deglucosylation cycle of the quality control system to
        assist in protein folding. We also showed that in comparison with
        control cells, patient's cells degraded misfolded glycoproteins at an
        increasing rate.
      explanation: >-
        Patient-cell experiments support the defined ER quality-control and
        degradation response, but not a downstream clinical effect.
- name: ER glycoprotein quality-control and enhanced degradation
  mechanism_confidence: PROVISIONAL
  description: >-
    Truncated Man6GlcNAc2- and Man8GlcNAc2-bearing glycoproteins enter the ER
    folding-quality-control cycle, and misfolded glycoproteins are degraded at
    an increased rate in the studied patient's cells. The contribution of this
    response to human manifestations remains unknown.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:19451548
    reference_title: Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also showed that in comparison with control cells, patient's cells
      degraded misfolded glycoproteins at an increasing rate. The
      Man(8)GlcNAc(2) isomer C on the patient's glycoproteins was found to
      promote the degradation of misfolded glycoproteins.
    explanation: >-
      The patient-cell study directly demonstrates enhanced degradation, while
      leaving its clinical importance unresolved.
- name: Multisystem glycoprotein dysfunction
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  description: >-
    Defective N-glycosylation manifests as neurodevelopmental disease,
    congenital anomalies, renal cystic disease, pericardial effusion, and severe
    skeletal dysplasia in the most severe fetal presentations.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of these patients had a similar phenotype with failure to thrive,
      dysmorphic features, seizures, hepatic and/or renal cysts; the other three
      patients died in utero from a lethal skeletal dysplasia.
    explanation: >-
      The review directly supports both the recurrent liveborn multisystem
      phenotype and the severe prenatal skeletal branch.
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three suffered from intellectual disability, muscular hypotonia,
      microcephaly and renal cysts, but none had skeletal dysplasia.
    explanation: >-
      The fetal skeletal-dysplasia paper summarizes recurrent liveborn ALG9-CDG
      manifestations and distinguishes them from the fetal skeletal phenotype.
  downstream:
  - target: Neurodevelopmental and brain involvement
    description: >-
      ALG9-CDG glycoprotein dysfunction is associated with developmental delay,
      hypotonia, seizures, microcephaly, and brain MRI abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: >-
        The second case report supports a neurologic branch with hypotonia,
        seizures, psychomotor delay, and brain structural/myelination findings.
  - target: Growth, hepatic, and renal involvement
    description: >-
      Liveborn ALG9-CDG patients frequently show failure to thrive and hepatic
      or renal involvement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:28932688
      reference_title: "ALG9-CDG: New clinical case and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seven of these patients had a similar phenotype with failure to thrive,
        dysmorphic features, seizures, hepatic and/or renal cysts; the other
        three patients died in utero from a lethal skeletal dysplasia.
      explanation: >-
        The ALG9-CDG review directly supports growth failure with hepatic and/or
        renal cystic involvement in the liveborn phenotype.
  - target: Prenatal skeletal and hydrops involvement
    description: >-
      The severe prenatal ALG9-CDG spectrum includes lethal skeletal dysplasia
      and ALG9 has been reported among CDG genes associated with nonimmune
      hydrops fetalis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:25966638
      reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study shows that some pathogenic variants in ALG9 can present as a
        lethal skeletal dysplasia with visceral malformations as the most severe
        phenotype.
      explanation: >-
        The fetal series supports a severe prenatal skeletal branch of ALG9-CDG.
  - target: Cardiac and pericardial involvement
    description: >-
      ALG9-CDG can include cardiovascular findings, particularly pericardial
      effusion in the reported infant case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: >-
        The second case report directly includes pericardial effusion among
        ALG9-CDG clinical features.
  - target: Dysmorphic involvement
    description: >-
      Multisystem ALG9-CDG includes dysmorphic findings such as inverted
      nipples, but the client proteins and developmental intermediates are
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: >-
        The case report directly supports inverted nipples within the
        multisystem clinical presentation.
- name: Neurodevelopmental and brain involvement
  description: >-
    Liveborn ALG9-CDG includes neurodevelopmental delay, hypotonia, seizures,
    microcephaly, delayed myelination, and cerebral/cerebellar volume loss.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ALG9 defect found in the patient with CDG--who presented with
      developmental delay, hypotonia, seizures, and hepatomegaly--shows that
      efficient lipid-linked oligosaccharide synthesis is required for proper
      human development and physiology.
    explanation: >-
      The defining ALG9-CDG report links the glycosylation defect to
      developmental delay, hypotonia, and seizures.
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The second case report documents brain volume loss and delayed myelination
      on MRI.
  downstream:
  - target: Global developmental delay
    description: Developmental delay is a reported liveborn ALG9-CDG manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ALG9 defect found in the patient with CDG--who presented with
        developmental delay, hypotonia, seizures, and hepatomegaly--shows that
        efficient lipid-linked oligosaccharide synthesis is required for proper
        human development and physiology.
      explanation: The defining report directly lists developmental delay.
  - target: Hypotonia
    description: Hypotonia is a recurrent neurologic manifestation of ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: The second case report directly lists hypotonia.
  - target: Seizure
    description: Seizures are part of the liveborn ALG9-CDG neurologic spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:28932688
      reference_title: "ALG9-CDG: New clinical case and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        She developed failure to thrive and seizures.
      explanation: The ALG9-CDG review's additional case directly reports seizures.
  - target: Microcephaly
    description: Microcephaly is reported among liveborn ALG9-CDG patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:25966638
      reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All three suffered from intellectual disability, muscular hypotonia,
        microcephaly and renal cysts, but none had skeletal dysplasia.
      explanation: The fetal series summarizes microcephaly in liveborn ALG9-CDG patients.
  - target: Progressive microcephaly
    description: Orphanet records progressive microcephaly as a frequent ALG9-CDG phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: ORPHA:79328
      reference_title: ALG9-CDG
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000253 | Progressive microcephaly | Frequent (79-30%)"
      explanation: Orphanet reports progressive microcephaly as frequent.
  - target: Intellectual disability
    description: Intellectual disability is a very frequent neurodevelopmental manifestation in Orphanet's ALG9-CDG record.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: ORPHA:79328
      reference_title: ALG9-CDG
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
      explanation: Orphanet reports intellectual disability as very frequent.
  - target: Delayed myelination
    description: Delayed myelination is a reported brain MRI finding in ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Magnetic resonance imaging of the brain showed volume loss in the
        cerebral hemispheres and cerebellum and delayed myelination.
      explanation: The MRI report directly documents delayed myelination.
  - target: Cerebral atrophy
    description: Cerebral volume loss is a reported brain MRI finding in ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Magnetic resonance imaging of the brain showed volume loss in the
        cerebral hemispheres and cerebellum and delayed myelination.
      explanation: The MRI report directly documents cerebral volume loss.
  - target: Cerebellar atrophy
    description: Cerebellar volume loss is a reported brain MRI finding in ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Magnetic resonance imaging of the brain showed volume loss in the
        cerebral hemispheres and cerebellum and delayed myelination.
      explanation: The MRI report directly documents cerebellar volume loss.
- name: Growth, hepatic, and renal involvement
  description: >-
    ALG9-CDG liveborn presentations include failure to thrive, hepatic
    enlargement or cysts, and renal cystic disease.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of these patients had a similar phenotype with failure to thrive,
      dysmorphic features, seizures, hepatic and/or renal cysts; the other three
      patients died in utero from a lethal skeletal dysplasia.
    explanation: >-
      The review summarizes failure to thrive with hepatic and/or renal cysts in
      the liveborn ALG9-CDG phenotype.
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second case report directly lists failure to thrive, cystic renal
      disease, and hepatosplenomegaly.
  downstream:
  - target: Failure to thrive
    description: Failure to thrive is a recurrent liveborn ALG9-CDG feature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:28932688
      reference_title: "ALG9-CDG: New clinical case and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seven of these patients had a similar phenotype with failure to thrive,
        dysmorphic features, seizures, hepatic and/or renal cysts; the other
        three patients died in utero from a lethal skeletal dysplasia.
      explanation: The review lists failure to thrive in the recurrent phenotype.
  - target: Hepatomegaly
    description: Hepatomegaly or hepatosplenomegaly is part of the visceral ALG9-CDG phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ALG9 defect found in the patient with CDG--who presented with
        developmental delay, hypotonia, seizures, and hepatomegaly--shows that
        efficient lipid-linked oligosaccharide synthesis is required for proper
        human development and physiology.
      explanation: The defining report directly lists hepatomegaly.
  - target: Renal cyst
    description: Renal cysts or cystic renal disease are recurrent ALG9-CDG findings.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: The second case report directly lists cystic renal disease.
- name: Prenatal skeletal and hydrops involvement
  description: >-
    Severe prenatal ALG9-CDG can present with lethal skeletal dysplasia with
    visceral malformations, and ALG9 has been reported among CDG genes associated
    with nonimmune hydrops fetalis.
  locations:
  - preferred_term: skeletal system
    term:
      id: UBERON:0001434
      label: skeletal system
  evidence:
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study shows that some pathogenic variants in ALG9 can present as a
      lethal skeletal dysplasia with visceral malformations as the most severe
      phenotype.
    explanation: >-
      The fetal series supports lethal skeletal dysplasia as the severe prenatal
      end of the ALG9-CDG spectrum.
  - reference: PMID:31420886
    reference_title: "Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genes reported for CDG with NIHF for 15 distinct families include:
      PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7%
      (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15).
    explanation: >-
      The systematic review identifies ALG9 among CDG genes reported with
      nonimmune hydrops fetalis.
  downstream:
  - target: Skeletal dysplasia
    description: Skeletal dysplasia is the defining severe prenatal ALG9-CDG phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:25966638
      reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A rare lethal autosomal recessive syndrome with skeletal dysplasia,
        polycystic kidneys and multiple malformations was first described by
        Gillessen-Kaesbach et al and subsequently by Nishimura et al.
      explanation: The fetal series directly supports skeletal dysplasia.
  - target: Hydrops fetalis
    description: ALG9 is reported among CDG genes associated with nonimmune hydrops fetalis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:31420886
      reference_title: "Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The genes reported for CDG with NIHF for 15 distinct families include:
        PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7%
        (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15).
      explanation: The systematic review directly reports ALG9 among CDG-NIHF genes.
- name: Cardiac and pericardial involvement
  description: >-
    ALG9-CDG can include cardiovascular findings, including pericardial effusion
    reported in an affected infant.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second case report directly lists pericardial effusion among ALG9-CDG
      features.
  downstream:
  - target: Pericardial effusion
    description: Pericardial effusion is the reported cardiovascular manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: The second case report directly lists pericardial effusion.
  - target: Abnormal heart morphology
    description: Orphanet records abnormal heart morphology as a frequent cardiovascular phenotype in ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: ORPHA:79328
      reference_title: ALG9-CDG
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001627 | Abnormal heart morphology | Frequent (79-30%)"
      explanation: Orphanet reports abnormal heart morphology as frequent.
- name: Dysmorphic involvement
  description: >-
    Dysmorphic manifestations are part of the reported ALG9-CDG spectrum;
    inverted nipples were documented in an affected infant.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The case report directly includes inverted nipples among the multisystem
      features of ALG9-CDG.
  downstream:
  - target: Inverted nipples
    description: Inverted nipples were reported as a dysmorphic ALG9-CDG finding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_alg9_cdg_model
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female infant's features included psychomotor retardation, seizures,
        hypotonia, diffuse brain atrophy with delayed myelination, failure to
        thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
        esotropia, and inverted nipples.
      explanation: The case report directly lists inverted nipples.
phenotypes:
- name: Global developmental delay
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay and intellectual disability are recurrent neurologic
    manifestations of liveborn ALG9-CDG.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ALG9 defect found in the patient with CDG--who presented with
      developmental delay, hypotonia, seizures, and hepatomegaly--shows that
      efficient lipid-linked oligosaccharide synthesis is required for proper
      human development and physiology.
    explanation: >-
      The original ALG9-CDG report directly lists developmental delay in the
      affected patient.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet reports global developmental delay as very frequent.
- name: Hypotonia
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Hypotonia is repeatedly reported in liveborn ALG9-CDG.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second case report directly lists hypotonia among the infant's
      features.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
    explanation: Orphanet reports hypotonia as frequent.
- name: Inverted nipples
  category: Integumentary
  frequency: FREQUENT
  description: >-
    Inverted nipples were reported in a liveborn individual with ALG9-CDG.
  phenotype_term:
    preferred_term: Inverted nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second reported infant had inverted nipples.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003186 | Inverted nipples | Frequent (79-30%)"
    explanation: Orphanet reports inverted nipples as frequent.
- name: Seizure
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Seizures occur in liveborn ALG9-CDG and can accompany failure to thrive and
    congenital anomalies.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She developed failure to thrive and seizures.
    explanation: >-
      The ALG9-CDG review's additional case directly supports seizures as part
      of the phenotype.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Very frequent (99-80%)"
    explanation: Orphanet reports seizure as very frequent.
- name: Microcephaly
  category: Neurologic
  description: >-
    Microcephaly is part of the liveborn ALG9-CDG neurologic phenotype.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three suffered from intellectual disability, muscular hypotonia,
      microcephaly and renal cysts, but none had skeletal dysplasia.
    explanation: >-
      The fetal skeletal-dysplasia paper summarizes microcephaly among the
      previously reported liveborn ALG9-CDG patients.
- name: Progressive microcephaly
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Orphanet records progressive microcephaly as a frequent ALG9-CDG
    manifestation.
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  evidence:
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000253 | Progressive microcephaly | Frequent (79-30%)"
    explanation: Orphanet reports progressive microcephaly as frequent.
- name: Intellectual disability
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability is a very frequent neurodevelopmental manifestation
    in Orphanet's ALG9-CDG record.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet reports intellectual disability as very frequent.
- name: Failure to thrive
  category: Growth
  description: >-
    Failure to thrive is reported in liveborn ALG9-CDG.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of these patients had a similar phenotype with failure to thrive,
      dysmorphic features, seizures, hepatic and/or renal cysts; the other three
      patients died in utero from a lethal skeletal dysplasia.
    explanation: >-
      The review identifies failure to thrive as a recurrent liveborn ALG9-CDG
      manifestation.
- name: Hepatomegaly
  category: Hepatic
  frequency: FREQUENT
  description: >-
    Liver enlargement is part of the ALG9-CDG multisystem phenotype.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ALG9 defect found in the patient with CDG--who presented with
      developmental delay, hypotonia, seizures, and hepatomegaly--shows that
      efficient lipid-linked oligosaccharide synthesis is required for proper
      human development and physiology.
    explanation: >-
      The original ALG9-CDG case directly reports hepatomegaly.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Frequent (79-30%)"
    explanation: Orphanet reports hepatomegaly as frequent.
- name: Renal cyst
  category: Renal
  description: >-
    Renal cysts and cystic renal disease are recurrent ALG9-CDG findings.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second reported infant had cystic renal disease.
- name: Pericardial effusion
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Pericardial effusion is a reported cardiovascular manifestation of
    ALG9-CDG.
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female infant's features included psychomotor retardation, seizures,
      hypotonia, diffuse brain atrophy with delayed myelination, failure to
      thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly,
      esotropia, and inverted nipples.
    explanation: >-
      The second reported infant had pericardial effusion.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001698 | Pericardial effusion | Frequent (79-30%)"
    explanation: Orphanet reports pericardial effusion as frequent.
- name: Abnormal heart morphology
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Orphanet records abnormal heart morphology as a frequent cardiovascular
    manifestation of ALG9-CDG.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001627 | Abnormal heart morphology | Frequent (79-30%)"
    explanation: Orphanet reports abnormal heart morphology as frequent.
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    Nonimmune hydrops fetalis has been reported in ALG9-CDG families reviewed
    in a systematic literature synthesis.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:31420886
    reference_title: "Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genes reported for CDG with NIHF for 15 distinct families include:
      PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7%
      (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15).
    explanation: >-
      This review identifies ALG9 among CDG genes reported with nonimmune
      hydrops fetalis.
- name: Skeletal dysplasia
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Some ALG9 variants cause a severe prenatal skeletal dysplasia with
    polycystic kidneys and multiple malformations.
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A rare lethal autosomal recessive syndrome with skeletal dysplasia,
      polycystic kidneys and multiple malformations was first described by
      Gillessen-Kaesbach et al and subsequently by Nishimura et al.
    explanation: >-
      The ALG9 fetal series directly supports skeletal dysplasia in the severe
      prenatal phenotype.
  - reference: ORPHA:79328
    reference_title: ALG9-CDG
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002652 | Skeletal dysplasia | Frequent (79-30%)"
    explanation: Orphanet reports skeletal dysplasia as frequent.
- name: Delayed myelination
  category: Neurologic
  description: >-
    Delayed myelination has been documented on brain MRI in ALG9-CDG.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The second ALG9-CDG case report directly documents delayed myelination on
      brain MRI.
- name: Cerebral atrophy
  category: Neurologic
  description: >-
    Cerebral-hemisphere volume loss has been reported on brain MRI in ALG9-CDG.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The second ALG9-CDG case report directly documents cerebral-hemisphere
      volume loss on MRI.
- name: Cerebellar atrophy
  category: Neurologic
  description: >-
    Cerebellar volume loss has been reported on brain MRI in ALG9-CDG.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The second ALG9-CDG case report directly documents cerebellar volume loss
      on MRI.
imaging_findings:
- name: Cerebral atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  diagnostic: false
  description: >-
    Brain MRI in one reported infant showed cerebral-hemisphere volume loss.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The case report directly documents cerebral volume loss on MRI.
- name: Cerebellar atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  located_in:
    preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  diagnostic: false
  description: >-
    Brain MRI in one reported infant showed cerebellar volume loss.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The case report directly documents cerebellar volume loss on MRI.
- name: Delayed myelination on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  diagnostic: false
  description: >-
    Brain MRI in one reported infant showed delayed myelination.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging of the brain showed volume loss in the cerebral
      hemispheres and cerebellum and delayed myelination.
    explanation: >-
      The case report directly documents delayed myelination on MRI.
genetic:
- name: ALG9
  association: Biallelic loss-of-function variants
  features: >-
    Reported ALG9-CDG variants include missense alleles in liveborn patients and
    a homozygous c.1173+2T>A splice variant in fetal-lethal
    Gillessen-Kaesbach-Nishimura skeletal dysplasia. These observations establish
    a phenotypic range from liveborn multisystem disease to prenatal lethality,
    but the small number of families does not establish a variant-class severity
    correlation.
  gene_term:
    preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous point-mutation 1567G-->A (amino acid substitution E523K) was
      detected in the ALG9 gene.
    explanation: >-
      The defining ALG9-CDG report identifies a homozygous ALG9 variant in the
      affected patient.
  - reference: PMID:25966638
    reference_title: "A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected patients were shown to have a novel homozygous splice variant
      NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding
      alpha-1,2-mannosyltransferase, involved in the formation of the
      lipid-linked oligosaccharide precursor of N-glycosylation.
    explanation: >-
      The fetal series directly links homozygous ALG9 splice variants to the
      severe prenatal form.
diagnosis:
- name: Serum transferrin isoelectric focusing
  description: >-
    Transferrin isoelectric focusing is a nonspecific biochemical screen that
    can detect a type I CDG hypoglycosylation pattern but cannot distinguish
    ALG9-CDG from other type I congenital disorders of glycosylation.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: A type I CDG transferrin pattern that requires etiologic follow-up.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum
      transferrin analyzed by isoelectric focusing.
    explanation: >-
      This directly supports the type I transferrin pattern as a biochemical
      screening result; it does not establish the ALG9 subtype.
- name: ALG9 molecular genetic testing
  description: >-
    Molecular diagnosis requires two pathogenic or likely pathogenic ALG9
    variants affecting opposite alleles (in trans), interpreted with the
    biochemical and clinical findings.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: ALG9
        term:
          id: hgnc:15672
          label: ALG9
  results: Biallelic pathogenic or likely pathogenic ALG9 variants in trans.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A defect in the ALG9 enzyme was suggested by the accumulation of the
      DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 in the patient's fibroblasts and
      confirmed by mutation analysis: the patient is homozygous for the ALG9
      mutation p.Y286C.
    explanation: >-
      A confirmed affected individual was homozygous for an ALG9 variant,
      illustrating biallelic molecular confirmation.
- name: Glycan profiling
  description: >-
    Glycan profiling can corroborate an abnormal type I glycosylation pattern,
    but it is a biochemical characterization method and cannot by itself
    establish biallelic ALG9 etiology.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: Abnormal glycan profile consistent with a type I glycosylation defect.
  evidence:
  - reference: PMID:28932688
    reference_title: "ALG9-CDG: New clinical case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metabolic work-up included analysis of a transferrin isoelectric
      focusing, which showed a type 1 pattern. This was confirmed by glycan
      profiling
    explanation: >-
      The case report supports glycan profiling as confirmation of the
      biochemical pattern, not as a method for identifying an ALG9 genotype.
biochemical:
- name: Type I carbohydrate-deficient transferrin pattern
  presence: ABNORMAL
  context: >-
    ALG9-CDG produces a type I CDG transferrin pattern from impaired synthesis
    or transfer of lipid-linked oligosaccharide precursors.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: Protein hypoglycosylation
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A type I carbohydrate-deficient transferrin pattern directly reports
      hypoglycosylation of a serum glycoprotein; it is not ALG9-specific.
    evidence:
    - reference: PMID:15945070
      reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypoglycosylation was confirmed by the typical CDG type 1 pattern of
        serum transferrin analyzed by isoelectric focusing.
      explanation: >-
        The patient-level transferrin pattern is an indirect readout of the
        upstream lipid-linked-oligosaccharide defect and is not ALG9-specific.
  evidence:
  - reference: PMID:15945070
    reference_title: "CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum
      transferrin analyzed by isoelectric focusing.
    explanation: >-
      This is the reported biochemical diagnostic signature in a confirmed
      ALG9-CDG patient.
- name: Accumulated DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8
  presence: ABNORMAL
  context: >-
    Patient cells accumulate truncated lipid-linked oligosaccharides upstream
    of the ALG9-dependent mannosyltransferase steps.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: ALG9 alpha-1,2-mannosyltransferase deficiency
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Accumulation of DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 reports the
      ALG9-dependent mannosyltransferase block in lipid-linked oligosaccharide
      assembly.
    evidence:
    - reference: PMID:15148656
      reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using this approach, we have found, in a patient with CDG, a deficiency
        of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
        accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
        structures
      explanation: >-
        The cultured-cell biochemical study directly links accumulation of the
        two truncated intermediates to ALG9 enzyme deficiency.
  evidence:
  - reference: PMID:15148656
    reference_title: "Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using this approach, we have found, in a patient with CDG, a deficiency of
      the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an
      accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8)
      structures, which was paralleled by the transfer of incomplete
      oligosaccharides precursors to protein.
    explanation: >-
      The defining biochemical report directly describes the accumulated
      DolPP-linked oligosaccharide species.
treatments: []
differential_diagnoses: []
clinical_trials:
- name: NCT04199000
  status: RECRUITING
  description: >-
    Recruiting CDG-wide observational natural-history research relevant to
    genetically, enzymatically, or molecularly confirmed CDG subtypes such as
    ALG9-CDG; it does not provide treatment-efficacy evidence.
  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 study is observational and CDG-wide rather than ALG9-specific, so it
      only partially supports relevance to ALG9-CDG natural-history research.
datasets: []
📚

References & Deep Research

References

9
ORPHA:79328
ALG9-CDG
No top-level findings curated for this source.
PMID:15148656
Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL.
No top-level findings curated for this source.
PMID:15945070
CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features.
No top-level findings curated for this source.
PMID:19451548
Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient.
No top-level findings curated for this source.
PMID:25966638
A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.
No top-level findings curated for this source.
PMID:28742265
Congenital disorders of glycosylation: The Saudi experience.
No top-level findings curated for this source.
PMID:28932688
ALG9-CDG: New clinical case and review of the literature.
No top-level findings curated for this source.
PMID:31420886
Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review.
No top-level findings curated for this source.
clinicaltrials:NCT04199000
Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
ALG9–congenital disorder of glycosylation (ALG9-CDG; historical CDG-IL) — Disease Characteristics Research Report
Edison Scientific Literature 22 citations 2026-05-11T12:44:11.480867

ALG9–congenital disorder of glycosylation (ALG9-CDG; historical CDG-IL) — Disease Characteristics Research Report

Target disease

  • Disease name: ALG9–congenital disorder of glycosylation (ALG9-CDG)
  • Category: Mendelian, inborn error of metabolism; N-linked glycosylation defect (CDG type I pattern on transferrin testing) (frank2004identificationandfunctional pages 1-2, davis2017alg9cdgnewclinical pages 5-6)
  • MONDO ID: Not retrievable with the available tools in this run (gap)

Executive summary

ALG9-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ALG9, which encodes an ER α1,2-mannosyltransferase required for stepwise assembly of the dolichol-linked oligosaccharide precursor for N-glycosylation. The disorder shows a broad phenotypic spectrum ranging from a liveborn multisystem neurodevelopmental disorder (developmental delay, hypotonia, seizures, progressive microcephaly, hepatomegaly; often renal cystic disease and pericardial effusion) to prenatal-lethal skeletal dysplasia with polycystic kidneys and multiple malformations (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2). Diagnostic hallmarks include type I transferrin isoelectric focusing abnormalities, accumulation of truncated lipid-linked oligosaccharide intermediates (DolPP-GlcNAc2Man6/Man8), and N-glycan profiling showing truncation with relative enrichment of smaller high-mannose species (Man4–Man6) and depletion of Man7–Man9 (frank2004identificationandfunctional pages 2-5, davis2017alg9cdgnewclinical pages 5-6).

Evidence map (structured summary)

Disease / identifier Gene Inheritance Key pathogenic variant(s) reported Core phenotypes reported Biochemical / diagnostic findings Evidence type Year Key citation(s)
ALG9-congenital disorder of glycosylation; ALG9-CDG; former name CDG-IL ALG9 (alpha-1,2-mannosyltransferase) Autosomal recessive General disease definition; multiple homozygous variants across reports Multisystem N-glycosylation disorder with neurodevelopmental impairment and variable visceral involvement Type I CDG on transferrin isoelectric focusing; abnormal N-glycosylation due to defective dolichol-linked oligosaccharide assembly (frank2004identificationandfunctional pages 1-2, francisco2023congenitaldisordersof pages 1-2) Human disease definition / review 2004, 2023 (frank2004identificationandfunctional pages 1-2, francisco2023congenitaldisordersof pages 1-2)
Initial molecularly defined liveborn case ALG9 Autosomal recessive (homozygous variant) c.1567G>A, p.Glu523Lys (also described in secondary summaries as p.E523K) Developmental delay, central hypotonia, seizures, severe microcephaly, hepatomegaly, bronchial asthma Serum transferrin IEF: increased disialo- and asialo-transferrin consistent with CDG-I; fibroblast LLO accumulation of DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8; transfer of truncated glycans to protein; yeast complementation confirmed functional defect (frank2004identificationandfunctional pages 1-2, frank2004identificationandfunctional pages 2-5) Human case report with functional validation 2004 (frank2004identificationandfunctional pages 1-2, frank2004identificationandfunctional pages 2-5)
Second liveborn case expanding phenotype ALG9 Autosomal recessive (homozygous variant) c.860A>G, p.Tyr286Cys / p.Y286C Psychomotor retardation, seizures, hypotonia, diffuse cerebral and cerebellar atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, inverted nipples; progressive microcephaly later documented Typical CDG type I transferrin pattern by IEF; ALG9 defect suggested by DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 accumulation; molecular confirmation by yeast complementation (weinstein2005cdg‐ilaninfant pages 1-2) Human case report 2005 (weinstein2005cdg‐ilaninfant pages 1-2)
Later liveborn case with glycomics confirmation ALG9 Autosomal recessive (homozygous variant; both parents carriers) c.860A>G, p.Tyr287Cys / p.Y287C Facial dysmorphism, CNS involvement, developmental delay, failure to thrive; MRI with moderate global cerebral atrophy; prenatal renal cysts/minor cardiac malformations reported in broader review of literature Transferrin IEF type I: decreased tetrasialo-Tf with increased disialo-Tf and small asialo-Tf; plasma and fibroblast LC-MS N-glycan profiling showed increased Man4-Man6 with absent/reduced Man7-Man9, consistent with ALG9 block (davis2017alg9cdgnewclinical pages 5-6, davis2017alg9cdgnewclinical media b6fa124e, davis2017alg9cdgnewclinical media 966d80b6) Human case report / glycomics 2017 (davis2017alg9cdgnewclinical pages 5-6, davis2017alg9cdgnewclinical media b6fa124e, davis2017alg9cdgnewclinical media 966d80b6)
Lethal fetal skeletal dysplasia / Gillessen-Kaesbach–Nishimura syndrome end of spectrum ALG9 Autosomal recessive (homozygous splice variant) c.1173+2T>A (reported as c.1173+2T4A in extracted text due to formatting), splice donor; exon 10 skipping Lethal fetal phenotype with skeletal dysplasia, polycystic kidneys, multiple malformations; characteristic round pelvis, mesomelic upper-limb shortening, defective cervical vertebral ossification; demonstrates severe prenatal end of ALG9-CDG spectrum Mass spectrometric transferrin analysis showed increased monoglycosylated transferrin, confirming CDG; RNA analysis demonstrated exon 10 skipping (tham2016anovelphenotype pages 1-2) Fetal pathology / exome / RNA study 2016 (tham2016anovelphenotype pages 1-2)
Saudi cohort / recurrent founder-like variant series ALG9 Autosomal recessive (all homozygous in this cohort) c.1075G>A, p.Glu359Lys / p.E359K Eight patients from four unrelated families: dysmorphic features, early-onset refractory epilepsy, progressive microcephaly, severe developmental disability, failure to thrive, skeletal dysplasia, mild hepatomegaly with normal transaminases, hydrops fetalis; brain MRI with delayed myelination and cerebral/cerebellar atrophy Clinical series emphasized phenotype; biochemical details not provided in extracted cohort text (alsubhi2017congenitaldisordersof pages 6-6) Human case series 2017 (alsubhi2017congenitaldisordersof pages 6-6)
Cross-report phenotype synthesis ALG9 Autosomal recessive Missense variants (p.Y286C/p.Y287C, p.E523K/p.E530K) generally associated with liveborn disease; splice variant c.1173+2T>A associated with prenatal lethal presentation; recurrent p.E359K in Saudi cohort Recurrent features across reports: neurodevelopmental delay/disability, hypotonia, seizures, progressive microcephaly, renal cysts/cystic kidneys, hepatomegaly, failure to thrive, pericardial effusion/cardiac tamponade, hydrops fetalis, and severe skeletal dysplasia/lethal fetal disease at the most severe end Core diagnostic signature across reports: abnormal transferrin glycoforms (type I pattern or increased monoglycosylated transferrin), truncated LLO intermediates (Man6/Man8), and glycomics showing buildup of shorter high-mannose species (Man4-6) with loss of Man7-9 (tham2016anovelphenotype pages 1-2, davis2017alg9cdgnewclinical pages 7-9, davis2017alg9cdgnewclinical pages 1-2) Human literature synthesis 2016–2017 (tham2016anovelphenotype pages 1-2, davis2017alg9cdgnewclinical pages 7-9, davis2017alg9cdgnewclinical pages 1-2)

Table: This table summarizes the main knowledge-base fields for ALG9-CDG/CDG-IL, including identifiers, inheritance, reported pathogenic variants, phenotype spectrum, and hallmark biochemical findings. It condenses the available human case reports, fetal pathology evidence, and broader literature synthesis into a citation-linked reference.

1. Disease information

1.1 What is the disease?

ALG9-CDG is a congenital disorder of N-linked glycosylation due to defective lipid-linked oligosaccharide (LLO) assembly in the endoplasmic reticulum, leading to transfer of incomplete glycan precursors to proteins and under-occupancy of N-glycosylation sites (a “CDG type I” biochemical pattern) (frank2004identificationandfunctional pages 1-2, frank2004identificationandfunctional pages 2-5).

1.2 Key identifiers (available from retrieved sources)

  • Gene: ALG9 (α1,2-mannosyltransferase) (tham2016anovelphenotype pages 1-2)
  • Historical disease name: CDG-IL (defined as a novel CDG-I subtype in 2004) (frank2004identificationandfunctional pages 1-2)
  • Current naming convention: gene-based “ALG9-CDG” used in modern CDG nosology (francisco2023congenitaldisordersof pages 1-2)

Not retrievable in this run (gaps needing external database lookup): OMIM disease number, Orphanet ID, ICD-10/ICD-11 code, MeSH, MONDO.

1.3 Synonyms / alternative names

  • ALG9-CDG
  • CDG-IL (historical subtype name)
  • In the fetal-lethal extreme: Gillessen-Kaesbach–Nishimura syndrome due to ALG9 variants (as framed by Tham et al.) (tham2016anovelphenotype pages 1-2)

1.4 Evidence source type

The currently retrievable evidence is primarily individual patients and small case series, including fetal autopsy/genomics studies and country-specific cohorts, rather than large aggregated natural-history datasets specific to ALG9-CDG (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

2. Etiology

2.1 Disease causal factors

  • Genetic cause: biallelic loss-of-function or deleterious missense/splice variants in ALG9 impair LLO assembly and N-glycosylation (frank2004identificationandfunctional pages 1-2, tham2016anovelphenotype pages 1-2).
  • Mechanistic cause: defects in ALG9 α1,2-mannosyltransferase activity lead to intracellular accumulation of truncated LLO intermediates (notably DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8) and transfer of incomplete precursors to proteins (frank2004identificationandfunctional pages 2-5).

2.2 Risk factors

  • Consanguinity/family recurrence: multiple reports involve homozygous variants and familial clustering, consistent with autosomal recessive inheritance and increased risk in consanguineous settings (davis2017alg9cdgnewclinical pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

No gene–environment interaction evidence specific to ALG9-CDG was identified in the retrieved sources.

3. Phenotypes

3.1 Phenotype spectrum (current understanding)

The phenotype spectrum spans: - Liveborn multisystem neurodevelopmental disease: developmental delay/psychomotor retardation, hypotonia, seizures/epilepsy, progressive microcephaly, failure to thrive, and hepatomegaly (frank2004identificationandfunctional pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6). - Renal phenotype: cystic kidneys/cystic renal disease and multiple small renal cysts (weinstein2005cdg‐ilaninfant pages 1-2, tham2016anovelphenotype pages 1-2). - Cardiac phenotype: pericardial effusion (including prenatal detection) and progression to cardiac tamponade in at least one reported infant (weinstein2005cdg‐ilaninfant pages 1-2). - Severe prenatal end: lethal fetal skeletal dysplasia with polycystic kidneys and multiple malformations (Gillessen-Kaesbach–Nishimura syndrome) (tham2016anovelphenotype pages 1-2).

3.2 Phenotype characteristics (onset, severity, progression)

  • Onset: often prenatal (hydrops fetalis; pericardial effusion; renal cysts detectable by fetal imaging) to early infancy (failure to thrive, hypotonia, seizures) (weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).
  • Severity: ranges from survivable but severe neurodevelopmental disability to prenatal/neonatal lethality in the skeletal dysplasia phenotype (tham2016anovelphenotype pages 1-2).
  • Progression: progressive microcephaly has been emphasized in case reports/series; seizure control can be difficult (weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

3.3 Approximate frequency of features (from the retrieved evidence)

Formal pooled percentages for ALG9-CDG features were not extractable from the retrieved texts. However, a Saudi cohort described 8 patients from 4 unrelated families with a shared homozygous variant and recurrent features including refractory epilepsy, progressive microcephaly, skeletal dysplasia, and hydrops fetalis (alsubhi2017congenitaldisordersof pages 6-6).

3.4 Suggested HPO terms (non-exhaustive)

Based on the described phenotypes: - Seizures (HP:0001250) - Developmental delay / intellectual disability (HP:0001263 / HP:0001249) - Hypotonia (HP:0001252) - Progressive microcephaly / microcephaly (HP:0000252) - Failure to thrive (HP:0001508) - Hepatomegaly (HP:0002240) - Renal cysts / cystic kidney disease (HP:0000107) - Pericardial effusion (HP:0001698) - Hydrops fetalis (HP:0001789) - Skeletal dysplasia / limb shortening / mesomelia (e.g., HP:0002652; HP:0003027)

3.5 Quality-of-life impact

Direct validated quality-of-life instruments (e.g., EQ-5D, SF-36) were not found in the retrieved sources for ALG9-CDG. Nonetheless, severe developmental disability, refractory epilepsy, and multisystem involvement imply high caregiver burden and profound impairment in daily functioning (alsubhi2017congenitaldisordersof pages 6-6, weinstein2005cdg‐ilaninfant pages 1-2).

4. Genetic / molecular information

4.1 Causal gene

  • ALG9 encodes an ER α1,2-mannosyltransferase involved in LLO biosynthesis for N-glycosylation and is required for proper human development and physiology (frank2004identificationandfunctional pages 1-2).

4.2 Pathogenic variants (from retrieved primary reports)

Reported homozygous variants include: - c.1567G>A (p.Glu523Lys / E523K) in the defining 2004 case (frank2004identificationandfunctional pages 2-5). - c.860A>G (p.Tyr286Cys / p.Y286C) in the 2005 case (weinstein2005cdg‐ilaninfant pages 1-2). - c.860A>G (p.Tyr287Cys / p.Y287C) in the 2017 case report with detailed glycomics (davis2017alg9cdgnewclinical pages 5-6). - c.1173+2T>A (splice donor; exon 10 skipping) associated with lethal fetal skeletal dysplasia (tham2016anovelphenotype pages 1-2). - c.1075G>A (p.Glu359Lys / p.E359K) in 8 Saudi patients (alsubhi2017congenitaldisordersof pages 6-6).

4.3 Variant type/class and functional consequences

  • Variants include missense substitutions and splice-site disruption causing exon skipping and predicted frameshift/out-of-frame transcript (tham2016anovelphenotype pages 1-2).
  • Functional validation in the defining work used yeast complementation, demonstrating that the patient allele impairs ALG9 function (residual activity noted), consistent with a loss-of-function/hypomorphic mechanism (frank2004identificationandfunctional pages 2-5).

4.4 Population allele frequency

One missense allele (Y287C) is described as very rare in population data (ExAC allele frequency reported in the 2017 review/case context), consistent with ultra-rare recessive disease (davis2017alg9cdgnewclinical pages 7-9).

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No ALG9-CDG-specific modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities were identified in the retrieved sources.

5. Environmental information

No environmental, lifestyle, toxin, radiation, or infectious triggers were identified as contributing factors in the retrieved evidence. ALG9-CDG is best supported as a primary monogenic disorder (frank2004identificationandfunctional pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2).

6. Mechanism / pathophysiology

6.1 Pathway placement and biochemical chain of causality

1) Primary trigger: biallelic pathogenic ALG9 variants (frank2004identificationandfunctional pages 2-5, tham2016anovelphenotype pages 1-2). 2) Molecular defect: reduced ALG9 α1,2-mannosyltransferase function during ER LLO assembly; human ALG9 catalyzes mannose transfer onto at least two acceptor substrates (DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8), consistent with dual-step involvement (frank2004identificationandfunctional pages 2-5). 3) Biochemical consequence: accumulation of truncated LLO intermediates (DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8) and transfer of incomplete precursors to protein N-glycosylation sites (frank2004identificationandfunctional pages 2-5). 4) Cellular consequence: protein underglycosylation and aberrant glycan structures can perturb ER quality control (calnexin/calreticulin cycle), glycoprotein folding/trafficking, and ER-associated degradation (ERAD), proposed as contributors to phenotype (frank2004identificationandfunctional pages 2-5). 5) Tissue/organ outcomes: multisystem developmental and organ dysfunction, with prominent neurologic involvement; renal cystic disease; cardiac involvement such as pericardial effusion; and, in severe fetal cases, skeletal dysplasia with visceral malformations (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2).

6.2 Direct abstract-quoted mechanistic evidence

  • Defining paper (2004) explicitly ties mechanism to LLO intermediates: it reports “a deficiency of the ALG9 α1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc2Man6 and -GlcNAc2Man8 structures” and notes this was “paralleled by the transfer of incomplete oligosaccharides precursors to protein” (frank2004identificationandfunctional pages 1-2).
  • 2017 case report glycomics: “N-glycan profile… showed significant increase…Man4…Man5…Man6 with absence of…Man7…Man8…Man9” and interprets “blockage of N-glycan biosynthesis after Man6 indicated a probable defect in ALG9” (davis2017alg9cdgnewclinical pages 5-6).
  • Fetal-lethal phenotype: “Mass spectrometric analysis showed an increase in monoglycosylated transferrin… confirming that this is a congenital disorder of glycosylation (CDG)” and “RNA analysis demonstrated skipping of exon 10” for the splice variant (tham2016anovelphenotype pages 1-2).

6.3 Ontology suggestions

  • GO Biological Process: protein N-linked glycosylation; dolichol-linked oligosaccharide biosynthetic process; glycoprotein folding/quality control (supported mechanistically) (frank2004identificationandfunctional pages 2-5).
  • GO Cellular Component: endoplasmic reticulum membrane/lumen (ALG9 is a multispanning ER protein in the N-glycosylation pathway) (frank2004identificationandfunctional pages 2-5).
  • CL (cell types): broad systemic involvement; evidence does not specify a single primary cell type, but fibroblast biochemical studies are commonly used diagnostically (patient fibroblasts studied) (frank2004identificationandfunctional pages 2-5, davis2017alg9cdgnewclinical pages 5-6).

6.4 Molecular profiling (omics)

Targeted N-glycan profiling by LC-MS in plasma and fibroblasts demonstrates a truncation signature (Man4–Man6 enrichment; Man7–Man9 depletion) consistent with pathway blockade at ALG9 (davis2017alg9cdgnewclinical pages 5-6).

7. Anatomical structures affected

7.1 Organ systems (supported by case literature)

  • Central nervous system: diffuse brain atrophy, delayed myelination (weinstein2005cdg‐ilaninfant pages 1-2).
  • Kidney: cystic renal disease / polycystic kidneys in severe fetal phenotype (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2).
  • Heart/pericardium: pericardial effusion and tamponade (weinstein2005cdg‐ilaninfant pages 1-2).
  • Liver/spleen: hepatomegaly and hepatosplenomegaly (weinstein2005cdg‐ilaninfant pages 1-2, frank2004identificationandfunctional pages 1-2).
  • Skeletal system: lethal fetal skeletal dysplasia phenotype; skeletal dysplasia also reported in pediatric cohort (tham2016anovelphenotype pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

7.2 UBERON suggestions (non-exhaustive)

  • Brain; kidney; liver; heart/pericardium; skeletal system (supported by multi-organ clinical findings) (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2).

7.3 Subcellular localization

Endoplasmic reticulum (ER) LLO assembly pathway (frank2004identificationandfunctional pages 2-5).

8. Temporal development

  • Prenatal manifestations: pericardial effusion; renal cysts; hydrops fetalis; fetal skeletal dysplasia with lethality for severe splice variant cases (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).
  • Infant/childhood course: hypotonia, failure to thrive, seizures with difficult control, progressive microcephaly and neurodevelopmental impairment (weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

9. Inheritance and population

9.1 Inheritance

Autosomal recessive inheritance is supported by homozygous variants in affected children/fetuses and parental heterozygosity in families (davis2017alg9cdgnewclinical pages 5-6, weinstein2005cdg‐ilaninfant pages 1-2).

9.2 Epidemiology

ALG9-CDG is ultra-rare; early literature comprised a small number of families, but notable aggregation has been reported in regional cohorts. In a Saudi CDG cohort, ALG9-CDG accounted for 8 patients from 4 unrelated families, reported as 28.5% of the cohort’s CDG population (cohort composition rather than population prevalence) (alsubhi2017congenitaldisordersof pages 6-6). CDG-wide epidemiology reviews emphasize that generating robust prevalence/incidence data for CDG is challenging and often relies on case reports/series and allelic frequency, and also provide context that CDG are collectively rare inherited metabolic disorders (piedade2022epidemiologyofcongenital pages 1-2).

9.3 Population genetics

No robust carrier-frequency estimates for ALG9-CDG were extractable from the retrieved texts; one reported allele is extremely rare in population databases (ExAC) (davis2017alg9cdgnewclinical pages 7-9).

10. Diagnostics

10.1 Biochemical testing

  • Transferrin isoelectric focusing (TIEF): characteristic CDG type I pattern, e.g., increased disialo-/asialo-transferrin and decreased tetrasialo-transferrin (frank2004identificationandfunctional pages 2-5, davis2017alg9cdgnewclinical pages 5-6).
  • LLO analysis in patient fibroblasts: accumulation of DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 (frank2004identificationandfunctional pages 2-5, weinstein2005cdg‐ilaninfant pages 1-2).
  • Mass spectrometry glycomics / N-glycan profiling: truncation signature consistent with ALG9 blockade, including increased Man4–Man6 and depletion/absence of Man7–Man9 (davis2017alg9cdgnewclinical pages 5-6, davis2017alg9cdgnewclinical media b6fa124e).

Image evidence (real-world implementation of glycomics): Figures demonstrating the diagnostic N-glycan signature in plasma and fibroblasts are available from the 2017 clinical case report (davis2017alg9cdgnewclinical media b6fa124e, davis2017alg9cdgnewclinical media 966d80b6).

10.2 Genetic testing

  • Confirmatory molecular diagnosis was achieved via targeted sequencing after biochemical suspicion (davis2017alg9cdgnewclinical pages 5-6) and via exome + RNA studies in fetal cases (tham2016anovelphenotype pages 1-2).
  • Modern CDG practice has shifted from purely transferrin-pattern based naming to gene-based nosology, reflecting widespread adoption of NGS (francisco2023congenitaldisordersof pages 1-2).

10.3 Differential diagnosis

The fetal skeletal dysplasia phenotype overlaps with ALG3- and ALG12-CDG skeletal features, motivating a diagnostic grouping of certain N-glycosylation disorders within skeletal dysplasias (tham2016anovelphenotype pages 1-2).

11. Outcome / prognosis

Prognosis is variable: - Prenatal-lethal outcomes are documented for severe splice-variant-associated skeletal dysplasia with visceral malformations (tham2016anovelphenotype pages 1-2). - Survival with severe neurodevelopmental impairment is documented in liveborn cases; severe epilepsy and progressive microcephaly can occur, and cardiac tamponade secondary to pericardial effusion is a life-threatening complication (weinstein2005cdg‐ilaninfant pages 1-2).

Quantitative survival curves or life expectancy data were not available in the retrieved evidence.

12. Treatment

12.1 Disease-specific therapy

No ALG9-CDG-specific targeted therapy was identified in the retrieved sources.

12.2 Supportive/standard-of-care elements (real-world implementations)

  • Epilepsy management: antiepileptic therapy is used; seizure control may be difficult (weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).
  • Management of pericardial effusion/tamponade: pericardiocentesis was required in at least one case due to tamponade (weinstein2005cdg‐ilaninfant pages 1-2).
  • Nutritional support / failure-to-thrive management: failure to thrive is prominent in reported cases and requires supportive care, although specific protocols were not detailed in the retrieved texts (weinstein2005cdg‐ilaninfant pages 1-2, alsubhi2017congenitaldisordersof pages 6-6).

12.3 CDG expert recommendations relevant to ALG9-CDG (2024)

A 2024 analysis from the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) provides expert recommendations for baseline and longitudinal cardiac surveillance (echocardiogram and ECG at diagnosis; annual in early childhood with spacing later) due to cardiomyopathy/pericardial effusion risks in CDG broadly (zemet2024cardiomyopathyanuncommon pages 1-3). While ALG9-CDG was not among the cardiomyopathy cases listed, pericardial effusion is clearly part of ALG9-CDG phenotypes, making structured cardiac surveillance clinically prudent (weinstein2005cdg‐ilaninfant pages 1-2, zemet2024cardiomyopathyanuncommon pages 1-3).

12.4 Suggested MAXO terms (examples)

  • Antiepileptic drug therapy (MAXO: antiepileptic therapy)
  • Pericardiocentesis / pericardial drainage procedure
  • Nutritional support / enteral nutrition
  • Cardiac surveillance (echocardiography; electrocardiography)

13. Prevention

No primary prevention is currently established for ALG9-CDG. Prevention focuses on genetic counseling and reproductive options: - Carrier testing and cascade testing in families with a known pathogenic variant. - Prenatal diagnosis is feasible (fetal ultrasound findings plus molecular testing), and fetal presentation has been described for severe cases (tham2016anovelphenotype pages 1-2, weinstein2005cdg‐ilaninfant pages 1-2).

14. Other species / natural disease

No naturally occurring ALG9-CDG-like disease in non-human species was identified in the retrieved evidence.

15. Model organisms

15.1 Functional models used in the evidence base

  • Yeast complementation assays were used to demonstrate functional homology between human and yeast ALG9 and the deleterious effect of patient variants, providing strong mechanistic support (frank2004identificationandfunctional pages 2-5).

15.2 Translational relevance and limitations

Yeast assays robustly establish enzymatic pathway function and variant impact but do not recapitulate the multi-organ developmental phenotypes; vertebrate models were not retrieved in this run.

Recent developments (2023–2024 prioritized)

2023: CDG field state-of-the-art (context relevant to ALG9-CDG)

A 2023 “state of the art in 2022” review emphasizes that CDG are a heterogeneous family of rare metabolic diseases and highlights that multi-omics advances have accelerated progress but targeted therapies remain a major unmet need; it also documents the modern gene-based nomenclature and challenges in CDG classification (francisco2023congenitaldisordersof pages 1-2).

2024: Expert guidance on cardiac monitoring in CDG

A 2024 FCDGC study identified cardiomyopathy in approximately ~6% of 305 molecularly confirmed CDG patients in their cohort and proposed standardized cardiac screening/follow-up (zemet2024cardiomyopathyanuncommon pages 1-3). Even though ALG9-CDG was not specifically represented among their cardiomyopathy subset, the presence of pericardial effusion/tamponade in ALG9-CDG case reports supports heightened cardiac vigilance (weinstein2005cdg‐ilaninfant pages 1-2).

URLs and publication dates (where available from retrieved texts)

  • Frank CG et al. Am J Hum Genet (published electronically May 17, 2004). https://doi.org/10.1086/422367 (frank2004identificationandfunctional pages 1-2)
  • Weinstein M et al. Am J Med Genet A (2005). https://doi.org/10.1002/ajmg.a.30851 (weinstein2005cdg‐ilaninfant pages 1-2)
  • Tham E et al. Eur J Hum Genet (published online May 13, 2015; journal issue 2016). https://doi.org/10.1038/ejhg.2015.91 (tham2016anovelphenotype pages 1-2)
  • Davis K et al. Mol Genet Metab Rep (Dec 2017). https://doi.org/10.1016/j.ymgmr.2017.08.004 (davis2017alg9cdgnewclinical pages 1-2)
  • Francisco R et al. Orphanet J Rare Dis (Oct 2023). https://doi.org/10.1186/s13023-023-02879-z (francisco2023congenitaldisordersof pages 1-2)
  • Zemet R et al. Mol Genet Metab (Aug 2024). https://doi.org/10.1016/j.ymgme.2024.108513 (zemet2024cardiomyopathyanuncommon pages 1-3)
  • Piedade A et al. Journal of Rare Diseases (Dec 2022). https://doi.org/10.1007/s44162-022-00003-6 (piedade2022epidemiologyofcongenital pages 1-2)

Limitations of this report (important for knowledge-base curation)

1) Ontology IDs (OMIM/Orphanet/MONDO/ICD/MeSH) and PMIDs were not retrievable with the available tools in this run; the report therefore prioritizes DOI/URLs and direct excerpts from accessible full text. 2) ALG9-CDG remains ultra-rare; feature frequencies, survival statistics, and validated QoL metrics are not well defined in the retrieved primary literature. 3) ALG9-specific 2023–2024 primary case expansions were not retrievable here; “latest research” sections therefore focus on CDG-wide advances and consensus recommendations.

References

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  12. (piedade2022epidemiologyofcongenital pages 1-2): Ana Piedade, Rita Francisco, Jaak Jaeken, Peymaneh Sarkhail, Sandra Brasil, Carlos R. Ferreira, Tatiana Rijoff, Carlota Pascoal, Alexandre Gil, Ana Beatriz Lourenço, Marta Abreu, Mafalda Gomes, Paula A. Videira, and Vanessa dos Reis Ferreira. Epidemiology of congenital disorders of glycosylation (cdg)—overview and perspectives. Journal of Rare Diseases, Dec 2022. URL: https://doi.org/10.1007/s44162-022-00003-6, doi:10.1007/s44162-022-00003-6. This article has 35 citations.

  13. (zemet2024cardiomyopathyanuncommon pages 1-3): Roni Zemet, Kyle D. Hope, Andrew C. Edmondson, Rameen Shah, Maria Patino, Abigail M. Yesso, Justin H. Berger, Kyriakie Sarafoglou, Austin Larson, Christina Lam, Eva Morava, and Fernando Scaglia. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: recommendations for baseline screening and follow-up evaluation. Molecular Genetics and Metabolism, 142:108513, Aug 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108513, doi:10.1016/j.ymgme.2024.108513. This article has 14 citations and is from a peer-reviewed journal.