👪

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.

⚙

Pathophysiology

7

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.

ALG9 link

dolichol-linked oligosaccharide biosynthetic process link ↓ DECREASED protein N-linked glycosylation link ↓ DECREASED

mannosyltransferase activity link ↓ DECREASED

endoplasmic reticulum link

Downstream

Truncated lipid-linked oligosaccharide accumulation Reduced ALG9 activity causes accumulation of incomplete DolPP-linked oligosaccharides.

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

Accumulated incomplete lipid-linked oligosaccharides are transferred to proteins, producing hypoglycosylation and a type I CDG biochemical pattern.

protein N-linked glycosylation link ↓ DECREASED

Downstream

Multisystem glycoprotein dysfunction Protein hypoglycosylation contributes to neurologic, hepatic, renal, cardiac, and skeletal manifestations.

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 second case report confirms the downstream type I CDG transferrin hypoglycosylation pattern.

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.

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.

protein N-linked glycosylation link ↓ DECREASED

Downstream

Neurodevelopmental and brain involvement ALG9-CDG glycoprotein dysfunction is associated with developmental delay, hypotonia, seizures, microcephaly, and brain MRI abnormalities.

Growth, hepatic, and renal involvement Liveborn ALG9-CDG patients frequently show failure to thrive and hepatic or renal involvement.

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.

Cardiac and pericardial involvement ALG9-CDG can include cardiovascular findings, particularly pericardial effusion in the reported infant case.

Show evidence (2 references)

PMID:28932688 SUPPORT Human Clinical

"To date, a total of 10 patients from 6 different families have been reported with one of four ALG9 mutations."

The review frames the disease as a rare multisystem human disorder caused by ALG9 mutations.

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.

brain link

Downstream

Global developmental delay Developmental delay is a reported liveborn ALG9-CDG manifestation.

Generalized hypotonia Hypotonia is a recurrent neurologic manifestation of ALG9-CDG.

Seizure Seizures are part of the liveborn ALG9-CDG neurologic spectrum.

Microcephaly Microcephaly is reported among liveborn ALG9-CDG patients.

Abnormal myelination Delayed myelination is a reported brain MRI finding in ALG9-CDG.

Generalized cerebral atrophy/hypoplasia Cerebral and cerebellar volume loss are reported brain MRI findings.

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.

kidney link

Downstream

Failure to thrive Failure to thrive is a recurrent liveborn ALG9-CDG feature.

Hepatomegaly Hepatomegaly or hepatosplenomegaly is part of the visceral ALG9-CDG phenotype.

Renal cyst Renal cysts or cystic renal disease are recurrent ALG9-CDG findings.

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 causing nonimmune hydrops fetalis.

skeletal system link

Downstream

Skeletal dysplasia Skeletal dysplasia is the defining severe prenatal ALG9-CDG phenotype.

Hydrops fetalis ALG9 is reported among CDG genes associated with nonimmune hydrops fetalis.

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.

heart link

Downstream

Pericardial effusion Pericardial effusion is the reported cardiovascular manifestation.

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.

⬡

Pathograph

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

●

Phenotypes

12

Digestive 1

Hepatomegaly Hepatomegaly (HP:0002240)

Show evidence (1 reference)

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.

Genitourinary 1

Renal cyst Renal cyst (HP:0000107)

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 Microcephaly (HP:0000252)

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 Hydrops fetalis (HP:0001789)

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

Generalized hypotonia Generalized hypotonia (HP:0001290)

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 hypotonia among the infant's features.

Skeletal dysplasia Skeletal dysplasia (HP:0002652)

Show evidence (1 reference)

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.

Nervous System 2

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (1 reference)

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.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

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.

Growth 1

Failure to thrive Failure to thrive (HP:0001508)

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

Pericardial effusion Pericardial effusion (HP:0001698)

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 pericardial effusion.

Abnormal myelination Abnormal myelination (HP:0012447)

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.

Generalized cerebral atrophy/hypoplasia Generalized cerebral atrophy/hypoplasia (HP:0007058)

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 and cerebellar volume loss on MRI.

🧬

Genetic Associations

1

ALG9 (Loss of function mutation)

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.

💊

Treatments

2

Supportive seizure management

Action: supportive care MAXO:0000950

No ALG9-specific disease-modifying therapy is established; seizure care is supportive and symptom-directed.

Target Phenotypes: Seizure ↗

Show evidence (1 reference)

PMID:28932688 PARTIAL Human Clinical

"She developed failure to thrive and seizures."

The cited case supports seizures as a treatment target; specific antiepileptic regimens are not provided in the abstract, so the treatment claim is limited to supportive symptom management.

Cardiac surveillance

Action: supportive care MAXO:0000950

Cardiac monitoring is prudent in ALG9-CDG because pericardial effusion is a reported disease manifestation and CDG expert recommendations support periodic cardiac surveillance for CDG patients.

Target Phenotypes: Pericardial effusion ↗

Show evidence (1 reference)

PMID:38917675 PARTIAL Human Clinical

"Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood."

This CDG-wide recommendation supports cardiac surveillance generally; the ALG9-specific rationale comes from case evidence for pericardial effusion, so support is marked partial.

🔬

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 Truncated lipid-linked oligosaccharide accumulation Present Absent Diagnostic

A type I carbohydrate-deficient transferrin pattern reports impaired transfer of complete N-glycan precursors to serum glycoproteins.

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, which was paralleled by the transfer of incomplete oligosaccharides precursors..."

The defining biochemical report directly describes the accumulated DolPP-linked oligosaccharide species.

{ }

Source YAML

click to show

name: ALG9-congenital disorder of glycosylation
creation_date: "2026-05-11T16:30:19Z"
updated_date: "2026-05-18T06:00:42Z"
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
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
    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
    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: Saudi CDG cohort
  notes: >-
    ALG9-CDG is ultra-rare globally, but it represented a substantial fraction
    of one Saudi congenital-disorder-of-glycosylation cohort.
  evidence:
  - reference: PMID:28742265
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on molecular studies, the 27 CDG patients were classified into
      different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients,
      26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%),
      SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient).
    explanation: >-
      This provides a cohort-level estimate of ALG9-CDG representation within a
      molecularly diagnosed Saudi CDG cohort.
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
    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
    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.
pathophysiology:
- name: ALG9 alpha-1,2-mannosyltransferase deficiency
  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
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  molecular_functions:
  - preferred_term: mannosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0000030
      label: mannosyltransferase activity
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:15148656
    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
    evidence:
    - reference: PMID:15148656
      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: >-
    Accumulated incomplete lipid-linked oligosaccharides are transferred to
    proteins, producing hypoglycosylation and a type I CDG biochemical pattern.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan precursor
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  evidence:
  - reference: PMID:15945070
    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 second case report confirms the downstream type I CDG transferrin
      hypoglycosylation pattern.
  - reference: PMID:15945070
    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: Multisystem glycoprotein dysfunction
    description: >-
      Protein hypoglycosylation contributes to neurologic, hepatic, renal,
      cardiac, and skeletal manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15148656
      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 links inefficient lipid-linked oligosaccharide
        synthesis to human developmental and organ-system manifestations.
- name: 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: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:28932688
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, a total of 10 patients from 6 different families have been
      reported with one of four ALG9 mutations.
    explanation: >-
      The review frames the disease as a rare multisystem human disorder caused
      by ALG9 mutations.
  - reference: PMID:25966638
    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
    evidence:
    - reference: PMID:15945070
      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
    evidence:
    - reference: PMID:28932688
      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
    evidence:
    - reference: PMID:25966638
      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
    evidence:
    - reference: PMID:15945070
      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.
- 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
    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
    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
    evidence:
    - reference: PMID:15148656
      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: Generalized hypotonia
    description: Hypotonia is a recurrent neurologic manifestation of ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15945070
      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
    evidence:
    - reference: PMID:28932688
      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
    evidence:
    - reference: PMID:25966638
      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: Abnormal myelination
    description: Delayed myelination is a reported brain MRI finding in ALG9-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15945070
      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: Generalized cerebral atrophy/hypoplasia
    description: Cerebral and cerebellar volume loss are reported brain MRI findings.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15945070
      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 and 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
    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
    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
    evidence:
    - reference: PMID:28932688
      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
    evidence:
    - reference: PMID:15148656
      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
    evidence:
    - reference: PMID:15945070
      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 causing
    nonimmune hydrops fetalis.
  locations:
  - preferred_term: skeletal system
    term:
      id: UBERON:0001434
      label: skeletal system
  evidence:
  - reference: PMID:25966638
    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
    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
    evidence:
    - reference: PMID:25966638
      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
    evidence:
    - reference: PMID:31420886
      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
    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
    evidence:
    - reference: PMID:15945070
      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.
phenotypes:
- name: Global developmental delay
  category: Neurologic
  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
    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.
- name: Generalized hypotonia
  category: Neurologic
  description: >-
    Hypotonia is repeatedly reported in liveborn ALG9-CDG.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:15945070
    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.
- name: Seizure
  category: Neurologic
  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
    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.
- 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
    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: 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
    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
  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
    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.
- 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
    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
  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
    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.
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    Hydrops fetalis has been reported in ALG9-CDG within a Saudi CDG cohort.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:31420886
    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
  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
    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.
- name: Abnormal myelination
  category: Neurologic
  description: >-
    Delayed myelination has been documented on brain MRI in ALG9-CDG.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012447
      label: Abnormal myelination
  evidence:
  - reference: PMID:15945070
    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: Generalized cerebral atrophy/hypoplasia
  category: Neurologic
  description: >-
    Cerebral and cerebellar volume loss has been reported in ALG9-CDG.
  phenotype_term:
    preferred_term: Diffuse brain atrophy
    term:
      id: HP:0007058
      label: Generalized cerebral atrophy/hypoplasia
  evidence:
  - reference: PMID:15945070
    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 and cerebellar
      volume loss on MRI.
genetic:
- name: ALG9
  association: Loss of function mutation
  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, supporting a
    genotype-phenotype spectrum from severe liveborn multisystem disease to
    prenatal lethality.
  gene_term:
    preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  evidence:
  - reference: PMID:15148656
    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
    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 detects the type I CDG
    hypoglycosylation pattern that raises suspicion for ALG9-CDG.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  results: Type I congenital disorder of glycosylation transferrin pattern.
  evidence:
  - reference: PMID:15945070
    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 serum transferrin isoelectric focusing as a
      diagnostic biochemical test.
- name: ALG9 molecular genetic testing
  description: >-
    Molecular testing confirms ALG9-CDG by identifying biallelic pathogenic
    variants in ALG9.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    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 ALG9 variants.
  evidence:
  - reference: PMID:15945070
    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: >-
      This supports mutation analysis as confirmatory testing for ALG9-CDG.
- name: Glycan profiling
  description: >-
    Glycan profiling can confirm the type I biochemical pattern and support an
    ALG9-CDG diagnosis after transferrin screening.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  results: Glycan profile consistent with ALG9-CDG.
  evidence:
  - reference: PMID:28932688
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was confirmed by glycan profiling, which identified ahomozygous
      mutation in ALG9, c.860A > G (p.Tyr287Cys) (NM_1234567890).
    explanation: >-
      The ALG9-CDG review reports glycan profiling as a confirmatory diagnostic
      method in the additional case.
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: Truncated lipid-linked oligosaccharide accumulation
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A type I carbohydrate-deficient transferrin pattern reports impaired
      transfer of complete N-glycan precursors to serum glycoproteins.
  evidence:
  - reference: PMID:15945070
    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
    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:
- name: Supportive seizure management
  description: >-
    No ALG9-specific disease-modifying therapy is established; seizure care is
    supportive and symptom-directed.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28932688
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She developed failure to thrive and seizures.
    explanation: >-
      The cited case supports seizures as a treatment target; specific
      antiepileptic regimens are not provided in the abstract, so the treatment
      claim is limited to supportive symptom management.
- name: Cardiac surveillance
  description: >-
    Cardiac monitoring is prudent in ALG9-CDG because pericardial effusion is a
    reported disease manifestation and CDG expert recommendations support
    periodic cardiac surveillance for CDG patients.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:38917675
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac surveillance, including an echocardiogram and EKG, should be
      conducted at the time of diagnosis, annually throughout the first 5 years,
      followed by check-ups every 2-3 years if no concerns arise until
      adulthood.
    explanation: >-
      This CDG-wide recommendation supports cardiac surveillance generally; the
      ALG9-specific rationale comes from case evidence for pericardial effusion,
      so support is marked partial.
differential_diagnoses: []
clinical_trials: []
datasets: []

📚

References & Deep Research

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

(frank2004identificationandfunctional pages 1-2): Christian G. Frank, Wafaa Eyaid, Eric G. Berger, Markus Aebi, Claudia E. Grubenmann, and Thierry Hennet. Identification and functional analysis of a defect in the human alg9 gene: definition of congenital disorder of glycosylation type il. The American Journal of Human Genetics, 75:146-150, Jul 2004. URL: https://doi.org/10.1086/422367, doi:10.1086/422367. This article has 117 citations.
(davis2017alg9cdgnewclinical pages 5-6): Kellie Davis, Duncan Webster, Chris Smith, Sheryl Jackson, David Sinasac, Lorne Seargeant, Xing-Chang Wei, Patrick Ferreira, Julian Midgley, Yolanda Foster, Xueli Li, Miao He, and Walla Al-Hertani. Alg9-cdg: new clinical case and review of the literature. Molecular Genetics and Metabolism Reports, 13:55-63, Dec 2017. URL: https://doi.org/10.1016/j.ymgmr.2017.08.004, doi:10.1016/j.ymgmr.2017.08.004. This article has 29 citations.
(tham2016anovelphenotype pages 1-2): Emma Tham, Erik A Eklund, Anna Hammarsjö, Per Bengtson, Stefan Geiberger, Kristina Lagerstedt-Robinson, Helena Malmgren, Daniel Nilsson, Gintautas Grigelionis, Peter Conner, Peter Lindgren, Anna Lindstrand, Anna Wedell, Margareta Albåge, Katarzyna Zielinska, Ann Nordgren, Nikos Papadogiannakis, Gen Nishimura, and Giedre Grigelioniene. A novel phenotype in n-glycosylation disorders: gillessen-kaesbach–nishimura skeletal dysplasia due to pathogenic variants in alg9. European Journal of Human Genetics, 24:198-207, May 2016. URL: https://doi.org/10.1038/ejhg.2015.91, doi:10.1038/ejhg.2015.91. This article has 44 citations and is from a domain leading peer-reviewed journal.
(weinstein2005cdg‐ilaninfant pages 1-2): Michael Weinstein, Els Schollen, Gert Matthijs, Christine Neupert, Thierry Hennet, Claudia E. Grubenmann, Christian G. Frank, Markus Aebi, Joe T. R. Clarke, Anne Griffiths, Lorne Seargeant, and Nicola Poplawski. Cdg‐il: an infant with a novel mutation in the alg9 gene and additional phenotypic features. American Journal of Medical Genetics Part A, 136A:194-197, Jul 2005. URL: https://doi.org/10.1002/ajmg.a.30851, doi:10.1002/ajmg.a.30851. This article has 55 citations.
(frank2004identificationandfunctional pages 2-5): Christian G. Frank, Wafaa Eyaid, Eric G. Berger, Markus Aebi, Claudia E. Grubenmann, and Thierry Hennet. Identification and functional analysis of a defect in the human alg9 gene: definition of congenital disorder of glycosylation type il. The American Journal of Human Genetics, 75:146-150, Jul 2004. URL: https://doi.org/10.1086/422367, doi:10.1086/422367. This article has 117 citations.
(francisco2023congenitaldisordersof pages 1-2): Rita Francisco, Sandra Brasil, Joana Poejo, Jaak Jaeken, Carlota Pascoal, Paula A. Videira, and Vanessa dos Reis Ferreira. Congenital disorders of glycosylation (cdg): state of the art in 2022. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02879-z, doi:10.1186/s13023-023-02879-z. This article has 72 citations and is from a peer-reviewed journal.
(davis2017alg9cdgnewclinical media b6fa124e): Kellie Davis, Duncan Webster, Chris Smith, Sheryl Jackson, David Sinasac, Lorne Seargeant, Xing-Chang Wei, Patrick Ferreira, Julian Midgley, Yolanda Foster, Xueli Li, Miao He, and Walla Al-Hertani. Alg9-cdg: new clinical case and review of the literature. Molecular Genetics and Metabolism Reports, 13:55-63, Dec 2017. URL: https://doi.org/10.1016/j.ymgmr.2017.08.004, doi:10.1016/j.ymgmr.2017.08.004. This article has 29 citations.
(davis2017alg9cdgnewclinical media 966d80b6): Kellie Davis, Duncan Webster, Chris Smith, Sheryl Jackson, David Sinasac, Lorne Seargeant, Xing-Chang Wei, Patrick Ferreira, Julian Midgley, Yolanda Foster, Xueli Li, Miao He, and Walla Al-Hertani. Alg9-cdg: new clinical case and review of the literature. Molecular Genetics and Metabolism Reports, 13:55-63, Dec 2017. URL: https://doi.org/10.1016/j.ymgmr.2017.08.004, doi:10.1016/j.ymgmr.2017.08.004. This article has 29 citations.
(alsubhi2017congenitaldisordersof pages 6-6): Sarah Alsubhi, Amal Alhashem, Eissa Faqeih, Majid Alfadhel, Abdullah Alfaifi, Waleed Altuwaijri, Saud Alsahli, Hesham Aldhalaan, Fowzan S. Alkuraya, Khalid Hundallah, Adel Mahmoud, Ali Alasmari, Fuad Al Mutairi, Hanem Abduraouf, Layan AlRasheed, Saad Alshahwan, and Brahim Tabarki. Congenital disorders of glycosylation: the saudi experience. American Journal of Medical Genetics Part A, 173:2614-2621, Jul 2017. URL: https://doi.org/10.1002/ajmg.a.38358, doi:10.1002/ajmg.a.38358. This article has 45 citations.
(davis2017alg9cdgnewclinical pages 7-9): Kellie Davis, Duncan Webster, Chris Smith, Sheryl Jackson, David Sinasac, Lorne Seargeant, Xing-Chang Wei, Patrick Ferreira, Julian Midgley, Yolanda Foster, Xueli Li, Miao He, and Walla Al-Hertani. Alg9-cdg: new clinical case and review of the literature. Molecular Genetics and Metabolism Reports, 13:55-63, Dec 2017. URL: https://doi.org/10.1016/j.ymgmr.2017.08.004, doi:10.1016/j.ymgmr.2017.08.004. This article has 29 citations.
(davis2017alg9cdgnewclinical pages 1-2): Kellie Davis, Duncan Webster, Chris Smith, Sheryl Jackson, David Sinasac, Lorne Seargeant, Xing-Chang Wei, Patrick Ferreira, Julian Midgley, Yolanda Foster, Xueli Li, Miao He, and Walla Al-Hertani. Alg9-cdg: new clinical case and review of the literature. Molecular Genetics and Metabolism Reports, 13:55-63, Dec 2017. URL: https://doi.org/10.1016/j.ymgmr.2017.08.004, doi:10.1016/j.ymgmr.2017.08.004. This article has 29 citations.
(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.
(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.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

Deep Research

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

Target disease

Executive summary

Evidence map (structured summary)

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (available from retrieved sources)

1.3 Synonyms / alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Phenotype spectrum (current understanding)

3.2 Phenotype characteristics (onset, severity, progression)

3.3 Approximate frequency of features (from the retrieved evidence)

3.4 Suggested HPO terms (non-exhaustive)

3.5 Quality-of-life impact

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (from retrieved primary reports)

4.3 Variant type/class and functional consequences

4.4 Population allele frequency

4.5 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Pathway placement and biochemical chain of causality

6.2 Direct abstract-quoted mechanistic evidence

6.3 Ontology suggestions

6.4 Molecular profiling (omics)

7. Anatomical structures affected

7.1 Organ systems (supported by case literature)

7.2 UBERON suggestions (non-exhaustive)

7.3 Subcellular localization

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology

9.3 Population genetics

10. Diagnostics

10.1 Biochemical testing

10.2 Genetic testing

10.3 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Disease-specific therapy

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

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

12.4 Suggested MAXO terms (examples)

13. Prevention

14. Other species / natural disease

15. Model organisms

15.1 Functional models used in the evidence base

15.2 Translational relevance and limitations

Recent developments (2023–2024 prioritized)

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

2024: Expert guidance on cardiac monitoring in CDG

URLs and publication dates (where available from retrieved texts)

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