ALG12-congenital disorder of glycosylation is a rare autosomal recessive disorder of protein N-linked glycosylation caused by biallelic ALG12 variants. Loss of ALG12 mannosyltransferase activity disrupts N-glycan-precursor formation, produces a type I congenital disorder of glycosylation biochemical pattern, and causes variable neurodevelopmental, immune, coagulation, growth, skeletal, cardiac, and prenatal manifestations.
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name: ALG12-congenital disorder of glycosylation
creation_date: "2026-05-10T18:41:07Z"
updated_date: "2026-05-18T05:43:18Z"
description: >-
ALG12-congenital disorder of glycosylation is a rare autosomal recessive
disorder of protein N-linked glycosylation caused by biallelic ALG12
variants. Loss of ALG12 mannosyltransferase activity disrupts
N-glycan-precursor formation, produces a type I congenital disorder of
glycosylation biochemical pattern, and causes variable neurodevelopmental,
immune, coagulation, growth, skeletal, cardiac, and prenatal manifestations.
category: Mendelian
disease_term:
preferred_term: ALG12-congenital disorder of glycosylation
term:
id: MONDO:0011783
label: ALG12-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- ALG12-CDG
- CDG-Ig
- CDG1G
- congenital disorder of glycosylation type Ig
- mannosyltransferase 8 deficiency
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
ALG12-CDG is an autosomal recessive condition caused by biallelic
pathogenic ALG12 variants.
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG specifically is caused by biallelic pathogenic variants in
ALG12.
explanation: >-
The 2024 prenatal case report directly states biallelic ALG12 causation.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "ALG12 | HGNC:19358 | ALG12-congenital disorder of glycosylation | MONDO:0011783 | AR | Definitive"
explanation: >-
ClinGen classifies the ALG12-ALG12-CDG relationship as definitive with
autosomal recessive inheritance.
prevalence:
- population: Global published literature
notes: >-
ALG12-CDG is extremely rare, with only small case reports and case series
in the published literature.
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To date, only 15 patients have been diagnosed with ALG12-CDG globally.
explanation: >-
The 2021 case report provides a direct published patient-count estimate.
progression:
- phase: Variable severity
notes: >-
ALG12-CDG severity ranges from mild adult presentations to fatal
multisystem infantile disease.
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our cases broaden the recognized genetic and phenotypic spectrum of this
disorder and suggest a role for other genetic and environmental factors
in modulating disease phenotype.
explanation: >-
The within-family case series directly supports broad clinical
variability, including mild surviving adults and severe infantile death.
pathophysiology:
- name: ALG12 mannosyltransferase deficiency
description: >-
Pathogenic ALG12 variants impair the alpha-mannosyltransferase step needed
for dolichol-linked oligosaccharide biosynthesis and N-glycan precursor
formation.
genes:
- preferred_term: ALG12
term:
id: hgnc:19358
label: ALG12
biological_processes:
- preferred_term: dolichol-linked oligosaccharide biosynthetic process
modifier: DECREASED
term:
id: GO:0006488
label: dolichol-linked oligosaccharide biosynthetic process
molecular_functions:
- preferred_term: mannosyltransferase activity
modifier: DECREASED
term:
id: GO:0000030
label: mannosyltransferase activity
locations:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Congenital disorder of glycosylation type Ig (ALG12-CDG) is a rare
inherited metabolic disease caused by a defect in alpha-mannosyltransferase
8, encoded by the ALG12 gene (22q13.33).
explanation: >-
This directly identifies the disease-causing ALG12 enzyme defect.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The mechanism of pathogenicity is known to be loss-of-function.
explanation: >-
ClinGen supports loss of ALG12 function as the curated mechanism.
- reference: PMID:12217961
reference_title: ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the patient's fibroblasts, the biosynthetic intermediate
GlcNAc(2)Man(7) oligosaccharide was detected both on the lipid carrier
dolichyl pyrophosphate and on newly synthesized glycoproteins, thus
pointing to a defect in the dolichyl pyrophosphate-GlcNAc(2)Man(7)-dependent
ALG12 alpha1,6 mannosyltransferase.
explanation: >-
The original ALG12-CDG report directly localizes the ALG12 defect to
dolichyl-pyrophosphate-linked oligosaccharide biosynthesis.
downstream:
- target: N-glycan precursor formation defect
description: >-
Loss of ALG12 function impairs N-glycan precursor formation and transfer
to proteins.
causal_link_type: DIRECT
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Congenital disorder of glycosylation (CDG) type I is a group of rare
disorders caused by recessive mutations in up to 25 genes that impair
the N-glycan precursor formation and its transfer to proteins resulting
in hypoglycosylation of multiple proteins.
explanation: >-
The case report describes the biochemical class to which ALG12-CDG
belongs and links recessive pathway-gene defects to impaired
precursor formation.
- name: N-glycan precursor formation defect
description: >-
Impaired N-glycan precursor formation leads to hypoglycosylation of
transferrin and other plasma proteins, consistent with 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:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to a newborn Slovak patient's clinical and biochemical abnormalities,
the isoelectric focusing of transferrin was performed with observed
significant hypoglycosylation typical of CDG I.
explanation: >-
The transferrin result directly supports a type I CDG hypoglycosylation
pattern.
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Intact serum transferrin showed, as expected for a CDG type I defect,
underoccupancy of N-glycosylation sites.
explanation: >-
This supports protein N-glycosylation underoccupancy as a downstream
biochemical consequence.
downstream:
- target: Abnormal serum and IgG N-glycosylation
description: >-
Impaired ALG12 activity shifts serum N-glycan structures toward
truncated and abnormal high-mannose or hybrid species.
causal_link_type: DIRECT
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Furthermore, analysis of neutral serum N-glycans by mass spectrometry
revealed the accumulation of GlcNAc2Man5-7 and decreased levels of
GlcNAc2Man8-9, which indicated impaired ALG12 enzymatic activity.
explanation: >-
Serum N-glycan mass spectrometry directly links abnormal N-glycan
species to impaired ALG12 activity.
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As a whole, ALG12-CDG behaves as a dual CDG (CDG-I and II defects) and
it is associated with distinct, abnormal glycosylation of total serum
and IgG N-glycans.
explanation: >-
This supports downstream abnormal glycosylation of total serum and IgG
N-glycans.
- target: Neurodevelopmental and brain involvement
description: >-
Abnormal N-glycan precursor formation affects developmentally important
glycoproteins and is associated with neurologic and brain manifestations.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The relevance of N‐glycosylation for the folding, intracellular
trafficking, and function of many proteins, particularly during
development, support multiple mostly severe clinical phenotypes usually
comprising also neurological involvement.
explanation: >-
The full-text clinical report explains why impaired N-glycosylation can
produce developmental and neurologic disease, while the intermediates
between ALG12 deficiency and individual neurologic signs remain
unresolved.
- target: Growth and feeding impairment
description: >-
The ALG12-linked glycosylation defect is associated with impaired growth
and feeding failure in reported patients.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:12217961
reference_title: ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The severe disease was identified in a child presenting with psychomotor
retardation, hypotonia, growth retardation, dysmorphic features and
anorexia.
explanation: >-
The original ALG12-CDG patient report links the ALG12 defect to growth
retardation and anorexia.
- target: Dysmorphic and genitourinary developmental involvement
description: >-
Multisystem ALG12-CDG presentations include craniofacial dysmorphism and
male genital hypoplasia.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare
disorder caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase
which presents with intellectual disability, hypotonia, dysmorphic
features, low IgG levels with recurrent infections, male genital
hypoplasia, and coagulation abnormalities.
explanation: >-
The case-series abstract connects ALG12 mannosyltransferase deficiency
to dysmorphic and genital developmental features.
- target: Renal and skeletal developmental involvement
description: >-
Severe prenatal or neonatal ALG12-CDG presentations can include renal and
skeletal developmental abnormalities.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, skeletal abnormalities resembling a skeletal dysplasia
including shortened long bones and talipes equinovarus have been seen in
more severe neonatal presentation of this disorder.
explanation: >-
The prenatal case report directly supports a severe neonatal skeletal
branch of ALG12-CDG.
- target: Adult cardioskeletal structural involvement
description: >-
An unusually mild adult presentation included congenital cardiac and
spinal structural findings, with mechanism and modifier contribution still
uncertain.
causal_link_type: UNKNOWN
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and
has a University degree.
explanation: >-
This supports a reported cardioskeletal structural branch, while the
edge is marked unknown because the article discusses phenotype
heterogeneity and possible modifiers.
- name: Abnormal serum and IgG N-glycosylation
description: >-
Abnormal N-glycosylation of serum and IgG proteins contributes to
multisystem manifestations, including immune dysfunction and recurrent
infections.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: plasma cell
term:
id: CL:0000786
label: plasma cell
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: ABNORMAL
term:
id: GO:0006487
label: protein N-linked glycosylation
- preferred_term: immunoglobulin mediated immune response
modifier: DECREASED
term:
id: GO:0016064
label: immunoglobulin mediated immune response
evidence:
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG is a severe multisystem disease associated with low to
deficient serum immunoglobulins and recurrent infections.
explanation: >-
The glycophenotype report links ALG12-CDG to low serum immunoglobulins
and recurrent infections.
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As a whole, ALG12-CDG behaves as a dual CDG (CDG-I and II defects) and it
is associated with distinct, abnormal glycosylation of total serum and IgG
N-glycans.
explanation: >-
This supports abnormal IgG N-glycosylation as a disease-associated
biochemical mechanism.
downstream:
- target: Decreased circulating immunoglobulin concentration
description: Abnormal IgG N-glycosylation and immune-system involvement contribute to hypogammaglobulinemia.
evidence:
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG is a severe multisystem disease associated with low to
deficient serum immunoglobulins and recurrent infections.
explanation: >-
This directly supports the low-immunoglobulin downstream phenotype.
- target: Recurrent respiratory infections
description: Immunoglobulin deficiency contributes to recurrent infections.
evidence:
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG is a severe multisystem disease associated with low to
deficient serum immunoglobulins and recurrent infections.
explanation: >-
This directly supports recurrent infections as a downstream
immune-related manifestation.
- target: Abnormality of coagulation
description: Hypoglycosylation affects plasma proteins involved in coagulation.
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Increased levels of hypoglycosylated forms of F XI (also with
significant deficiency) and transferrin were also detected.
explanation: >-
The adult case supports hypoglycosylated coagulation factors as a
downstream manifestation of the glycosylation defect.
- name: Neurodevelopmental and brain involvement
description: >-
ALG12-CDG neurodevelopmental involvement includes developmental delay,
intellectual disability, hypotonia, and reported brain anomalies.
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
biological_processes:
- preferred_term: nervous system development
modifier: ABNORMAL
term:
id: GO:0007399
label: nervous system development
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: >-
The prenatal phenotype report summarizes the neurologic and brain feature
set reported in ALG12-CDG.
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The case-series abstract directly supports intellectual disability and
hypotonia as neurologic manifestations.
downstream:
- target: Global developmental delay
description: Developmental delay is part of the reported ALG12-CDG neurologic spectrum.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists developmental delay among ALG12-CDG features.
- target: Intellectual disability
description: Intellectual disability is part of the reported ALG12-CDG neurologic spectrum.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare
disorder caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase
which presents with intellectual disability, hypotonia, dysmorphic
features, low IgG levels with recurrent infections, male genital
hypoplasia, and coagulation abnormalities.
explanation: The case-series abstract directly lists intellectual disability.
- target: Generalized hypotonia
description: Hypotonia is part of the reported ALG12-CDG neurologic spectrum.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists hypotonia among ALG12-CDG features.
- name: Growth and feeding impairment
description: >-
ALG12-CDG can impair somatic growth and feeding, presenting as failure to
thrive, growth retardation, anorexia, or short stature.
evidence:
- reference: PMID:12217961
reference_title: ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The severe disease was identified in a child presenting with psychomotor
retardation, hypotonia, growth retardation, dysmorphic features and
anorexia.
explanation: >-
The original report describes growth retardation and anorexia in an
ALG12-CDG child.
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: >-
The prenatal phenotype report summarizes failure to thrive and/or short
stature in the broader ALG12-CDG phenotype.
downstream:
- target: Failure to thrive
description: Failure to thrive is a reported growth manifestation of ALG12-CDG.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists failure to thrive among ALG12-CDG features.
- target: Short stature
description: Short stature is a reported growth manifestation of ALG12-CDG.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists short stature as a growth manifestation.
- name: Dysmorphic and genitourinary developmental involvement
description: >-
ALG12-CDG can involve craniofacial dysmorphism and male genitourinary
developmental abnormalities.
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The case-series abstract lists dysmorphic features and male genital
hypoplasia in ALG12-CDG.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Common phenotypes include intellectual disability, hypotonia, dysmorphic
features, coagulation abnormalities and genitourinary abnormalities.
explanation: >-
ClinGen independently lists dysmorphic and genitourinary abnormalities as
common ALG12-CDG phenotypes.
downstream:
- target: Facial dysmorphism
description: Dysmorphic features include craniofacial involvement.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare
disorder caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase
which presents with intellectual disability, hypotonia, dysmorphic
features, low IgG levels with recurrent infections, male genital
hypoplasia, and coagulation abnormalities.
explanation: The case-series abstract lists dysmorphic features.
- target: Hypoplastic male external genitalia
description: Male genital hypoplasia is a genitourinary developmental manifestation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare
disorder caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase
which presents with intellectual disability, hypotonia, dysmorphic
features, low IgG levels with recurrent infections, male genital
hypoplasia, and coagulation abnormalities.
explanation: The case-series abstract lists male genital hypoplasia.
- name: Renal and skeletal developmental involvement
description: >-
Severe ALG12-CDG can involve prenatal renal malformation and
skeletal-dysplasia-like abnormalities.
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
- preferred_term: skeletal system
term:
id: UBERON:0001434
label: skeletal system
biological_processes:
- preferred_term: kidney development
modifier: ABNORMAL
term:
id: GO:0001822
label: kidney development
- preferred_term: skeletal system development
modifier: ABNORMAL
term:
id: GO:0001501
label: skeletal system development
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, skeletal abnormalities resembling a skeletal dysplasia
including shortened long bones and talipes equinovarus have been seen in
more severe neonatal presentation of this disorder.
explanation: >-
The prenatal report supports skeletal-dysplasia-like abnormalities in
severe neonatal ALG12-CDG.
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a case expanding the phenotype of ALG12-CDG to include
bilateral, multicystic kidneys in a neonatal demise identified with
homozygous pathogenic variants in the ALG12 gene at c.1001del
(p.N334Tfs*15) through clinical trio exome sequencing.
explanation: >-
The case report directly supports multicystic renal malformation in a
severe prenatal ALG12-CDG presentation.
downstream:
- target: Skeletal dysplasia
description: Skeletal dysplasia-like abnormalities are part of the severe neonatal branch.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, skeletal abnormalities resembling a skeletal dysplasia
including shortened long bones and talipes equinovarus have been seen in
more severe neonatal presentation of this disorder.
explanation: The report directly supports skeletal dysplasia-like abnormalities.
- target: Multicystic kidney dysplasia
description: Multicystic kidneys expand the renal phenotype of severe ALG12-CDG.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a case expanding the phenotype of ALG12-CDG to include
bilateral, multicystic kidneys in a neonatal demise identified with
homozygous pathogenic variants in the ALG12 gene at c.1001del
(p.N334Tfs*15) through clinical trio exome sequencing.
explanation: The case report directly supports multicystic kidney dysplasia.
- name: Adult cardioskeletal structural involvement
description: >-
A mild adult ALG12-CDG presentation included ventricular septal defect and
severe scoliosis; causal directness and possible modifier contributions are
unresolved.
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
- preferred_term: skeletal system
term:
id: UBERON:0001434
label: skeletal system
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and has
a University degree.
explanation: >-
The adult case report supports the reported co-occurrence of VSD and
severe scoliosis in a genetically diagnosed ALG12-CDG patient.
downstream:
- target: Ventricular septal defect
description: Ventricular septal defect was reported in the mild adult ALG12-CDG case.
causal_link_type: UNKNOWN
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and
has a University degree.
explanation: The case report directly identifies ventricular septal defect.
- target: Scoliosis
description: Severe scoliosis was reported in the mild adult ALG12-CDG case.
causal_link_type: UNKNOWN
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and
has a University degree.
explanation: The case report directly identifies severe scoliosis.
phenotypes:
- name: Global developmental delay
category: Neurologic
description: Developmental delay is a reported core feature of ALG12-CDG.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: >-
The prenatal phenotype report summarizes developmental delay among
reported ALG12-CDG features.
- name: Intellectual disability
category: Neurologic
description: Intellectual disability is a core neurodevelopmental phenotype in ALG12-CDG.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The case-series abstract directly lists intellectual disability among
ALG12-CDG presenting features.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Common phenotypes include intellectual disability, hypotonia, dysmorphic
features, coagulation abnormalities and genitourinary abnormalities.
explanation: >-
ClinGen names intellectual disability as a common phenotype for this
gene-disease assertion.
- name: Generalized hypotonia
category: Neurologic
description: Generalized hypotonia is a recurrent neurologic manifestation.
phenotype_term:
preferred_term: Generalized hypotonia
term:
id: HP:0001290
label: Generalized hypotonia
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists hypotonia as a currently reported feature.
- name: Failure to thrive
category: Growth
description: Feeding and growth impairment can present as failure to thrive.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists failure to thrive among current features.
- name: Short stature
category: Growth
description: Short stature is part of the reported growth phenotype.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The report lists short stature as an alternate growth manifestation.
- name: Recurrent respiratory infections
category: Immune
description: Recurrent respiratory infections reflect immune involvement.
phenotype_term:
preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: >-
The case-series abstract explicitly links low IgG levels with recurrent
infections.
- name: Facial dysmorphism
category: Craniofacial
description: Dysmorphic facial features are a common craniofacial manifestation.
phenotype_term:
preferred_term: Facial dysmorphism
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The case-series abstract explicitly lists dysmorphic features in
ALG12-CDG.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Common phenotypes include intellectual disability, hypotonia, dysmorphic
features, coagulation abnormalities and genitourinary abnormalities.
explanation: >-
ClinGen independently lists dysmorphic features as common in ALG12-CDG.
- name: Decreased circulating immunoglobulin concentration
category: Immune
description: Hypogammaglobulinemia or low serum immunoglobulins can occur.
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
evidence:
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG is a severe multisystem disease associated with low to
deficient serum immunoglobulins and recurrent infections.
explanation: The glycophenotype report directly supports low serum immunoglobulins.
- name: Abnormality of coagulation
category: Hematologic
description: ALG12-CDG can involve coagulation factor abnormalities.
phenotype_term:
preferred_term: Coagulation abnormalities
term:
id: HP:0001928
label: Abnormality of coagulation
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Currently reported features of ALG12-CDG include: developmental delay,
hypotonia, failure to thrive and/or short stature, brain anomalies,
recurrent infections, hypogammaglobulinemia, coagulation abnormalities,
and genitourinary abnormalities.
explanation: The case-series abstract lists coagulation abnormalities.
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Increased levels of hypoglycosylated forms of F XI (also with significant
deficiency) and transferrin were also detected.
explanation: >-
The adult case demonstrates hypoglycosylation and deficiency of a
coagulation factor.
- name: Hypoplastic male external genitalia
category: Genitourinary
description: Male genital hypoplasia is part of the reported ALG12-CDG genitourinary spectrum.
phenotype_term:
preferred_term: Male genital hypoplasia
term:
id: HP:0000050
label: Hypoplastic male external genitalia
evidence:
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The Tahata case-series abstract directly lists male genital hypoplasia.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Common phenotypes include intellectual disability, hypotonia, dysmorphic
features, coagulation abnormalities and genitourinary abnormalities.
explanation: >-
ClinGen supports genitourinary abnormalities as common in ALG12-CDG.
- name: Skeletal dysplasia
category: Musculoskeletal
description: Severe neonatal presentations can include skeletal dysplasia-like anomalies.
phenotype_term:
preferred_term: Skeletal dysplasia
term:
id: HP:0002652
label: Skeletal dysplasia
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, skeletal abnormalities resembling a skeletal dysplasia
including shortened long bones and talipes equinovarus have been seen in
more severe neonatal presentation of this disorder.
explanation: >-
The prenatal phenotype report directly supports a skeletal
dysplasia-like phenotype in severe neonatal ALG12-CDG.
- name: Multicystic kidney dysplasia
category: Renal
description: Bilateral multicystic kidneys have been reported as an expanded prenatal phenotype.
phenotype_term:
preferred_term: Multicystic kidney dysplasia
term:
id: HP:0000003
label: Multicystic kidney dysplasia
evidence:
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a case expanding the phenotype of ALG12-CDG to include
bilateral, multicystic kidneys in a neonatal demise identified with
homozygous pathogenic variants in the ALG12 gene at c.1001del
(p.N334Tfs*15) through clinical trio exome sequencing.
explanation: >-
This directly supports multicystic kidneys as a reported prenatal
extension of the phenotype.
- name: Ventricular septal defect
category: Cardiovascular
description: Ventricular septal defect has been reported in an unusually mild adult ALG12-CDG case.
phenotype_term:
preferred_term: Ventricular septal defect
term:
id: HP:0001629
label: Ventricular septal defect
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and
has a University degree.
explanation: >-
The adult case report directly identifies ventricular septal defect in an
ALG12-CDG patient.
- name: Scoliosis
category: Musculoskeletal
description: Scoliosis has been reported in a mild adult presentation.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here present an intriguing patient with an exceptional phenotype:
25-year-old women with a ventricular septal defect and severe idiopathic
scoliosis but no facial dysmorphism, who dances as a professional, and
has a University degree.
explanation: >-
The adult case report directly identifies severe scoliosis in an
ALG12-CDG patient.
biochemical:
- name: Type I transferrin hypoglycosylation pattern
presence: Present
specificity: Diagnostic support
biomarker_term:
preferred_term: N-glycan
term:
id: CHEBI:59520
label: N-glycan
readouts:
- target: N-glycan precursor formation defect
relationship: READOUT_OF
direction: PRESENT_ABSENT
endpoint_context: DIAGNOSTIC
interpretation: >-
A type I transferrin hypoglycosylation pattern reports impaired
N-glycosylation-site occupancy downstream of the ALG12 precursor defect.
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to a newborn Slovak patient's clinical and biochemical abnormalities,
the isoelectric focusing of transferrin was performed with observed
significant hypoglycosylation typical of CDG I.
explanation: >-
This directly supports transferrin isoelectric focusing as a biochemical
marker of type I CDG in ALG12-CDG.
- name: Aberrant serum oligomannose N-glycan profile
presence: Present
specificity: Diagnostic support
biomarker_term:
preferred_term: N-glycan
term:
id: CHEBI:59520
label: N-glycan
readouts:
- target: ALG12 mannosyltransferase deficiency
relationship: READOUT_OF
direction: PRESENT_ABSENT
endpoint_context: DIAGNOSTIC
interpretation: >-
Accumulation of GlcNAc2Man5-7 with reduced GlcNAc2Man8-9 reports impaired
ALG12 enzymatic activity.
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Furthermore, analysis of neutral serum N-glycans by mass spectrometry
revealed the accumulation of GlcNAc2Man5-7 and decreased levels of
GlcNAc2Man8-9, which indicated impaired ALG12 enzymatic activity.
explanation: >-
Serum N-glycan profiling directly supports an ALG12-associated
oligomannose signature.
- name: Hypoglycosylated antithrombin and factor XI
presence: Present
specificity: Supportive
readouts:
- target: Abnormal serum and IgG N-glycosylation
relationship: READOUT_OF
direction: PRESENT_ABSENT
endpoint_context: DIAGNOSTIC
interpretation: >-
Hypoglycosylated coagulation proteins report systemic plasma-protein
hypoglycosylation caused by the ALG12-CDG glycosylation defect.
evidence:
- reference: PMID:32530140
reference_title: "ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Congenital disorder of glycosylation diagnosis started through the
identification of antithrombin deficiency without SERPINC1 defect and the
detection of hypoglycosylated forms.
explanation: >-
The adult case shows a coagulation-protein hypoglycosylation clue to
diagnosis.
genetic:
- name: ALG12
association: Biallelic loss-of-function variants
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: ALG12
term:
id: hgnc:19358
label: ALG12
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis of the coding regions of the ALG12 gene of the patient
revealed a novel homozygous substitution mutation c.1439T>C
p.(Leu480Pro) within Exon 10.
explanation: >-
The case report documents a homozygous ALG12 variant in an affected
patient.
- reference: PMID:38717015
reference_title: Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a case expanding the phenotype of ALG12-CDG to include
bilateral, multicystic kidneys in a neonatal demise identified with
homozygous pathogenic variants in the ALG12 gene at c.1001del
(p.N334Tfs*15) through clinical trio exome sequencing.
explanation: >-
The prenatal case report identifies a homozygous pathogenic ALG12
frameshift variant.
- reference: CGGV:assertion_21631e85-8133-4703-a77c-c046effb6e56-2023-02-15T200000.000Z
reference_title: "ALG12 / ALG12-congenital disorder of glycosylation (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In summary, there is definitive evidence to support the relationship
between ALG12 and autosomal recessive ALG12 -congenital disorder of
glycosylation.
explanation: >-
ClinGen provides a deterministic structured assertion for the ALG12
gene-disease relationship.
diagnosis:
- name: Transferrin isoelectric focusing and serum glycomics
description: >-
Biochemical evaluation uses transferrin isoelectric focusing and serum
N-glycan profiling to detect a type I CDG pattern and ALG12-associated
oligomannose abnormalities.
diagnosis_term:
preferred_term: clinical laboratory procedure
term:
id: MAXO:0000006
label: clinical laboratory procedure
results: >-
Type I transferrin hypoglycosylation with accumulation of GlcNAc2Man5-7 and
decreased GlcNAc2Man8-9 supports ALG12-CDG.
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to a newborn Slovak patient's clinical and biochemical abnormalities,
the isoelectric focusing of transferrin was performed with observed
significant hypoglycosylation typical of CDG I.
explanation: >-
This supports transferrin isoelectric focusing as first-line biochemical
evidence of a type I CDG pattern.
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Furthermore, analysis of neutral serum N-glycans by mass spectrometry
revealed the accumulation of GlcNAc2Man5-7 and decreased levels of
GlcNAc2Man8-9, which indicated impaired ALG12 enzymatic activity.
explanation: >-
This supports serum N-glycan mass spectrometry for resolving the
ALG12-associated glycomic signature.
- name: ALG12 molecular genetic testing
description: >-
Molecular testing confirms ALG12-CDG by identifying biallelic pathogenic
ALG12 variants in a compatible biochemical and clinical context.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
results: >-
Homozygous or compound heterozygous pathogenic ALG12 variants confirm the
diagnosis when paired with compatible glycosylation abnormalities.
evidence:
- reference: PMID:34467644
reference_title: A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This comprehensive genomic and glycomic approach led to the confirmation
of the ALG12 pathogenic variant responsible for the clinical manifestation
of the disorder in the patient described.
explanation: >-
The case report directly supports combined genomic and glycomic
confirmation of the diagnosis.
- reference: PMID:37644541
reference_title: "Congenital disorders of glycosylation: narration of a story through its patents."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
CDG diagnosis has been at a rapid pace since the introduction of
whole-exome/whole-genome sequencing as a diagnostic tool.
explanation: >-
This CDG-wide review supports genome-scale sequencing as a modern
diagnostic approach for CDG; it is broader than ALG12-CDG alone.
treatments:
- name: Supportive multidisciplinary care
description: >-
No ALG12-CDG-specific disease-modifying therapy is established in the
fetched evidence; care is supportive and directed to infections,
nutrition/growth, neurodevelopmental needs, coagulation abnormalities, and
organ-specific complications.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
- preferred_term: Coagulation abnormalities
term:
id: HP:0001928
label: Abnormality of coagulation
evidence:
- reference: PMID:37644541
reference_title: "Congenital disorders of glycosylation: narration of a story through its patents."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
Since the first clinical report in 1980 of PMM2-CDG, the most common CDG
worldwide, research made great strides, but nearly all of them are still
missing a cure.
explanation: >-
This CDG-wide review supports the lack of curative therapy for most CDGs;
by itself it only partially supports ALG12-CDG-specific supportive care.
- name: IVIG/SCIG immunoglobulin replacement therapy
description: >-
Intravenous or subcutaneous immunoglobulin replacement is a disease-specific
supportive consideration for ALG12-CDG patients with low immunoglobulins and
recurrent infections. Validator-cache evidence supports the
antibody-deficiency indication, while direct published treatment-use details
are limited.
treatment_term:
preferred_term: immunoglobulin infusion therapy
term:
id: MAXO:0001480
label: immunoglobulin infusion therapy
therapeutic_agent:
- preferred_term: Therapeutic Immune Globulin
term:
id: NCIT:C2701
label: Therapeutic Immune Globulin
target_phenotypes:
- preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
- preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:31529350
reference_title: "ALG12-CDG: novel glycophenotype insights endorse the molecular defect."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-CDG is a severe multisystem disease associated with low to
deficient serum immunoglobulins and recurrent infections.
explanation: >-
This supports the hypogammaglobulinemia and recurrent-infection
indication for immunoglobulin replacement; it does not by itself document
treatment response.
- reference: PMID:31481313
reference_title: "Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder
caused by a deficiency of
dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which
presents with intellectual disability, hypotonia, dysmorphic features, low
IgG levels with recurrent infections, male genital hypoplasia, and
coagulation abnormalities.
explanation: >-
The case series supports the low-IgG and recurrent-infection phenotype
targeted by immunoglobulin replacement, but the cached abstract does not
directly quote treatment use.
clinical_trials:
- name: NCT04199000
status: RECRUITING
description: >-
CDG-wide observational natural-history study relevant to genetically,
enzymatically, or molecularly confirmed CDG subtypes such as ALG12-CDG.
evidence:
- reference: clinicaltrials:NCT04199000
reference_title: Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The purpose of this research is to study the natural history of
congenital disorders of glycosylation and its causes and treatments.
explanation: >-
The study is CDG-wide rather than ALG12-specific, so it partially
supports relevance to ALG12-CDG natural-history research.
notes: >-
Falcon deep research completed on 2026-05-10. The 2002 original ALG12-CDG
abstract was fetched as PMID:12217961, and this curation uses fetched PubMed,
ClinGen, and ClinicalTrials.gov caches with validator-checkable snippets.
datasets: []
ALG12‑CDG is a very rare autosomal recessive congenital disorder of glycosylation caused by deficiency of the ER luminal α1,6‑mannosyltransferase ALG12, which catalyzes addition of the 8th mannose during lipid‑linked oligosaccharide (LLO) assembly for protein N‑glycosylation. Biochemically it produces a type‑I carbohydrate‑deficient transferrin pattern and characteristic accumulation of truncated LLO/N‑glycans (notably Man7 intermediates and reduced Man8/Man9 species), with multisystem disease that often includes neurodevelopmental impairment, growth failure, dysmorphism, immunodeficiency (hypogammaglobulinemia), coagulation abnormalities, and variable severity up to early death. Recent (2023–2024) literature emphasizes accelerated CDG diagnosis via WES/WGS and emerging multi‑omics/proteomics tools, but also highlights the ongoing lack of targeted therapies for most CDGs, including ALG12‑CDG. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 1-1, monticelli2023congenitaldisordersof pages 1-2, pascoal2024revisitingtheimmunopathology pages 4-6)
CDG: congenital disorder(s) of glycosylation; ER: endoplasmic reticulum; LLO: lipid‑linked oligosaccharide; Tf IEF: transferrin isoelectric focusing; MALDI‑TOF: matrix‑assisted laser desorption/ionization time‑of‑flight; MS: mass spectrometry; WES/WGS: whole‑exome/whole‑genome sequencing.
The first molecularly defined report described “a deficiency in the ALG12 ER α1,6‑mannosyltransferase resulting in a novel type of glycosylation disorder” and explicitly stated: “The ALG12 mannosyltransferase defect defines a new type of congenital disorder of glycosylation, designated CDG‑Ig.” (Grubenmann et al., 2002‑09; Human Molecular Genetics; DOI https://doi.org/10.1093/hmg/11.19.2331) (grubenmann2002alg12mannosyltransferasedefect pages 1-2)
A later case report defined the entity as: “Congenital disorder of glycosylation type Ig (ALG12‑CDG) is a rare inherited metabolic disease caused by a defect in alpha‑mannosyltransferase 8, encoded by the ALG12 gene (22q13.33).” (Ziburová et al., 2021‑09; American Journal of Medical Genetics A; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 1-1)
Most disease‑specific information is derived from individual patient case reports/series plus aggregated reviews of CDG (e.g., immunopathology and diagnostic evolution). (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, monticelli2023congenitaldisordersof pages 1-2, pascoal2024revisitingtheimmunopathology pages 4-6)
Primary cause (genetic): biallelic pathogenic variants in ALG12, encoding an ER mannosyltransferase involved in N‑glycan precursor assembly. (ziburova2021anovelhomozygous pages 2-2, grubenmann2002alg12mannosyltransferasedefect pages 1-2)
Mechanistic definition from a 2021 report: ALG12 encodes “the dolichyl‑P‑mannose Man‑7‑GlcNAc‑2‑PP‑dolichyl‑alpha‑6‑mannosyltransferase,” and “this enzyme transfers the eighth mannose residue from dolichyl‑P‑mannose to lipid‑linked oligosaccharides.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 2-2)
No validated protective genetic or environmental factors were identified in the retrieved evidence.
Not specifically described for ALG12‑CDG in the retrieved evidence. In CDG more broadly, host glycan alterations may influence host–pathogen interactions, but ALG12‑specific GxE data were not retrieved. (pascoal2024revisitingtheimmunopathology pages 1-2)
ALG12‑CDG presents as a multisystem disorder with marked inter‑individual variability.
A 2021 synthesis of published cases reported frequent features including: “characteristic dysmorphism, psychomotor retardation, hypotonia, and/or skeletal abnormalities,” and also noted “feeding difficulties, respiratory distress, and frequent infections.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 5-5)
Direct QoL instrument data specific to ALG12‑CDG were not captured in the retrieved texts. Real‑world impact is inferred from multisystem disability (developmental delay, recurrent infections, feeding problems).
(ontology suggestions; not exhaustive) * Developmental delay — HP:0001263 * Intellectual disability — HP:0001249 * Hypotonia — HP:0001252 * Growth delay / failure to thrive — HP:0001508 / HP:0001507 * Microcephaly — HP:0000252 (reported in some cases) (sturiale2019alg12cdgnovelglycophenotype pages 6-8) * Recurrent respiratory infections — HP:0002205 (supported by recurrent pneumonias/infections) (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 5-5) * Hypogammaglobulinemia — HP:0004313 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6) * Abnormal coagulation / prolonged aPTT — HP:0011014 / HP:0030842 (sturiale2019alg12cdgnovelglycophenotype pages 6-8) * Cryptorchidism — HP:0000028; Micropenis — HP:0000054 (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
Reported variants include missense, frameshift, and (in later literature) intronic splice‑altering variants; most evidence supports loss‑of‑function or hypomorphic loss‑of‑function. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 1-1)
Examples: * Compound heterozygous missense: T67M and R146Q in the first report. (grubenmann2002alg12mannosyltransferasedefect pages 1-2) * Frameshift: c.1001delA (p.N334TfsX15) reported in a family case series. (tahata2019complexphenotypesin pages 1-2) * Missense: c.1439T>C (p.Leu480Pro) reported as homozygous in a Slovak patient. (ziburova2021anovelhomozygous pages 1-1) * Compound heterozygous missense: c.367G>A (p.Gly123Arg) and c.1439T>C (p.Leu480Pro) in another patient. (sturiale2019alg12cdgnovelglycophenotype pages 6-8)
Population frequency note (limited): p.Leu480Pro was described as having a very low ExAC frequency (“8 × 10−6”). (sturiale2019alg12cdgnovelglycophenotype pages 6-8)
No ALG12‑CDG‑specific modifier genes, epigenetic mechanisms, or recurrent chromosomal abnormalities were identified in the retrieved texts.
ALG12‑CDG is a Mendelian disorder primarily driven by biallelic ALG12 variants; no consistent non‑genetic causal environmental exposures were identified.
A 2021 report found MS evidence of impaired ALG12 activity: “analysis of neutral serum N‑glycans by mass spectrometry revealed the accumulation of GlcNAc2Man5–7 and decreased levels of GlcNAc2Man8–9.” (ziburova2021anovelhomozygous pages 1-1)
A 2024 immunopathology review classifies ALG12‑CDG among “predominantly antibody deficiencies” characterized by “hypogammaglobulinemia and low IgG.” (Pascoal et al., 2024‑03; Frontiers in Immunology; DOI https://doi.org/10.3389/fimmu.2024.1350101) (pascoal2024revisitingtheimmunopathology pages 3-4, pascoal2024revisitingtheimmunopathology pages 4-6)
Mechanistic framing in the same review: defective glycosylation can lead to “defective antibody glycosylation,” reducing stability and Fc receptor binding, likely contributing to antibody deficiency and infection susceptibility. (pascoal2024revisitingtheimmunopathology pages 4-6)
Based on reported phenotypes and biochemical effects: * Central nervous system (neurodevelopmental delay, hypotonia) (UBERON:0000955 — brain) * Immune system (hypogammaglobulinemia, infections) (UBERON:0002405 — immune system) * Liver / plasma protein production (coagulation factors, antithrombin, transaminases) (UBERON:0002107 — liver) (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 5-5) * Male reproductive system (micropenis, cryptorchidism) (UBERON:0000079 — male reproductive system) (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
Subcellular localization relevant to mechanism: endoplasmic reticulum (GO:0005783) consistent with ER mannosyltransferase role and LLO assembly. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2)
No formal staging system specific to ALG12‑CDG was identified.
Autosomal recessive, supported by homozygous and compound heterozygous cases. (ziburova2021anovelhomozygous pages 2-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8)
Robust incidence/prevalence estimates for ALG12‑CDG were not found in the retrieved evidence. However, multiple primary sources emphasize extreme rarity: * “To date, only 15 patients have been diagnosed with ALG12‑CDG globally.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 1-1) * Another excerpt states the Slovak case “brings the total number of published cases of this subtype to 16.” (ziburova2021anovelhomozygous pages 5-5)
Transferrin isoelectric focusing / carbohydrate‑deficient transferrin * Index case evidence: transferrin IEF demonstrated decreased tetrasialotransferrin with increased disialo/asialotransferrin (type‑I CDG pattern). (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
Lipid‑linked oligosaccharide analysis (patient fibroblasts) * Demonstrated accumulation of truncated DolPP‑GlcNAc2Man7 and loss of mature DolPP‑GlcNAc2Man9Glc3. (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
Serum N‑glycan profiling by MS * “Accumulation of GlcNAc2Man5–7 and decreased levels of GlcNAc2Man8–9” in neutral serum N‑glycans. (ziburova2021anovelhomozygous pages 1-1)
Exome/genome sequencing is widely used for CDG diagnosis broadly. A 2023 review states: “CDG diagnosis has been at a rapid pace since the introduction of whole‑exome/whole‑genome sequencing as a diagnostic tool.” (Monticelli et al., 2023‑08; Orphanet J Rare Dis; DOI https://doi.org/10.1186/s13023-023-02852-w) (monticelli2023congenitaldisordersof pages 1-2)
The same review also emphasizes: “genetic analysis is the most reliable diagnostic.” (monticelli2023congenitaldisordersof pages 14-15)
A comprehensive differential diagnosis list specific to ALG12‑CDG was not present in the retrieved texts. Practically, it overlaps with other CDG type I (LLO assembly/transfer) disorders, where transferrin IEF abnormalities prompt gene‑panel/WES/WGS confirmation.
Evidence indicates variable prognosis: * Severe early‑fatal multisystem disease is reported (e.g., infant death in a sibling group; fatal neonatal/infant outcomes in some cases). (tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 5-5) * Survivors can have chronic neurodevelopmental disability and recurrent infections. (tahata2019complexphenotypesin pages 1-2, grubenmann2002alg12mannosyltransferasedefect pages 2-3)
Quantitative survival curves or life expectancy estimates specific to ALG12‑CDG were not found in retrieved texts.
No ALG12‑CDG‑specific disease‑modifying therapy was identified in the retrieved evidence.
Suggested MAXO terms (examples) * Immunoglobulin replacement therapy (MAXO term for IVIG/SCIG) * Anti‑infective therapy / infection prophylaxis * Nutritional support / enteral feeding * Coagulation factor replacement / management of coagulopathy * Physical therapy / occupational therapy / speech therapy for developmental impairment
No interventional trials specific to ALG12‑CDG were found. A key real‑world research infrastructure is an observational CDG natural history study: * NCT04199000 (ClinicalTrials.gov; first posted 2019; recruiting): observational case‑only study with “genetically, enzymatically, or molecularly confirmed diagnosis of CDG or NGLY1 deficiency,” enrollment target 500; includes questionnaires, clinical exams, Nijmegen progression scale and PROMIS measures; allows biospecimen collection for biomarker/DNA studies. ALG12 is listed among keywords. URL: https://clinicaltrials.gov/study/NCT04199000 (NCT04199000 chunk 1, NCT04199000 chunk 2)
No primary prevention exists for Mendelian ALG12‑CDG beyond reproductive and carrier testing strategies: * Carrier testing in at‑risk families (based on known familial variants) * Prenatal diagnosis / preimplantation genetic testing where appropriate
These approaches were not detailed in the retrieved corpus but follow standard practice for autosomal recessive disorders.
No naturally occurring veterinary disease analogs for ALG12‑CDG were identified in the retrieved evidence.
Direct ALG12‑CDG functional modeling evidence in the retrieved corpus is limited but includes: * Yeast complementation/ortholog modeling: The original report used yeast functional complementation to show that ALG12 patient mutations fail to rescue an alg12 yeast mutant, supporting pathogenicity. (grubenmann2002alg12mannosyltransferasedefect pages 1-2)
No detailed mammalian or zebrafish ALG12‑specific in vivo phenotype data were retrieved in this tool run; therefore, this section should be revisited with dedicated model‑organism database searches (MGI/ZFIN/IMPC) if required.
A 2023 Orphanet Journal of Rare Diseases review (patent‑focused) summarizes the state of the field: * CDG comprises “more than 160” defects. (monticelli2023congenitaldisordersof pages 1-2) * “CDG diagnosis has been at a rapid pace since the introduction of whole‑exome/whole‑genome sequencing as a diagnostic tool.” (monticelli2023congenitaldisordersof pages 1-2) * Despite progress, “diagnostic tools, drugs, and biomarkers are still urgently needed.” (monticelli2023congenitaldisordersof pages 1-2)
A 2024 Frontiers in Immunology review places ALG12‑CDG into an inborn‑errors‑of‑immunity framing as predominantly antibody deficiency and discusses how glycosylation defects can compromise antibody properties and infection defense. (pascoal2024revisitingtheimmunopathology pages 3-4, pascoal2024revisitingtheimmunopathology pages 4-6)
A 2024 targeted proteomics paper describes an MRM assay to quantify low‑abundance ER glycosyltransferases in CDG patient fibroblasts and explicitly situates ALG12 among the ER enzymes in the pathway context (“ALG3, ALG9, ALG12…”). This represents a real‑world implementation of quantitative proteomics for CDG mechanism and potentially diagnostics/biomarker development. (Lin et al., 2024‑01; Int J Mol Sci; DOI https://doi.org/10.3390/ijms25021191) (lin2024targetedproteomicsreveals pages 1-2)
The following table summarizes key facts for knowledge‑base ingestion:
| Category | Key findings (concise) | Evidence type | Primary citations (include PMID if available; otherwise DOI/URL) |
|---|---|---|---|
| Disease definition | ALG12-congenital disorder of glycosylation (ALG12-CDG), historically CDG-Ig, is a rare type I CDG caused by deficiency of ALG12 ER α1,6-mannosyltransferase; severe multisystem disease with hypoglycosylation. OMIM/MIM reported in literature as #607143; one excerpt also cites OMIM:607144. | Human case report, review | Grubenmann et al., 2002, Hum Mol Genet, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, AJMG A, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, Mol Genet Metab, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2, tahata2019complexphenotypesin pages 1-2) |
| Gene/enzyme function | ALG12 encodes dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase / α-mannosyltransferase 8, which adds the 8th mannose to the lipid-linked oligosaccharide precursor during N-glycan biosynthesis in the ER. | Human case report, review | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Pascoal et al., 2024, Front Immunol, DOI: https://doi.org/10.3389/fimmu.2024.1350101 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2, pascoal2024revisitingtheimmunopathology pages 4-6) |
| Inheritance | Autosomal recessive; reported in homozygous and compound heterozygous states. | Human case report/series | Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2 (ziburova2021anovelhomozygous pages 2-2, tahata2019complexphenotypesin pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8) |
| Core phenotypes | Commonly reported: psychomotor/intellectual delay, hypotonia, growth retardation/failure to thrive, microcephaly, dysmorphic facial features, recurrent infections, feeding difficulties, respiratory distress, skeletal abnormalities; variable severity including neonatal/infantile fatal cases and milder presentations. | Human case report/series, review | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; de la Morena-Barrio et al., 2020, DOI: https://doi.org/10.1002/mgg3.1304 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 5-5) |
| Immune involvement | Predominantly antibody deficiency phenotype: hypogammaglobulinemia/low IgG, recurrent severe bacterial or sinopulmonary infections, altered lymphocyte counts/dysfunction. 2024 review groups ALG12-CDG with predominantly antibody deficiencies. | Human case report, review | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Pascoal et al., 2024, DOI: https://doi.org/10.3389/fimmu.2024.1350101; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6, ziburova2021anovelhomozygous pages 6-7) |
| Coagulation/endocrine | Reported coagulation abnormalities include low antithrombin III, prolonged APTT, decreased coagulation factors; endocrine/metabolic findings include undetectable IGF-1/IGF-BP3, hypoglycemia, low cholesterol, elevated transaminases, and male genital anomalies (micropenis/cryptorchidism). | Human case report/series | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, sturiale2019alg12cdgnovelglycophenotype pages 6-8, ziburova2021anovelhomozygous pages 5-5, tahata2019complexphenotypesin pages 1-2) |
| Diagnostics (transferrin IEF, LLO, serum N-glycan MS) | Serum transferrin IEF shows a type I CDG pattern with decreased tetrasialotransferrin and increased disialo-/asialotransferrin. Patient fibroblasts can show truncated LLO with accumulation of DolPP-GlcNAc2Man7 and absence/reduction of mature DolPP-GlcNAc2Man9Glc3. Serum N-glycan MS/MALDI-TOF shows accumulation of GlcNAc2Man5-7 with decreased GlcNAc2Man8-9; transferrin/total serum glycomics can reveal mono-glycosylated transferrin and increased high-mannose/hybrid glycans. | Human case report/series | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 1-1, sturiale2019alg12cdgnovelglycophenotype pages 6-8) |
| Variant examples | Reported pathogenic/likely pathogenic examples include compound heterozygous p.T67M and p.R146Q; c.1001delA (p.N334Tfs*15) with c.671C>T (p.T224M, reported as VUS in one series); c.367G>A (p.Gly123Arg) and c.1439T>C (p.Leu480Pro); homozygous c.1439T>C (p.Leu480Pro); novel p.Val26Asp. 2025 report (outside requested priority window) adds an intronic splice variant upstream of exon 2. | Human case report/series | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8, ziburova2021anovelhomozygous pages 1-1) |
| Epidemiology/patient counts | Extremely rare. Literature excerpts report “only 15 patients” worldwide by 2021 and “16 published cases” after the Slovak case; no robust prevalence/incidence estimate identified in available context. | Human case report, review | Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Piedade et al., 2022, J Rare Dis, DOI: https://doi.org/10.1007/s44162-022-00003-6 (ziburova2021anovelhomozygous pages 1-1, ziburova2021anovelhomozygous pages 5-5) |
| Management/supportive care | No disease-specific curative therapy identified in available context. Supportive care includes immunoglobulin replacement/IVIG in patients with hypogammaglobulinemia, management of infections, nutritional/supportive multidisciplinary care, and monitoring of coagulation/endocrine issues. Reported response to Ig infusion may be variable or limited in some ALG12-CDG cases. | Human case report, review | Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Pascoal et al., 2024, DOI: https://doi.org/10.3389/fimmu.2024.1350101 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6) |
| Research/real-world implementations | Real-world diagnosis increasingly uses WES/WGS for CDG discovery/confirmation; MS-based glycomics (MALDI-MS/UHPLC-ESI-MS) refines subtype-specific glycophenotypes; targeted proteomics/MRM assays for ER glycosyltransferases were introduced in 2024 and include the ALG12 pathway, supporting translational diagnostics/research. Patent review notes CDG diagnosis accelerated with WES/WGS and that diagnostic tools, drugs, and biomarkers remain urgently needed. | Review, translational research | Monticelli et al., 2023, DOI: https://doi.org/10.1186/s13023-023-02852-w; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Lin et al., 2024, DOI: https://doi.org/10.3390/ijms25021191 (monticelli2023congenitaldisordersof pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 1-2, lin2024targetedproteomicsreveals pages 1-2) |
| Clinical trial registry (NCT04199000) | Ongoing observational natural-history study: “Clinical and Basic Investigations Into Congenital Disorders of Glycosylation” (NCT04199000), recruiting, case-only, target enrollment 500, includes genetically/enzymatically/molecularly confirmed CDG or NGLY1 deficiency; outcomes include disease severity/progression measures and biomarker collection. ALG12 is listed among keywords, making the registry relevant to ALG12-CDG. | Trial registry | ClinicalTrials.gov NCT04199000: https://clinicaltrials.gov/study/NCT04199000 (NCT04199000 chunk 1, NCT04199000 chunk 2) |
Table: This table summarizes key disease facts, clinical and molecular findings, diagnostics, management, and current research implementations for ALG12-CDG using only evidence available in the conversation context. It is designed for rapid knowledge-base ingestion with source-linked citations.
References
(grubenmann2002alg12mannosyltransferasedefect pages 1-2): C. Grubenmann, C. Frank, S. Kjaergaard, E. Berger, M. Aebi, and T. Hennet. Alg12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics, 11 19:2331-9, Sep 2002. URL: https://doi.org/10.1093/hmg/11.19.2331, doi:10.1093/hmg/11.19.2331. This article has 103 citations and is from a domain leading peer-reviewed journal.
(grubenmann2002alg12mannosyltransferasedefect pages 2-3): C. Grubenmann, C. Frank, S. Kjaergaard, E. Berger, M. Aebi, and T. Hennet. Alg12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics, 11 19:2331-9, Sep 2002. URL: https://doi.org/10.1093/hmg/11.19.2331, doi:10.1093/hmg/11.19.2331. This article has 103 citations and is from a domain leading peer-reviewed journal.
(ziburova2021anovelhomozygous pages 1-1): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.
(monticelli2023congenitaldisordersof pages 1-2): Maria Monticelli, Tania D’Onofrio, Jaak Jaeken, Eva Morava, Giuseppina Andreotti, and Maria Vittoria Cubellis. Congenital disorders of glycosylation: narration of a story through its patents. Orphanet Journal of Rare Diseases, Aug 2023. URL: https://doi.org/10.1186/s13023-023-02852-w, doi:10.1186/s13023-023-02852-w. This article has 19 citations and is from a peer-reviewed journal.
(pascoal2024revisitingtheimmunopathology pages 4-6): Carlota Pascoal, Rita Francisco, Patrícia Mexia, Beatriz Luís Pereira, Pedro Granjo, Helena Coelho, Mariana Barbosa, Vanessa dos Reis Ferreira, and Paula Alexandra Videira. Revisiting the immunopathology of congenital disorders of glycosylation: an updated review. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1350101, doi:10.3389/fimmu.2024.1350101. This article has 15 citations and is from a peer-reviewed journal.
(OpenTargets Search: ALG12-congenital disorder of glycosylation-ALG12): Open Targets Query (ALG12-congenital disorder of glycosylation-ALG12, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(ziburova2021anovelhomozygous pages 2-2): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.
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(tahata2019complexphenotypesin pages 1-2): Shawn Tahata, Lauren B. Gunderson, Brendan Lanpher, and E. Morava. Complex phenotypes in alg12-congenital disorder of glycosylation (alg12-cdg): case series and review of the literature. Molecular genetics and metabolism, 128:409-414, Dec 2019. URL: https://doi.org/10.1016/j.ymgme.2019.08.007, doi:10.1016/j.ymgme.2019.08.007. This article has 25 citations and is from a peer-reviewed journal.
(ziburova2021anovelhomozygous pages 7-8): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.
(pascoal2024revisitingtheimmunopathology pages 1-2): Carlota Pascoal, Rita Francisco, Patrícia Mexia, Beatriz Luís Pereira, Pedro Granjo, Helena Coelho, Mariana Barbosa, Vanessa dos Reis Ferreira, and Paula Alexandra Videira. Revisiting the immunopathology of congenital disorders of glycosylation: an updated review. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1350101, doi:10.3389/fimmu.2024.1350101. This article has 15 citations and is from a peer-reviewed journal.
(ziburova2021anovelhomozygous pages 5-5): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.
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(NCT04199000 chunk 2): Eva Morava-Kozicz. Clinical and Basic Investigations Into Congenital Disorders of Glycosylation. Icahn School of Medicine at Mount Sinai. 2019. ClinicalTrials.gov Identifier: NCT04199000
(lin2024targetedproteomicsreveals pages 1-2): Qingsong Lin, Lei Zhou, Chuen Lam, Roman Sakson, Lars Beedgen, Patrick Bernhard, K. M. Alp, Nicole Lübbehusen, R. Röth, Beate Niesler, Marcin Luzarowski, Olga Shevchuk, Matthias P. Mayer, Christian Thiel, and Thomas Ruppert. Targeted proteomics reveals quantitative differences in low-abundance glycosyltransferases of patients with congenital disorders of glycosylation. International Journal of Molecular Sciences, 25:1191, Jan 2024. URL: https://doi.org/10.3390/ijms25021191, doi:10.3390/ijms25021191. This article has 5 citations.
(ziburova2021anovelhomozygous pages 6-7): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.