DPAGT1-congenital disorder of glycosylation

Summary

DPAGT1-congenital disorder of glycosylation (MONDO:0011964) is a disease caused by DPAGT1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DPAGT1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 295
• Phenotypes (HPO): 69

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

69 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000519	Developmental cataract	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0200134	Epileptic encephalopathy	Occasional (5-29%)
HP:0410263	Brain imaging abnormality	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000510	Rod-cone dystrophy	Occasional (5-29%)
HP:0000577	Exotropia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000662	Nyctalopia	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001072	Thickened skin	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001976	Reduced antithrombin III activity	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002089	Pulmonary hypoplasia	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002283	Global brain atrophy	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003186	Inverted nipples	Occasional (5-29%)
HP:0003429	CNS hypomyelination	Occasional (5-29%)
HP:0004855	Reduced protein S activity	Occasional (5-29%)
HP:0009125	Lipodystrophy	Occasional (5-29%)
HP:0010781	Skin dimple	Occasional (5-29%)
HP:0010845	EEG with generalized slow activity	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	DPAGT1-congenital disorder of glycosylation
Mondo ID	MONDO:0011964
MeSH	C535748
OMIM	608093
Orphanet	86309
DOID	DOID:0080562
NCIT	C126874
SNOMED CT	725079003
UMLS	C2931004
MedGen	419694
GARD	0009837
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type Ij · CDG 1J · CDG syndrome type Ij · CDG-Ij · CDG1J · CDGIj · congenital disorder of glycosylation type 1j · congenital disorder of glycosylation type Ij · congenital disorder of glycosylation, type Ij · dolichyl-phosphate N-acetylgalactosamine phosphotransferase deficiency · DPAGT1-CDG · DPAGT1-CDG (CDG-Ij) · DPAGT1-congenital disorder of glycosylation

Data availability: 295 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation type I › DPAGT1-congenital disorder of glycosylation

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG6-congenital disorder of glycosylation 1C, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

295 retrieved; paginated sample, class counts are floors:

117 likely benign, 114 uncertain significance, 25 conflicting classifications of pathogenicity, 15 pathogenic, 12 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
652390	NC_000011.9:g.(?118967698)(119170501_?)del	CBL	Pathogenic	criteria provided, single submitter
1180632	NM_001382.4(DPAGT1):c.902G>A (p.Arg301His)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373663	NM_001382.4(DPAGT1):c.1139C>T (p.Thr380Ile)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451203	NM_001382.4(DPAGT1):c.762_765del (p.Cys255fs)	DPAGT1	Pathogenic	criteria provided, single submitter
2927002	NM_001382.4(DPAGT1):c.732C>A (p.Tyr244Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
36919	NM_001382.4(DPAGT1):c.324G>C (p.Met108Ile)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36920	NM_001382.4(DPAGT1):c.699dup (p.Thr234fs)	DPAGT1	Pathogenic	criteria provided, single submitter
3752613	NM_001382.4(DPAGT1):c.980_981del (p.Ser327fs)	DPAGT1	Pathogenic	criteria provided, single submitter
381709	NM_001382.4(DPAGT1):c.1A>C (p.Met1Leu)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39774	NM_001382.4(DPAGT1):c.161+5G>A	DPAGT1	Pathogenic	no assertion criteria provided
4785074	NM_001382.4(DPAGT1):c.172C>T (p.Gln58Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
4786678	NM_001382.4(DPAGT1):c.737C>A (p.Ser246Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
521720	NM_001382.4(DPAGT1):c.380_395dup (p.Ser133fs)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565496	NM_001382.4(DPAGT1):c.360G>C (p.Leu120=)	DPAGT1	Pathogenic	criteria provided, single submitter
640003	NM_001382.4(DPAGT1):c.398C>G (p.Ser133Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
65471	NM_001382.4(DPAGT1):c.503T>C (p.Leu168Pro)	DPAGT1	Pathogenic	no assertion criteria provided
1460468	NM_001382.4(DPAGT1):c.6G>A (p.Trp2Ter)	LOC126861360	Pathogenic	criteria provided, single submitter
2944371	NM_001382.4(DPAGT1):c.79del (p.Thr27fs)	LOC126861360	Pathogenic	criteria provided, single submitter
39773	NM_001382.4(DPAGT1):c.206T>A (p.Ile69Asn)	LOC126861360	Pathogenic	no assertion criteria provided
567578	NM_001382.4(DPAGT1):c.26dup (p.Met9fs)	LOC126861360	Pathogenic	criteria provided, single submitter
1480366	NM_001382.4(DPAGT1):c.644-1G>T	DPAGT1	Likely pathogenic	criteria provided, single submitter
1685304	NM_001382.4(DPAGT1):c.643+1G>A	DPAGT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445686	NC_000011.9:g.(118971849_118972204)(118972786?)del	DPAGT1	Likely pathogenic	criteria provided, single submitter
2954181	NM_001382.4(DPAGT1):c.1005+1G>A	DPAGT1	Likely pathogenic	criteria provided, single submitter
3382969	NM_001382.4(DPAGT1):c.728+1del	DPAGT1	Likely pathogenic	criteria provided, single submitter
36918	NM_001382.4(DPAGT1):c.349G>A (p.Val117Ile)	DPAGT1	Likely pathogenic	criteria provided, single submitter
4786262	NM_001382.4(DPAGT1):c.282+1G>A	DPAGT1	Likely pathogenic	criteria provided, single submitter
4845787	NM_001382.4(DPAGT1):c.698dup (p.Thr234fs)	DPAGT1	Likely pathogenic	criteria provided, single submitter
65469	NM_001382.4(DPAGT1):c.341C>G (p.Ala114Gly)	DPAGT1	Likely pathogenic	criteria provided, single submitter
802807	NM_001382.4(DPAGT1):c.574G>C (p.Gly192Arg)	DPAGT1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DPAGT1	Definitive	Autosomal recessive	DPAGT1-congenital disorder of glycosylation	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPAGT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
DPAGT1	Orphanet:86309	DPAGT1-CDG
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DPAGT1	HGNC:2995	ENSG00000172269	Q9H3H5	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	gencc,clinvar
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	clinvar
NLRX1	HGNC:29890	ENSG00000160703	Q86UT6	NLR family member X1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPAGT1	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
NLRX1	NLR family member X1	Participates in antiviral signaling.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPAGT1	Enzyme (other)	yes	2.7.8.15	Glycosyl_transferase_4, GPT, DPAGT1_ins
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
NLRX1	Other/Unknown	no		Leu-rich_rpt, NACHT_NTPase, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
mucosa of transverse colon	1
right adrenal gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
trigeminal ganglion	1
cervix squamous epithelium	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPAGT1	271	ubiquitous	marker	mucosa of transverse colon, body of pancreas, right adrenal gland
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
NLRX1	262	ubiquitous	yes	lower esophagus mucosa, cervix squamous epithelium, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CBL	4,575
DPAGT1	1,928
NLRX1	1,310

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBL	P22681	33
DPAGT1	Q9H3H5	8
NLRX1	Q86UT6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective DPAGT1 causes CDG-1j, CMSTA2	1	1903.3×	0.014	DPAGT1
Signaling by EGFRvIII in Cancer	1	761.3×	0.014	CBL
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	634.4×	0.014	CBL
FLT3 signaling by CBL mutants	1	543.8×	0.014	CBL
Interleukin-6 family signaling	1	475.8×	0.014	CBL
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1	1	423.0×	0.014	CBL
Signaling by EGFR in Cancer	1	380.7×	0.014	CBL
Signaling by FGFR3	1	380.7×	0.014	CBL
FLT3 signaling in disease	1	380.7×	0.014	CBL
Signaling by FGFR4	1	346.1×	0.014	CBL
Listeria monocytogenes entry into host cells	1	346.1×	0.014	CBL
Interleukin-6 signaling	1	317.2×	0.014	CBL
Signaling by FGFR1	1	271.9×	0.014	CBL
InlB-mediated entry of Listeria monocytogenes into host cell	1	253.8×	0.014	CBL
Spry regulation of FGF signaling	1	237.9×	0.014	CBL
Constitutive Signaling by EGFRvIII	1	237.9×	0.014	CBL
Negative regulation of FLT3	1	237.9×	0.014	CBL
Regulation of NF-kappa B signaling	1	211.5×	0.014	NLRX1
Regulation of KIT signaling	1	200.3×	0.014	CBL
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	190.3×	0.014	CBL
Signaling by PTK6	1	181.3×	0.014	CBL
Signaling by Non-Receptor Tyrosine Kinases	1	181.3×	0.014	CBL
Negative regulation of MET activity	1	173.0×	0.014	CBL
Regulation of signaling by CBL	1	165.5×	0.014	CBL
Negative regulation of FGFR3 signaling	1	146.4×	0.014	CBL
Negative regulation of FGFR4 signaling	1	135.9×	0.014	CBL
Signaling by FGFR2	1	135.9×	0.014	CBL
Negative regulation of FGFR1 signaling	1	122.8×	0.014	CBL
Negative regulation of FGFR2 signaling	1	122.8×	0.014	CBL
EGFR downregulation	1	115.3×	0.014	CBL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	1872.4×	0.014	CBL
regulation of Rap protein signal transduction	1	1404.3×	0.014	CBL
negative regulation of RIG-I signaling pathway	1	702.2×	0.014	NLRX1
ubiquitin-dependent endocytosis	1	624.1×	0.014	CBL
negative regulation of macrophage cytokine production	1	401.2×	0.014	NLRX1
negative regulation of interferon-beta production	1	351.1×	0.014	NLRX1
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.014	DPAGT1
positive regulation of receptor-mediated endocytosis	1	267.5×	0.014	CBL
negative regulation of epidermal growth factor receptor signaling pathway	1	255.3×	0.014	CBL
cellular response to platelet-derived growth factor stimulus	1	216.1×	0.014	CBL
mast cell degranulation	1	208.1×	0.014	CBL
response to gamma radiation	1	193.7×	0.014	CBL
negative regulation of T cell activation	1	175.5×	0.014	CBL
negative regulation of innate immune response	1	170.2×	0.014	NLRX1
positive regulation of epidermal growth factor receptor signaling pathway	1	165.2×	0.014	CBL
response to testosterone	1	156.0×	0.014	CBL
response to starvation	1	156.0×	0.014	CBL
cellular response to nerve growth factor stimulus	1	156.0×	0.014	CBL
symbiont entry into host cell	1	133.8×	0.016	CBL
negative regulation of T cell receptor signaling pathway	1	122.1×	0.016	CBL
negative regulation of interleukin-6 production	1	117.0×	0.016	NLRX1
protein monoubiquitination	1	114.6×	0.016	CBL
response to activity	1	108.0×	0.016	CBL
protein K63-linked ubiquitination	1	89.2×	0.018	CBL
protein N-linked glycosylation	1	87.8×	0.018	DPAGT1
protein autoubiquitination	1	78.0×	0.020	CBL
negative regulation of canonical NF-kappaB signal transduction	1	57.3×	0.026	NLRX1
male gonad development	1	52.0×	0.027	CBL
response to ethanol	1	48.9×	0.028	CBL
negative regulation of inflammatory response	1	45.7×	0.029	NLRX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DPAGT1	0	0
CBL	0	0
NLRX1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DPAGT1	7	Binding:7
CBL	4	Binding:2, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPAGT1	2.7.8.15	UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase
CBL	2.3.2.27	RING-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DPAGT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CBL, NLRX1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DPAGT1	7	—
CBL	4	—
NLRX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.