congenital disorder of glycosylation type 1E

Summary

congenital disorder of glycosylation type 1E (MONDO:0012123) is a disease caused by DPM1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DPM1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 247
• Phenotypes (HPO): 59

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0005484	Secondary microcephaly	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001976	Reduced antithrombin III activity	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0004855	Reduced protein S activity	Frequent (30-79%)
HP:0005543	Reduced protein C activity	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0100321	Abnormality of the dentate nucleus	Frequent (30-79%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000319	Smooth philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001395	Hepatic fibrosis	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001847	Long hallux	Occasional (5-29%)
HP:0001852	Sandal gap	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002057	Prominent glabella	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002164	Nail dysplasia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0003186	Inverted nipples	Occasional (5-29%)
HP:0003241	External genital hypoplasia	Occasional (5-29%)
HP:0003560	Muscular dystrophy	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0005469	Flat occiput	Occasional (5-29%)
HP:0006380	Knee flexion contracture	Occasional (5-29%)
HP:0006879	Pontocerebellar atrophy	Occasional (5-29%)
HP:0007333	Hypoplasia of the frontal lobes	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of glycosylation type 1E
Mondo ID	MONDO:0012123
MeSH	C535743
OMIM	608799
Orphanet	79322
DOID	DOID:0080557
NCIT	C126871
SNOMED CT	725078006
UMLS	C1837396
MedGen	324784
GARD	0009831
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type Ie · carbohydrate-deficient glycoprotein syndrome type 1E · CDG 1E · CDG syndrome type Ie · CDG-Ie · CDG1E · CDGIe · congenital disorder of glycosylation caused by mutation in DPM1 · congenital disorder of glycosylation type 1E · congenital disorder of glycosylation type 1e · congenital disorder of glycosylation type Ie · congenital disorder of glycosylation, type Ie · Dol-P-mannosyltransferase deficiency · DPM1 congenital disorder of glycosylation · DPM1-CDG (CDG-Ie)

Data availability: 247 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 › congenital disorder of glycosylation type 1E

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, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, 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

247 retrieved; paginated sample, class counts are floors:

107 uncertain significance, 92 likely benign, 17 pathogenic, 15 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 benign/likely benign, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3248272	NC_000020.10:g.(?49520406)(49571842_?)del	ADNP	Pathogenic	criteria provided, single submitter
1998916	NM_003859.3(DPM1):c.527_533del (p.Leu176fs)	ADNP-AS1	Pathogenic	criteria provided, single submitter
3657851	NM_003859.3(DPM1):c.566T>A (p.Leu189Ter)	ADNP-AS1	Pathogenic	criteria provided, single submitter
464504	NM_003859.3(DPM1):c.409G>T (p.Glu137Ter)	ADNP-AS1	Pathogenic	criteria provided, single submitter
6298	NM_003859.3(DPM1):c.628del (p.Gln210fs)	ADNP-AS1	Pathogenic	no assertion criteria provided
656838	NC_000020.11:g.(?50934864)(50958574_?)del	ADNP-AS1	Pathogenic	criteria provided, single submitter
100635	NM_003859.3(DPM1):c.373-5T>A	DPM1	Pathogenic	no assertion criteria provided
100636	NM_003859.3(DPM1):c.455G>T (p.Gly152Val)	DPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100637	NC_000020.11:g.(50936263_50940865)_(50948664_50955185)del	DPM1	Pathogenic	no assertion criteria provided
1444616	NM_003859.3(DPM1):c.571C>T (p.Arg191Ter)	DPM1	Pathogenic	criteria provided, single submitter
1454916	NM_003859.3(DPM1):c.173_174del (p.Asn57_Tyr58insTer)	DPM1	Pathogenic	criteria provided, single submitter
1455808	NM_003859.3(DPM1):c.52del (p.Glu18fs)	DPM1	Pathogenic	criteria provided, single submitter
2712030	NM_003859.3(DPM1):c.182del (p.Ile61fs)	DPM1	Pathogenic	criteria provided, single submitter
3631040	NM_003859.3(DPM1):c.564-1G>T	DPM1	Pathogenic	criteria provided, single submitter
570864	NM_003859.3(DPM1):c.331_343del (p.Gly111fs)	DPM1	Pathogenic	criteria provided, multiple submitters, no conflicts
6296	NM_003859.3(DPM1):c.274C>G (p.Arg92Gly)	DPM1	Pathogenic	criteria provided, multiple submitters, no conflicts
663599	NM_003859.3(DPM1):c.1A>C (p.Met1Leu)	DPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
857465	NM_003859.3(DPM1):c.490_493del (p.Ile164fs)	DPM1	Pathogenic	criteria provided, single submitter
2424782	NC_000020.10:g.(?49507942)(49576762_?)del	MOCS3	Pathogenic	criteria provided, single submitter
100634	NM_003859.3(DPM1):c.742T>C (p.Ser248Pro)	ADNP-AS1	Likely pathogenic	criteria provided, single submitter
2023666	NM_003859.3(DPM1):c.495-1G>T	ADNP-AS1	Likely pathogenic	criteria provided, single submitter
3729459	NM_003859.3(DPM1):c.563+1G>A	ADNP-AS1	Likely pathogenic	criteria provided, single submitter
3779283	NM_003859.3(DPM1):c.566T>G (p.Leu189Ter)	ADNP-AS1	Likely pathogenic	criteria provided, single submitter
583717	NC_000020.11:g.(?50940845)(50942146_?)del	ADNP-AS1	Likely pathogenic	criteria provided, single submitter
1098270	NM_003859.3(DPM1):c.371A>G (p.His124Arg)	DPM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328165	NM_003859.3(DPM1):c.439C>T (p.Arg147Cys)	ADNP-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476452	NM_003859.3(DPM1):c.649G>A (p.Ala217Thr)	ADNP-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500757	NM_003859.3(DPM1):c.494+2T>C	ADNP-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338751	NM_003859.3(DPM1):c.759A>G (p.Leu253=)	ADNP-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259186	NM_003859.3(DPM1):c.22C>T (p.Arg8Cys)	DPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
DPM1	Definitive	Autosomal recessive	congenital disorder of glycosylation type 1E	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPM1	Orphanet:79322	DPM1-CDG
ADNP	Orphanet:404448	Helsmoortel-Van der Aa syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DPM1	HGNC:3005	ENSG00000000419	O60762	Dolichol-phosphate mannosyltransferase subunit 1	gencc,clinvar
MOCS3	HGNC:15765	ENSG00000124217	O95396	Adenylyltransferase and sulfurtransferase MOCS3	clinvar
ADNP	HGNC:15766	ENSG00000101126	Q9H2P0	Activity-dependent neuroprotector homeobox protein	clinvar
ADNP-AS1	HGNC:51227	ENSG00000259456		ADNP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPM1	Dolichol-phosphate mannosyltransferase subunit 1	Transfers mannose from GDP-mannose to dolichol monophosphate to form dolichol phosphate mannose (Dol-P-Man) which is the mannosyl donor in pathways leading to N-glycosylation, glycosyl phosphatidylinositol membrane anchoring, and O-mannosy…
MOCS3	Adenylyltransferase and sulfurtransferase MOCS3	Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln).
ADNP	Activity-dependent neuroprotector homeobox protein	May be involved in transcriptional regulation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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)	2	6.0×	0.112
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPM1	Enzyme (other)	yes	2.4.1.83	Glyco_trans_2-like, Nucleotide-diphossugar_trans, DPM1-like
MOCS3	Enzyme (other)	yes	2.7.7.80	ThiF_NAD_FAD-bd, Rhodanese-like_dom, MOCS3/Uba4
ADNP	Transcription factor	no		HD, Homeodomain-like_sf, Znf_C2H2_type
ADNP-AS1	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sperm	2
epithelium of nasopharynx	1
germinal epithelium of ovary	1
male germ cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPM1	295	ubiquitous	marker	epithelium of nasopharynx, germinal epithelium of ovary, sperm
MOCS3	188	ubiquitous	yes	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis
ADNP	295	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
ADNP-AS1	136	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DPM1	3,598
MOCS3	2,263
ADNP	2,228
ADNP-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MOCS3	O95396	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPM1	O60762	88.61
ADNP	Q9H2P0	57.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 4 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
Synthesis of dolichyl-phosphate mannose	1	1268.9×	0.002	DPM1
Defective DPM1 causes DPM1-CDG	1	1268.9×	0.002	DPM1
Defective DPM3 causes DPM3-CDG	1	1268.9×	0.002	DPM1
Defective DPM2 causes DPM2-CDG	1	1268.9×	0.002	DPM1
Molybdenum cofactor biosynthesis	1	543.8×	0.004	MOCS3
Maturation of DENV proteins	1	70.5×	0.021	DPM1
ChAHP complex assembly	1	61.4×	0.021	ADNP
Metabolism of water-soluble vitamins and cofactors	1	60.4×	0.021	MOCS3
Metabolism of vitamins and cofactors	1	38.8×	0.028	MOCS3
Metabolism	1	3.9×	0.237	MOCS3

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
intracellular nitric oxide homeostasis	1	1872.4×	0.003	ADNP
dolichol phosphate mannose biosynthetic process	1	1872.4×	0.003	DPM1
tRNA wobble position uridine thiolation	1	1404.3×	0.003	MOCS3
protein urmylation	1	1404.3×	0.003	MOCS3
tRNA thio-modification	1	1404.3×	0.003	MOCS3
response to oxygen levels	1	1404.3×	0.003	DPM1
GDP-mannose metabolic process	1	936.2×	0.004	DPM1
Mo-molybdopterin cofactor biosynthetic process	1	802.5×	0.004	MOCS3
dolichyl monophosphate biosynthetic process	1	624.1×	0.005	DPM1
response to carbohydrate	1	561.7×	0.005	ADNP
negative regulation of synaptic transmission	1	561.7×	0.005	ADNP
estrous cycle	1	468.1×	0.005	ADNP
short-term memory	1	432.1×	0.005	ADNP
tRNA wobble uridine modification	1	401.2×	0.005	MOCS3
protein O-linked glycosylation via mannose	1	312.1×	0.006	DPM1
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.006	DPM1
obsolete cGMP-mediated signaling	1	267.5×	0.006	ADNP
positive regulation of axon extension	1	170.2×	0.009	ADNP
GPI anchor biosynthetic process	1	165.2×	0.009	DPM1
positive regulation of synapse assembly	1	81.4×	0.017	ADNP
neuron apoptotic process	1	61.7×	0.021	ADNP
positive regulation of canonical Wnt signaling pathway	1	51.5×	0.025	ADNP
positive regulation of neuron projection development	1	45.7×	0.026	ADNP
negative regulation of neuron apoptotic process	1	37.0×	0.031	ADNP
neuron differentiation	1	33.4×	0.033	ADNP
regulation of gene expression	1	27.8×	0.038	ADNP
negative regulation of gene expression	1	23.0×	0.044	ADNP
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ADNP

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DPM1	0	0
MOCS3	0	0
ADNP	0	0
ADNP-AS1	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
MOCS3	2	Binding:2
DPM1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPM1	2.4.1.83	dolichyl-phosphate beta-D-mannosyltransferase
MOCS3	2.7.7.80, 2.8.1.11	molybdopterin-synthase adenylyltransferase, molybdopterin synthase sulfurtransferase

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	MOCS3
D	Druggable family + AlphaFold only, no drug	1	DPM1
E	Difficult family or no structure, no drug	2	ADNP, ADNP-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DPM1	1	—
MOCS3	2	—
ADNP	0	—
ADNP-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.