DDOST-congenital disorder of glycosylation

Summary

DDOST-congenital disorder of glycosylation (MONDO:0013789) is a disease caused by DDOST (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDOST (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 208
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000565	Esotropia	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001397	Hepatic steatosis	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003256	Abnormality of the coagulation cascade	Very frequent (80-99%)
HP:0003429	CNS hypomyelination	Very frequent (80-99%)
HP:0003642	Type I transferrin isoform profile	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005616	Accelerated skeletal maturation	Very frequent (80-99%)
HP:0007301	Oromotor apraxia	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0410018	Recurrent ear infections	Very frequent (80-99%)
HP:0000958	Dry skin	Occasional (5-29%)
HP:0009125	Lipodystrophy	Occasional (5-29%)
HP:0000832	Primary hypothyroidism	Very rare (<1-4%)
HP:0012593	Nephrotic range proteinuria	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	DDOST-congenital disorder of glycosylation
Mondo ID	MONDO:0013789
OMIM	614507
Orphanet	300536
DOID	DOID:0080569
SNOMED CT	733083006
UMLS	C3281084
MedGen	482714
GARD	0012398
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type · carbohydrate deficient glycoprotein syndrome type Ir · CDG syndrome type Ir · CDG-Ir · CDG1R · congenital disorder of glycosylation type 1r · congenital disorder of glycosylation type Ir · congenital disorder of glycosylation, type Ir · DDOST-CDG · DDOST-CDG (CDG-Ir) · DDOST-congenital disorder of glycosylation

Data availability: 208 ClinVar variants · 4 GenCC gene-disease records.

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 › DDOST-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, DPAGT1-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, 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

208 retrieved; paginated sample, class counts are floors:

107 uncertain significance, 68 likely benign, 14 benign, 9 benign/likely benign, 5 conflicting classifications of pathogenicity, 2 pathogenic, 2 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30245	NM_005216.5(DDOST):c.1214_1235del (p.Ile405fs)	DDOST	Pathogenic	criteria provided, single submitter
30246	NM_005216.5(DDOST):c.599G>A (p.Gly200Asp)	DDOST	Pathogenic	criteria provided, single submitter
522968	NM_005216.5(DDOST):c.645G>C (p.Gln215His)	DDOST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449294	NM_005216.5(DDOST):c.10A>G (p.Ser4Gly)	DDOST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1460715	NC_000001.11:g.20661370G>A	DDOST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166992	NM_005216.5(DDOST):c.1148C>T (p.Thr383Ile)	DDOST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151283	NC_000001.11:g.20661386A>C	DDOST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2161338	NM_005216.5(DDOST):c.795G>A (p.Arg265=)	DDOST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424757	NC_000001.10:g.(?19199339)(22987879_?)dup	AKR7A2	Uncertain significance	criteria provided, single submitter
1002236	NM_005216.5(DDOST):c.710G>A (p.Arg237His)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009035	NM_005216.5(DDOST):c.627G>A (p.Pro209=)	DDOST	Uncertain significance	criteria provided, single submitter
1031522	NM_005216.5(DDOST):c.573C>A (p.Asn191Lys)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1056150	NM_005216.5(DDOST):c.142C>T (p.Arg48Trp)	DDOST	Uncertain significance	criteria provided, single submitter
1058001	NM_005216.5(DDOST):c.619T>G (p.Phe207Val)	DDOST	Uncertain significance	criteria provided, single submitter
1063745	NM_005216.5(DDOST):c.733G>A (p.Asp245Asn)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349560	NM_005216.5(DDOST):c.712G>A (p.Val238Ile)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367117	NM_005216.5(DDOST):c.509T>C (p.Val170Ala)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1373128	NM_005216.5(DDOST):c.502A>G (p.Thr168Ala)	DDOST	Uncertain significance	criteria provided, single submitter
1382384	NM_005216.5(DDOST):c.917A>G (p.Asn306Ser)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1386079	NM_005216.5(DDOST):c.597G>A (p.Thr199=)	DDOST	Uncertain significance	criteria provided, single submitter
1389493	NM_005216.5(DDOST):c.1196C>T (p.Thr399Met)	DDOST	Uncertain significance	criteria provided, single submitter
1397292	NM_005216.5(DDOST):c.709C>T (p.Arg237Cys)	DDOST	Uncertain significance	criteria provided, single submitter
1398039	NM_005216.5(DDOST):c.1096G>A (p.Asp366Asn)	DDOST	Uncertain significance	criteria provided, single submitter
1410490	NM_005216.5(DDOST):c.188A>C (p.Asp63Ala)	DDOST	Uncertain significance	criteria provided, single submitter
1413206	NM_005216.5(DDOST):c.851AGG[2] (p.Glu286del)	DDOST	Uncertain significance	criteria provided, single submitter
1414963	NM_005216.5(DDOST):c.782C>T (p.Pro261Leu)	DDOST	Uncertain significance	criteria provided, single submitter
1418877	NM_005216.5(DDOST):c.236A>G (p.Asn79Ser)	DDOST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1421823	NM_005216.5(DDOST):c.109C>T (p.Leu37Phe)	DDOST	Uncertain significance	criteria provided, single submitter
1440690	NM_005216.5(DDOST):c.869G>T (p.Arg290Leu)	DDOST	Uncertain significance	criteria provided, single submitter
1441109	NM_005216.5(DDOST):c.427C>G (p.His143Asp)	DDOST	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
DDOST	Definitive	Autosomal recessive	DDOST-congenital disorder of glycosylation	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDOST	Orphanet:300536	DDOST-CDG

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDOST	HGNC:2728	ENSG00000244038	P39656	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 48 kDa subunit	gencc,clinvar
AKR7A2	HGNC:389	ENSG00000053371	O43488	Aflatoxin B1 aldehyde reductase member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDOST	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 48 kDa subunit	Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Se…
AKR7A2	Aflatoxin B1 aldehyde reductase member 2	Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDOST	Enzyme (other)	yes	2.4.99.18	DDOST_48_kDa_subunit, OST48_N, OST48_MD
AKR7A2	Other/Unknown	no		NADP_OxRdtase_dom, NAD(P)_OxRdtase_dom_sf, AKR_Detox_Biosynth

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
corpus epididymis	1
stromal cell of endometrium	1
duodenum	1
mucosa of transverse colon	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDOST	284	ubiquitous	marker	corpus epididymis, stromal cell of endometrium, body of pancreas
AKR7A2	283	ubiquitous	marker	mucosa of transverse colon, duodenum, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDOST	3,163
AKR7A2	1,880

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDOST	P39656	6
AKR7A2	O43488	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Advanced glycosylation endproduct receptor signaling	1	356.9×	0.014	DDOST
Aflatoxin activation and detoxification	1	317.2×	0.014	AKR7A2
PD-L1(CD274) glycosylation and translocation to plasma membrane	1	259.6×	0.014	DDOST
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.016	DDOST
Maturation of spike protein	1	132.8×	0.017	DDOST
Maturation of DENV proteins	1	105.7×	0.017	DDOST
Biological oxidations	1	64.9×	0.024	AKR7A2
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.027	DDOST
Asparagine N-linked glycosylation	1	30.1×	0.040	DDOST
Neutrophil degranulation	1	11.5×	0.093	DDOST
Metabolism	1	5.8×	0.165	AKR7A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
daunorubicin metabolic process	1	766.0×	0.006	AKR7A2
aldehyde metabolic process	1	648.1×	0.006	AKR7A2
doxorubicin metabolic process	1	648.1×	0.006	AKR7A2
obsolete protein N-linked glycosylation via asparagine	1	337.0×	0.008	DDOST
response to cytokine	1	187.2×	0.011	DDOST
glycoprotein biosynthetic process	1	168.5×	0.011	DDOST
protein N-linked glycosylation	1	131.7×	0.011	DDOST
T cell activation	1	129.6×	0.011	DDOST
carbohydrate metabolic process	1	68.0×	0.017	AKR7A2
regulation of protein stability	1	62.9×	0.017	DDOST
lipid metabolic process	1	45.8×	0.022	AKR7A2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDOST	0	0
AKR7A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DDOST	2	Binding:2
AKR7A2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDOST	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	DDOST
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AKR7A2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DDOST	2	—
AKR7A2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.