congenital disorder of glycosylation, type IAA

Summary

congenital disorder of glycosylation, type IAA (MONDO:0014904) is a disease caused by NUS1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: NUS1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 389

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of glycosylation, type IAA
Mondo ID	MONDO:0014904
OMIM	617082
DOID	DOID:0080553
UMLS	C4310727
MedGen	934694
GARD	0025031
Is cancer (heuristic)	no

Also known as: CDG1AA · congenital disorder of glycosylation, type 1aa · congenital disorder of glycosylation, type IAA · congenital disorder of glycosylation, type IAA; CDG1AA

Data availability: 389 ClinVar variants · 3 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 › congenital disorder of glycosylation, type IAA

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, 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 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

389 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 144 likely benign, 33 pathogenic, 11 conflicting classifications of pathogenicity, 7 benign, 6 likely pathogenic, 3 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2427242	NC_000006.11:g.(?116441236)(119252888_?)del	ASF1A	Pathogenic	criteria provided, single submitter
1011945	NC_000006.11:g.(?118028088)(118028178_?)del	NUS1	Pathogenic	criteria provided, single submitter
1351781	NM_138459.5(NUS1):c.765_769dup (p.His257fs)	NUS1	Pathogenic	criteria provided, single submitter
1357547	NM_138459.5(NUS1):c.719T>G (p.Leu240Ter)	NUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386407	NM_138459.5(NUS1):c.15C>A (p.Tyr5Ter)	NUS1	Pathogenic	criteria provided, single submitter
1453662	NM_138459.5(NUS1):c.74_75delinsAA (p.Trp25Ter)	NUS1	Pathogenic	criteria provided, single submitter
1460025	NC_000006.11:g.(?118014185)(118014350_?)del	NUS1	Pathogenic	criteria provided, single submitter
1492830	NM_138459.5(NUS1):c.868C>T (p.Arg290Cys)	NUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2002848	NM_138459.5(NUS1):c.250dup (p.Arg84fs)	NUS1	Pathogenic	criteria provided, single submitter
2101645	NM_138459.5(NUS1):c.695C>G (p.Ser232Ter)	NUS1	Pathogenic	criteria provided, single submitter
2112620	NM_138459.5(NUS1):c.482del (p.Gly161fs)	NUS1	Pathogenic	criteria provided, single submitter
2427241	NC_000006.11:g.(?117996834)(117997268_?)del	NUS1	Pathogenic	criteria provided, single submitter
2747349	NM_138459.5(NUS1):c.234_280dup (p.Leu94fs)	NUS1	Pathogenic	criteria provided, single submitter
2758134	NM_138459.5(NUS1):c.378del (p.Val127fs)	NUS1	Pathogenic	criteria provided, single submitter
2769035	NM_138459.5(NUS1):c.836_837dup (p.Ala280fs)	NUS1	Pathogenic	criteria provided, single submitter
2822088	NM_138459.5(NUS1):c.565A>T (p.Lys189Ter)	NUS1	Pathogenic	criteria provided, single submitter
2838328	NM_138459.5(NUS1):c.368_372del (p.Trp123fs)	NUS1	Pathogenic	criteria provided, single submitter
2851443	NM_138459.5(NUS1):c.415+2T>G	NUS1	Pathogenic	criteria provided, single submitter
2851556	NM_138459.5(NUS1):c.110G>A (p.Trp37Ter)	NUS1	Pathogenic	criteria provided, single submitter
2852858	NM_138459.5(NUS1):c.225del (p.Ser76fs)	NUS1	Pathogenic	criteria provided, single submitter
2860526	NM_138459.5(NUS1):c.94_101del (p.Thr32fs)	NUS1	Pathogenic	criteria provided, single submitter
2866116	NM_138459.5(NUS1):c.119_132dup (p.Ser45fs)	NUS1	Pathogenic	criteria provided, single submitter
3246047	NC_000006.11:g.(?117996834)(118028178_?)del	NUS1	Pathogenic	criteria provided, single submitter
3377426	NM_138459.5(NUS1):c.51T>A (p.Cys17Ter)	NUS1	Pathogenic	criteria provided, single submitter
3647294	NM_138459.5(NUS1):c.111del (p.Trp37fs)	NUS1	Pathogenic	criteria provided, single submitter
3656390	NM_138459.5(NUS1):c.427del (p.Arg143fs)	NUS1	Pathogenic	criteria provided, single submitter
3723608	NM_138459.5(NUS1):c.692-1G>C	NUS1	Pathogenic	criteria provided, single submitter
3725504	NM_138459.5(NUS1):c.16G>T (p.Glu6Ter)	NUS1	Pathogenic	criteria provided, single submitter
4722823	NM_138459.5(NUS1):c.302del (p.Met101fs)	NUS1	Pathogenic	criteria provided, single submitter
4725352	NM_138459.5(NUS1):c.98G>A (p.Trp33Ter)	NUS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
NUS1	Strong	Autosomal recessive	congenital disorder of glycosylation, type IAA	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NUS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
NUS1	HGNC:21042	ENSG00000153989	Q96E22	Dehydrodolichyl diphosphate synthase complex subunit NUS1	gencc,clinvar
ASF1A	HGNC:20995	ENSG00000111875	Q9Y294	Histone chaperone ASF1A	clinvar
DCBLD1	HGNC:21479	ENSG00000164465	Q8N8Z6	Discoidin, CUB and LCCL domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NUS1	Dehydrodolichyl diphosphate synthase complex subunit NUS1	With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
ASF1A	Histone chaperone ASF1A	Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NUS1	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_sf, Nus1/NgBR
ASF1A	Other/Unknown	no		ASF1-like, ASF1-like_sf
DCBLD1	Other/Unknown	no		FA58C, CUB_dom, LCCL

Expression context

Cohort genes with no expression data: 0.

3 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
islet of Langerhans	2
secondary oocyte	2
endometrium	1
tibia	1
adrenal tissue	1
oocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NUS1	255	broad	marker	endometrium, tibia, islet of Langerhans
ASF1A	294	ubiquitous	marker	oocyte, secondary oocyte, adrenal tissue
DCBLD1	218	ubiquitous	marker	secondary oocyte, islet of Langerhans, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASF1A	3,540
NUS1	2,058
DCBLD1	513

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASF1A	Q9Y294	20
NUS1	Q96E22	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DCBLD1	Q8N8Z6	68.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Defective DHDDS causes RP59	1	2855.0×	0.002	NUS1
Synthesis of dolichyl-phosphate	1	815.7×	0.004	NUS1
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	335.9×	0.007	ASF1A
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.020	ASF1A
Cellular Senescence	1	68.8×	0.020	ASF1A
Cellular responses to stress	1	18.4×	0.062	ASF1A
Cellular responses to stimuli	1	15.7×	0.063	ASF1A

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
dolichyl diphosphate biosynthetic process	1	4213.0×	0.004	NUS1
regulation of intracellular cholesterol transport	1	2106.5×	0.004	NUS1
DNA replication-dependent chromatin assembly	1	1053.2×	0.004	ASF1A
dolichyl monophosphate biosynthetic process	1	936.2×	0.004	NUS1
positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	842.6×	0.004	NUS1
vascular endothelial growth factor signaling pathway	1	526.6×	0.005	NUS1
muscle cell differentiation	1	421.3×	0.005	ASF1A
positive regulation of cell migration involved in sprouting angiogenesis	1	366.4×	0.005	NUS1
DNA repair-dependent chromatin remodeling	1	337.0×	0.005	ASF1A
replication fork processing	1	210.7×	0.008	ASF1A
cholesterol homeostasis	1	78.0×	0.019	NUS1
nucleosome assembly	1	70.2×	0.019	ASF1A
osteoblast differentiation	1	60.6×	0.020	ASF1A
DNA repair	1	31.9×	0.034	ASF1A
angiogenesis	1	31.2×	0.034	NUS1
cell differentiation	1	14.6×	0.068	NUS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NUS1	0	0
ASF1A	0	0
DCBLD1	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
ASF1A	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NUS1	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]

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	NUS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ASF1A, DCBLD1

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)
NUS1	0	—
ASF1A	3	—
DCBLD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.