mucopolysaccharidosis type 3D

Summary

mucopolysaccharidosis type 3D (MONDO:0009658) is a disease caused by GNS (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (Netherlands) [Orphanet-validated]
• Causal gene: GNS (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 755
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.1	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.1	Australia	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mucopolysaccharidosis type 3D
Mondo ID	MONDO:0009658
OMIM	252940
Orphanet	79272
DOID	DOID:0111402
ICD-11	1780990193
NCIT	C84900
SNOMED CT	15892005
UMLS	C0086650
MedGen	88602
GARD	0007074
Is cancer (heuristic)	no

Also known as: glucosamine N-acetyl-6-sulfatase deficiency · GNS deficiency · MPS III D · MPS IIID · MPS3D · MPSIIID · Mucopoly-saccharidosis type 3D · mucopolysaccharidosis type 3D · mucopolysaccharidosis type IIID · mucopolysaccharidosis, type IIID · N-acetylglucosamine-6-sulfate sulfatase deficiency · Sanfilippo D · Sanfilippo syndrome D · Sanfilippo syndrome type D

Data availability: 755 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › mucopolysaccharidosis type 3 › mucopolysaccharidosis type 3D

Related subtypes (3): mucopolysaccharidosis type 3A, mucopolysaccharidosis type 3B, mucopolysaccharidosis type 3C

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

600 retrieved; paginated sample, class counts are floors:

358 likely benign, 162 uncertain significance, 43 pathogenic, 13 benign, 10 likely pathogenic, 8 pathogenic/likely pathogenic, 3 benign/likely benign, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069391	NM_002076.4(GNS):c.355del (p.Ser119fs)	GNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072342	NM_002076.4(GNS):c.506G>A (p.Trp169Ter)	GNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1073389	NM_002076.4(GNS):c.538A>T (p.Lys180Ter)	GNS	Pathogenic	criteria provided, single submitter
1075562	NM_002076.4(GNS):c.887_888del (p.Leu296fs)	GNS	Pathogenic	criteria provided, single submitter
1075633	NM_002076.4(GNS):c.1414C>T (p.Gln472Ter)	GNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1075873	NM_002076.4(GNS):c.638del (p.Leu213fs)	GNS	Pathogenic	criteria provided, single submitter
1299282	NM_002076.4(GNS):c.875+2del	GNS	Pathogenic	criteria provided, single submitter
1323028	NM_002076.4(GNS):c.459+1_459+2del	GNS	Pathogenic	criteria provided, single submitter
1354681	NM_002076.4(GNS):c.386dup (p.Asn130fs)	GNS	Pathogenic	criteria provided, single submitter
1358146	NM_002076.4(GNS):c.526G>T (p.Glu176Ter)	GNS	Pathogenic	criteria provided, single submitter
1360836	NM_002076.4(GNS):c.1459C>T (p.Gln487Ter)	GNS	Pathogenic	criteria provided, single submitter
1391029	NM_002076.4(GNS):c.1021_1022insTCTT (p.Arg341fs)	GNS	Pathogenic	criteria provided, single submitter
1402148	NM_002076.4(GNS):c.379del (p.Gln127fs)	GNS	Pathogenic	criteria provided, single submitter
1408205	NM_002076.4(GNS):c.118del (p.Val40fs)	GNS	Pathogenic	criteria provided, single submitter
1413883	NM_002076.4(GNS):c.23del (p.Pro8fs)	GNS	Pathogenic	criteria provided, single submitter
1414671	NM_002076.4(GNS):c.1249C>T (p.Gln417Ter)	GNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1418992	NM_002076.4(GNS):c.841_842insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGACTAATTCTT (p.Ser280_Ser281insPhePhePhePhePhePhePheXaaXaaXaaXaaProArgAspProProAlaSerAlaSerGlnSerAlaGlyIleThrGlyValSerHisArgAlaArgProThrAsnSer)	GNS	Pathogenic	criteria provided, single submitter
1452923	NM_002076.4(GNS):c.875+1G>A	GNS	Pathogenic	criteria provided, single submitter
1453303	NM_002076.4(GNS):c.654C>A (p.Tyr218Ter)	GNS	Pathogenic	criteria provided, single submitter
1453450	NM_002076.4(GNS):c.4del (p.Arg2fs)	GNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455915	NM_002076.4(GNS):c.214_220del (p.Ala72fs)	GNS	Pathogenic	criteria provided, single submitter
1459210	NM_002076.4(GNS):c.148dup (p.Val50fs)	GNS	Pathogenic	criteria provided, single submitter
1460021	NM_002076.4(GNS):c.1420-2A>G	GNS	Pathogenic	criteria provided, single submitter
1722378	NM_002076.4(GNS):c.714G>A (p.Trp238Ter)	GNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1936254	NM_002076.4(GNS):c.257_258del (p.Val86fs)	GNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1961741	NM_002076.4(GNS):c.255T>G (p.Tyr85Ter)	GNS	Pathogenic	criteria provided, single submitter
1974056	NM_002076.4(GNS):c.1414dup (p.Gln472fs)	GNS	Pathogenic	criteria provided, single submitter
1999386	NM_002076.4(GNS):c.286_287del (p.Ala96fs)	GNS	Pathogenic	criteria provided, single submitter
2031201	NM_002076.4(GNS):c.974C>G (p.Ser325Ter)	GNS	Pathogenic	criteria provided, single submitter
2033415	NM_002076.4(GNS):c.246del (p.Ser83fs)	GNS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GNS	Definitive	Autosomal recessive	mucopolysaccharidosis type 3D	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNS	Orphanet:79272	Sanfilippo syndrome type D

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
GNS	HGNC:4422	ENSG00000135677	P15586	N-acetylglucosamine-6-sulfatase	gencc,clinvar
C12orf56	HGNC:26967	ENSG00000185306	Q8IXR9	Uncharacterized protein C12orf56	clinvar
MOK	HGNC:9833	ENSG00000080823	Q9UQ07	MAPK/MAK/MRK overlapping kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNS	N-acetylglucosamine-6-sulfatase	Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units of heparin sulfate and keratan sulfate.
MOK	MAPK/MAK/MRK overlapping kinase	Able to phosphorylate several exogenous substrates and to undergo autophosphorylation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Phosphatase	1	28.0×	0.106
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNS	Phosphatase	yes	3.1.6.14	Sulfatase_N, GlcNAc_6-SO4ase, Alkaline_phosphatase_core_sf
C12orf56	Other/Unknown	no		DUF4551
MOK	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
adrenal tissue	1
nephron tubule	1
visceral pleura	1
lower esophagus mucosa	1
primordial germ cell in gonad	1
sperm	1
left testis	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNS	299	ubiquitous	marker	adrenal tissue, visceral pleura, nephron tubule
C12orf56	141	tissue_specific	marker	sperm, lower esophagus mucosa, primordial germ cell in gonad
MOK	208	ubiquitous	marker	right uterine tube, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNS	1,282
MOK	1,000
C12orf56	170

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GNS	P15586	89.29
MOK	Q9UQ07	76.98
C12orf56	Q8IXR9	71.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS IIID - Sanfilippo syndrome D	1	11420.0×	4e-04	GNS
Keratan sulfate degradation	1	713.8×	0.003	GNS
Lysosome Vesicle Biogenesis	1	326.3×	0.004	GNS
Neutrophil degranulation	1	23.1×	0.043	GNS

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
keratan sulfate proteoglycan catabolic process	1	2808.7×	0.001	GNS
glycosaminoglycan catabolic process	1	1203.7×	0.001	GNS
heparan sulfate proteoglycan catabolic process	1	936.2×	0.001	GNS
intracellular signal transduction	1	19.1×	0.052	MOK

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
GNS	0	0
C12orf56	0	0
MOK	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
MOK	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNS	3.1.6.14	N-acetylglucosamine-6-sulfatase

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	0
D	Druggable family + AlphaFold only, no drug	2	GNS, MOK
E	Difficult family or no structure, no drug	1	C12orf56

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)
GNS	0	—
C12orf56	0	—
MOK	26	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05648851	Not specified	COMPLETED	A Natural History Study of Sanfilippo Syndrome Type D