Mucopolysaccharidosis-plus syndrome

Summary

Mucopolysaccharidosis-plus syndrome (MONDO:0015012) is a disease caused by VPS33A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VPS33A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11
• Phenotypes (HPO): 71

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000093	Proteinuria	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000943	Dysostosis multiplex	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0001433	Hepatosplenomegaly	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002086	Abnormality of the respiratory system	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0000100	Nephrotic syndrome	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0002092	Pulmonary arterial hypertension	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002159	Heparan sulfate excretion in urine	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0003073	Hypoalbuminemia	Frequent (30-79%)
HP:0003541	Urinary glycosaminoglycan excretion	Frequent (30-79%)
HP:0006536	Airway obstruction	Frequent (30-79%)
HP:0031123	Recurrent gastroenteritis	Frequent (30-79%)
HP:0000105	Enlarged kidney	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0000629	Periorbital fullness	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001552	Barrel-shaped chest	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0001928	Abnormality of coagulation	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mucopolysaccharidosis-plus syndrome
Mondo ID	MONDO:0015012
OMIM	617303
Orphanet	505248
SNOMED CT	1187113001
UMLS	C4310627
MedGen	934594
GARD	0017944
Is cancer (heuristic)	no

Also known as: MPSPS · mucopolysaccharidosis-like plus disease · mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders · mucopolysaccharidosis-plus syndrome

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › mucopolysaccharidosis-plus syndrome

Related subtypes (58): lower respiratory tract disorder, respiratory system cancer, respiratory system benign neoplasm, allergic respiratory disease, paranasal sinus disorder, upper respiratory tract disorder, pertussis, severe acute respiratory syndrome, sleep apnea syndrome, diaphragm disorder, pulmonary tuberculosis, altitude sickness, perinatal asphyxia, pulmonary nodular lymphoid hyperplasia, tracheobronchopathia osteochondroplastica, Williams-Campbell syndrome, cystic fibrosis, growth delay-hydrocephaly-lung hypoplasia syndrome, laryngo-onycho-cutaneous syndrome, congenital pulmonary lymphangiectasia, familial primary pulmonary hypoplasia, Mounier-Kuhn syndrome, Young syndrome, lung agenesis-heart defect-thumb anomalies syndrome, sudden infant death-dysgenesis of the testes syndrome, alpha 1-antitrypsin deficiency, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, autoimmune interstitial lung disease-arthritis syndrome, congenital bronchobiliary fistula, bronchogenic cyst, primary ciliary dyskinesia, congenital pulmonary airway malformation, transient hyperammonemia of the newborn, congenital pulmonary sequestration, Siegler-Brewer-Carey syndrome, tracheal agenesis, 16q24.1 microdeletion syndrome, staphylococcal necrotizing pneumonia, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, plastic bronchitis, recurrent respiratory papillomatosis, IgG4-related mediastinitis, bronchopulmonary dysplasia, infantile apnea, diffuse alveolar hemorrhage, respiratory or thoracic malformation, pulmonary agenesis, eosinophilic granuloma, disorder of pharynx, respiratory tract neoplasm, pulmonary alveolar proteinosis with hypogammaglobulinemia, respiratory tract infectious disorder, Middle East respiratory syndrome, reactive airway disease, acinar dysplasia, pulmonary hypoplasia, isolated left bronchial isomerism, bronchiectasis and nasal polyposis

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

11 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 benign, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374985	NM_022916.6(VPS33A):c.1492C>T (p.Arg498Trp)	VPS33A	Likely pathogenic	criteria provided, single submitter
1029869	NM_022916.6(VPS33A):c.1420A>G (p.Met474Val)	VPS33A	Uncertain significance	criteria provided, single submitter
1029870	NM_022916.6(VPS33A):c.1457C>T (p.Ser486Leu)	VPS33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500222	NM_022916.6(VPS33A):c.599G>C (p.Arg200Pro)	VPS33A	Uncertain significance	criteria provided, single submitter
3055566	NM_022916.6(VPS33A):c.102+174del	VPS33A	Uncertain significance	criteria provided, single submitter
4081001	NM_022916.6(VPS33A):c.1441-571A>G	VPS33A	Uncertain significance	criteria provided, single submitter
1237523	NM_022916.6(VPS33A):c.1440+23G>A	VPS33A	Benign	criteria provided, multiple submitters, no conflicts
1256644	NM_022916.6(VPS33A):c.1165-82GT[19]	VPS33A	Benign	criteria provided, multiple submitters, no conflicts
1258741	NM_022916.6(VPS33A):c.102+167dup	VPS33A	Benign	criteria provided, multiple submitters, no conflicts
708440	NM_022916.6(VPS33A):c.624G>A (p.Arg208=)	VPS33A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
778667	NM_022916.6(VPS33A):c.282T>C (p.Ala94=)	VPS33A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
VPS33A	Strong	Autosomal recessive	mucopolysaccharidosis-plus syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS33A	Orphanet:505248	Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS33A	HGNC:18179	ENSG00000139719	Q96AX1	Vacuolar protein sorting-associated protein 33A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS33A	Vacuolar protein sorting-associated protein 33A	Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS33A	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
endothelial cell	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS33A	249	ubiquitous	yes	buccal mucosa cell, monocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS33A	2,087

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS33A	Q96AX1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
SARS-CoV-2 modulates autophagy	1	1038.2×	1e-03	VPS33A

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of developmental pigmentation	1	5617.3×	0.002	VPS33A
melanosome localization	1	3370.4×	0.002	VPS33A
obsolete regulation of lysosomal lumen pH	1	2106.5×	0.002	VPS33A
regulation of SNARE complex assembly	1	1296.3×	0.002	VPS33A
endosomal vesicle fusion	1	1123.5×	0.002	VPS33A
platelet formation	1	702.2×	0.003	VPS33A
lysosome localization	1	526.6×	0.003	VPS33A
autophagosome maturation	1	351.1×	0.004	VPS33A
endosome to lysosome transport	1	337.0×	0.004	VPS33A
vesicle-mediated transport	1	96.3×	0.011	VPS33A
intracellular protein transport	1	64.8×	0.015	VPS33A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS33A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	VPS33A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS33A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.