Isolated dystonia

Summary

Isolated dystonia (MONDO:0015494) is a disease with 1 cohort gene (5 GWAS associations across 2 studies) and 1 clinical trial.

At a glance

• Cohort genes: 1
• GWAS associations: 5
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated dystonia
Mondo ID	MONDO:0015494
Orphanet	156159
UMLS	C5679608
MedGen	1842310
GARD	0019985
Is cancer (heuristic)	no

Also known as: isolated dystonic disorder · nonsyndromic dystonia (disease) · nonsyndromic dystonic disorder · Pure dystonia

Data availability: 5 GWAS associations (2 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › isolated dystonia

Related subtypes (23): lymphatic malformation 5, Woodhouse-Sakati syndrome, severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome, torsion dystonia 7, developmental malformations-deafness-dystonia syndrome, dopa-responsive dystonia due to sepiapterin reductase deficiency, ataxia - oculomotor apraxia type 4, striatonigral degeneration, childhood-onset, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, dystonia 28, childhood-onset, combined dystonia, dystonia 30, dystonia 31, dystonia 32, dystonia 33, dystonia 34, myoclonic, dystonia 35, childhood-onset, familial idiopathic torsion dystonia, dystonia, focal, task-specific, dystonia 37, early-onset, with striatal lesions, dystonia 22, juvenile-onset, dystonia 22, adult-onset, autosomal dominant dopa-responsive dystonia

Subtypes (2): generalized dystonia, focal, segmental or multifocal dystonia

Genetics & variants

GWAS landscape

5 GWAS associations across 2 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs35880757	3e-07	NRXN1	?	0.8
rs118023704	4e-07	GRIK1 - CLDN17	?	0.88
rs5999117	6e-07	LARGE1	?	0.63
rs9514836	7e-07	TNFSF13B - HCFC2P1	?	1.48
rs7717255	9e-07	RNA5SP189 - LINC01950	?	0.52

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90428086	Laabs BH	2024	2,537	2,278	Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.
GCST90428088	Laabs BH	2024	0	0	Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs35880757	2	50400940	T>A,G		intron_variant	NRXN1	3e-07	Tier 4: intronic/intergenic
rs118023704	21	29952942	C>A		intergenic_variant	GRIK1 - CLDN17	4e-07	Tier 4: intronic/intergenic
rs5999117	22	33830597	T>A	0.05	intron_variant	LARGE1	6e-07	Tier 4: intronic/intergenic
rs9514836	13	108342011	A>C,G	0.05	intron_variant	TNFSF13B - HCFC2P1	7e-07	Tier 4: intronic/intergenic
rs7717255	5	106604145	C>A,G,T	0.05	intergenic_variant	RNA5SP189 - LINC01950	9e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 0 · 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
VPS16	Strong	Autosomal dominant	dystonia 30	5

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
VPS16	HGNC:14584	ENSG00000215305	Q9H269	Vacuolar protein sorting-associated protein 16 homolog	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS16	Vacuolar protein sorting-associated protein 16 homolog	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)
VPS16	Other/Unknown	no		Vps16_C, Vps16_N, VPS16

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
granulocyte	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS16	275	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS16	1,832

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS16	Q9H269	1

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	VPS16

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
vacuole fusion, non-autophagic	1	5617.3×	0.001	VPS16
regulation of SNARE complex assembly	1	1296.3×	0.002	VPS16
endosomal vesicle fusion	1	1123.5×	0.002	VPS16
autophagosome maturation	1	351.1×	0.004	VPS16
endosome to lysosome transport	1	337.0×	0.004	VPS16
endosomal transport	1	244.2×	0.005	VPS16
intracellular protein transport	1	64.8×	0.015	VPS16

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
VPS16	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	VPS16

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)
VPS16	0	—

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
NCT01934296	Not specified	COMPLETED	Chronic Effects of DBS in Parkinson’s Disease and Dystonia