Generalized dystonia

Summary

Generalized dystonia (MONDO:0000476) is a disease with 4 cohort genes (3 GWAS associations across 5 studies) and 2 clinical trials.

At a glance

• Cohort genes: 4
• GWAS associations: 3
• ClinVar variants: 5
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized dystonia
Mondo ID	MONDO:0000476
MeSH	D004422
Orphanet	376724
DOID	DOID:0050835
SNOMED CT	425492002
UMLS	C1848954
MedGen	341342
GARD	0021618
Is cancer (heuristic)	no

Also known as: childhood torsion disease · dystonia deformans musculorum · dystonia deformans progressiva · dystonia, Idiopathic torsion · dystonias, Idiopathic torsion · dystonias, torsion · generalised isolated dystonia · generalized isolated dystonia · Idiopathic torsion dystonia · idiopathic torsion dystonia · Idiopathic torsion dystonias · Oppenheim Ziehen disease · Oppenheim-Ziehen disease · Progressive torsion spasm · spasm, Progressive torsion · torsion disease of childhood · torsion disease, childhood · torsion dystonia · torsion dystonia, Idiopathic · torsion spasm, Progressive

Data availability: 5 ClinVar variants · 3 GWAS associations (5 studies) · 10 cell lines.

Disease family

An umbrella term covering 3 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 › generalized dystonia

Related subtypes (1): focal, segmental or multifocal dystonia

Subtypes (3): torsion dystonia 6, dystonia 21, early-onset generalized dystonia

Genetics & variants

GWAS landscape

3 GWAS associations across 5 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs867373044	7e-13	LINC02668	G	3.09
rs144374636	5e-12	CUBN	G	3.73
rs546500934	6e-12	SRGAP3	G	3.27

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477516	Verma A	2024	2,403	446,676	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477515	Verma A	2024	781	120,298	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480011	Verma A	2024	781	120,298	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481865	Verma A	2024	307	59,272	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435909	Zhou W	2018	253	395,209	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic 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	3

MAF distribution

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

Functional consequences

Consequence	Count
intron_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs867373044	10	3253920	G>C	0	intron_variant	LINC02668	7e-13	Tier 4: intronic/intergenic
rs144374636	10	16981135	G>A,C	0	intron_variant	CUBN	5e-12	Tier 4: intronic/intergenic
rs546500934	3	9080671	G>A,T	0	intron_variant	SRGAP3	6e-12	Tier 4: intronic/intergenic

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
813004	NM_014727.3(KMT2B):c.6517_6518insA (p.Arg2173fs)	KMT2B	Pathogenic	no assertion criteria provided
263251	NM_000360.4(TH):c.1200+9C>T	TH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373983	NM_004082.5(DCTN1):c.581C>T (p.Pro194Leu)	DCTN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
375458	NM_000168.6(GLI3):c.2000G>T (p.Arg667Leu)	GLI3	Uncertain significance	criteria provided, multiple submitters, no conflicts
549493	NM_014727.3(KMT2B):c.4955G>A (p.Gly1652Asp)	KMT2B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TH	Orphanet:101150	Autosomal recessive dopa-responsive dystonia
KMT2B	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2B	Orphanet:589618	Dystonia 28
DCTN1	Orphanet:139589	Distal hereditary motor neuropathy type 7
DCTN1	Orphanet:178509	Perry syndrome
DCTN1	Orphanet:803	Amyotrophic lateral sclerosis
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TH	HGNC:11782	ENSG00000180176	P07101	Tyrosine 3-monooxygenase	clinvar
KMT2B	HGNC:15840	ENSG00000272333	Q9UMN6	Histone-lysine N-methyltransferase 2B	clinvar
DCTN1	HGNC:2711	ENSG00000204843	Q14203	Dynactin subunit 1	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TH	Tyrosine 3-monooxygenase	Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.
KMT2B	Histone-lysine N-methyltransferase 2B	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism.
DCTN1	Dynactin subunit 1	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Transcription factor	2	4.1×	0.223
Enzyme (other)	1	3.0×	0.441
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TH	Enzyme (other)	yes	1.14.16.2	ArAA_hydroxylase, Tyr_3_mOase, ArAA_hydroxylase_Fe/CU_BS
KMT2B	Transcription factor	no		SET_dom, Znf_PHD, Znf_CXXC
DCTN1	Other/Unknown	no		CAP-Gly_domain, Dynactin, CAP-Gly_dom_sf
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
left testis	1
lower esophagus mucosa	1
right testis	1
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1
olfactory bulb	1
tendon of biceps brachii	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TH	147	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis
KMT2B	269	ubiquitous	marker	right testis, left testis, lower esophagus mucosa
DCTN1	275	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCTN1	3,654
TH	3,526
GLI3	2,825
KMT2B	2,639

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCTN1	Q14203	13
TH	P07101	7
KMT2B	Q9UMN6	4
GLI3	P10071	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Catecholamine biosynthesis	1	713.8×	0.039	TH
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	407.9×	0.039	GLI3
RUNX2 regulates osteoblast differentiation	1	114.2×	0.046	GLI3
Formation of WDR5-containing histone-modifying complexes	1	66.4×	0.046	KMT2B
Deactivation of the beta-catenin transactivating complex	1	58.3×	0.046	KMT2B
GLI3 is processed to GLI3R by the proteasome	1	56.0×	0.046	GLI3
XBP1(S) activates chaperone genes	1	53.9×	0.046	DCTN1
COPI-independent Golgi-to-ER retrograde traffic	1	51.9×	0.046	DCTN1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	48.4×	0.046	DCTN1
Hedgehog ‘off’ state	1	44.6×	0.046	GLI3
PKMTs methylate histone lysines	1	40.2×	0.046	KMT2B
Loss of Nlp from mitotic centrosomes	1	39.6×	0.046	DCTN1
Loss of proteins required for interphase microtubule organization from the centrosome	1	39.6×	0.046	DCTN1
Hedgehog ‘on’ state	1	39.6×	0.046	GLI3
Epigenetic regulation by WDR5-containing histone modifying complexes	1	38.6×	0.046	KMT2B
AURKA Activation by TPX2	1	38.1×	0.046	DCTN1
Signaling by ALK fusions and activated point mutants	1	37.6×	0.046	DCTN1
Transcriptional regulation by RUNX1	1	36.6×	0.046	KMT2B
Recruitment of mitotic centrosome proteins and complexes	1	34.0×	0.046	DCTN1
Regulation of PLK1 Activity at G2/M Transition	1	31.7×	0.046	DCTN1
Formation of the beta-catenin:TCF transactivating complex	1	30.1×	0.046	KMT2B
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	30.1×	0.046	KMT2B
Recruitment of NuMA to mitotic centrosomes	1	29.1×	0.046	DCTN1
Anchoring of the basal body to the plasma membrane	1	28.3×	0.046	DCTN1
COPI-mediated anterograde transport	1	27.4×	0.046	DCTN1
MHC class II antigen presentation	1	22.3×	0.054	DCTN1
Chromatin organization	1	20.4×	0.057	KMT2B
Chromatin modifying enzymes	1	18.1×	0.061	KMT2B
Epigenetic regulation of gene expression	1	17.8×	0.061	KMT2B
RNA Polymerase II Transcription	1	5.6×	0.177	KMT2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dopamine biosynthetic process from tyrosine	1	4213.0×	0.004	TH
lateral ganglionic eminence cell proliferation	1	4213.0×	0.004	GLI3
lambdoid suture morphogenesis	1	4213.0×	0.004	GLI3
sagittal suture morphogenesis	1	4213.0×	0.004	GLI3
mammary gland specification	1	4213.0×	0.004	GLI3
anterior semicircular canal development	1	4213.0×	0.004	GLI3
lateral semicircular canal development	1	4213.0×	0.004	GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	2106.5×	0.005	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	2106.5×	0.005	GLI3
epinephrine biosynthetic process	1	2106.5×	0.005	TH
larynx morphogenesis	1	2106.5×	0.005	GLI3
positive regulation of neuromuscular junction development	1	2106.5×	0.005	DCTN1
nose morphogenesis	1	1404.3×	0.005	GLI3
negative regulation of alpha-beta T cell differentiation	1	1404.3×	0.005	GLI3
frontal suture morphogenesis	1	1404.3×	0.005	GLI3
cell differentiation involved in kidney development	1	1404.3×	0.005	GLI3
hindgut morphogenesis	1	1053.2×	0.006	GLI3
serotonin biosynthetic process	1	1053.2×	0.006	TH
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	1053.2×	0.006	GLI3
heart development	2	39.4×	0.006	TH, GLI3
optic nerve morphogenesis	1	842.6×	0.006	GLI3
regulation of bone development	1	842.6×	0.006	GLI3
mating behavior	1	702.2×	0.007	TH
forebrain radial glial cell differentiation	1	702.2×	0.007	GLI3
hyaloid vascular plexus regression	1	601.9×	0.007	TH
synaptic transmission, dopaminergic	1	526.6×	0.007	TH
forebrain dorsal/ventral pattern formation	1	526.6×	0.007	GLI3
norepinephrine biosynthetic process	1	526.6×	0.007	TH
tongue development	1	526.6×	0.007	GLI3
positive regulation of microtubule nucleation	1	526.6×	0.007	DCTN1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TH	0	0
KMT2B	0	0
DCTN1	0	0
GLI3	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
KMT2B	15	Binding:15
TH	8	Binding:8
DCTN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TH	1.14.16.2	tyrosine 3-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	TH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	KMT2B, DCTN1, GLI3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TH	8	—
KMT2B	15	—
DCTN1	1	—
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT02509338	Not specified	TERMINATED	Validation of the Implantation of a New Electrode for the Treatment of Dystonia