Torsion dystonia 6

Summary

Torsion dystonia 6 (MONDO:0011264) is a disease caused by THAP1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: THAP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 171
• Phenotypes (HPO): 9
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		53	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0007325	Generalized dystonia	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0012049	Laryngeal dystonia	Occasional (5-29%)
HP:0012179	Craniofacial dystonia	Occasional (5-29%)
HP:0031008	Lingual dystonia	Occasional (5-29%)
HP:0002451	Limb dystonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	torsion dystonia 6
Mondo ID	MONDO:0011264
MeSH	C538003
OMIM	602629
Orphanet	98806
DOID	DOID:0090039
NCIT	C156361
SNOMED CT	702448007
UMLS	C1414216
MedGen	236274
GARD	0009630
Is cancer (heuristic)	no

Also known as: adolescent-onset dystonia of mixed type · dystonia 6 · dystonia 6, torsion · DYT-THAP1 · DYT6 · generalised cervical and upper-limb-onset dystonia · generalised isolated dystonia caused by mutation in THAP1 · generalized cervical and upper-limb-onset dystonia · generalized isolated dystonia caused by mutation in THAP1 · idiopathic torsion dystonia of mixed type · THAP1 generalised isolated dystonia · THAP1 generalized isolated dystonia · torsion dystonia adult onset mixed type · torsion dystonia type 6

Data availability: 171 ClinVar variants · 6 GenCC gene-disease records · 10 cell lines.

Disease family

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 › torsion dystonia 6

Related subtypes (2): dystonia 21, early-onset generalized dystonia

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

171 retrieved; paginated sample, class counts are floors:

68 uncertain significance, 26 pathogenic, 23 likely benign, 18 benign, 12 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 9 likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069320	NM_018105.3(THAP1):c.482_485del (p.Lys161fs)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070763	NM_018105.3(THAP1):c.85C>T (p.Arg29Ter)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405735	NM_018105.3(THAP1):c.1A>T (p.Met1Leu)	THAP1	Pathogenic	criteria provided, single submitter
1406166	NM_018105.3(THAP1):c.108G>A (p.Trp36Ter)	THAP1	Pathogenic	criteria provided, single submitter
1457202	NM_018105.3(THAP1):c.348del (p.Ile116fs)	THAP1	Pathogenic	criteria provided, single submitter
1458222	NC_000008.10:g.(?42693105)(42698237_?)del	THAP1	Pathogenic	criteria provided, single submitter
1647	NM_018105.3(THAP1):c.460del (p.Gln154fs)	THAP1	Pathogenic	no assertion criteria provided
1649	NM_018105.3(THAP1):c.388_389del (p.Val131fs)	THAP1	Pathogenic	no assertion criteria provided
1650	NM_018105.3(THAP1):c.474del (p.Lys158fs)	THAP1	Pathogenic	no assertion criteria provided
1651	NM_018105.3(THAP1):c.25G>T (p.Gly9Cys)	THAP1	Pathogenic	no assertion criteria provided
1711673	NM_018105.3(THAP1):c.2del (p.Met1fs)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2113153	NM_018105.3(THAP1):c.115_116insGGCCGGGAGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGAATGGGAGGCAG (p.Ala38_Ala39insGlyProGlyAlaValAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyArgIleThrArgSerXaaXaaXaaXaaLysLysLysLysLysLysLysGluTrpGluAla)	THAP1	Pathogenic	criteria provided, single submitter
2584745	NM_018105.3(THAP1):c.134T>G (p.Phe45Cys)	THAP1	Pathogenic	criteria provided, single submitter
2815851	NM_018105.3(THAP1):c.389C>G (p.Ser130Ter)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2816229	NM_018105.3(THAP1):c.100_101insCA (p.Lys34fs)	THAP1	Pathogenic	criteria provided, single submitter
31631	NM_018105.3(THAP1):c.70A>G (p.Lys24Glu)	THAP1	Pathogenic	no assertion criteria provided
31632	NM_018105.3(THAP1):c.68A>C (p.His23Pro)	THAP1	Pathogenic	no assertion criteria provided
3720817	NM_018105.3(THAP1):c.63_66del (p.Phe22fs)	THAP1	Pathogenic	criteria provided, single submitter
4072017	NM_018105.3(THAP1):c.62C>G (p.Ser21Cys)	THAP1	Pathogenic	criteria provided, single submitter
429366	NM_018105.3(THAP1):c.505C>T (p.Arg169Ter)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444750	NM_018105.2(THAP1):c.270_273del	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4687251	NC_000008.10:g.(42693480_42694328)_(42694525_42698166)del	THAP1	Pathogenic	criteria provided, single submitter
532261	NM_018105.3(THAP1):c.131del (p.Asn44fs)	THAP1	Pathogenic	criteria provided, single submitter
532262	NM_018105.3(THAP1):c.289C>T (p.Gln97Ter)	THAP1	Pathogenic	criteria provided, single submitter
532263	NM_018105.3(THAP1):c.7C>T (p.Gln3Ter)	THAP1	Pathogenic	criteria provided, single submitter
568461	NM_018105.3(THAP1):c.305dup (p.Pro103fs)	THAP1	Pathogenic	criteria provided, single submitter
569769	NM_018105.3(THAP1):c.201CAA[2] (p.Asn69del)	THAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
582441	NM_018105.3(THAP1):c.2T>C (p.Met1Thr)	THAP1	Pathogenic	criteria provided, single submitter
654563	NM_018105.3(THAP1):c.331C>T (p.Gln111Ter)	THAP1	Pathogenic	criteria provided, single submitter
807516	NM_018105.3(THAP1):c.112del (p.Ala38fs)	THAP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
THAP1	Strong	Autosomal dominant	torsion dystonia 6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THAP1	Orphanet:98806	Primary dystonia, DYT6 type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
THAP1	HGNC:20856	ENSG00000131931	Q9NVV9	THAP domain-containing protein 1	gencc,clinvar
HOOK3	HGNC:23576	ENSG00000168172	Q86VS8	Protein Hook homolog 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THAP1	THAP domain-containing protein 1	DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression.
HOOK3	Protein Hook homolog 3	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THAP1	Transcription factor	no		THAP_Znf, THAP1/10, THAP_Znf_sf
HOOK3	Other/Unknown	no		CH_dom, Hook_C, CH_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
secondary oocyte	1
calcaneal tendon	1
sural nerve	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THAP1	260	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
HOOK3	257	ubiquitous	marker	calcaneal tendon, sural nerve, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HOOK3	2,350
THAP1	1,682

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HOOK3	Q86VS8	5
THAP1	Q9NVV9	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
interkinetic nuclear migration	1	1685.2×	0.007	HOOK3
Golgi localization	1	1053.2×	0.007	HOOK3
microtubule anchoring at centrosome	1	702.2×	0.007	HOOK3
protein localization to perinuclear region of cytoplasm	1	702.2×	0.007	HOOK3
cytoskeleton-dependent intracellular transport	1	468.1×	0.007	HOOK3
protein localization to centrosome	1	337.0×	0.007	HOOK3
neuronal stem cell population maintenance	1	337.0×	0.007	HOOK3
early endosome to late endosome transport	1	324.1×	0.007	HOOK3
negative regulation of neurogenesis	1	312.1×	0.007	HOOK3
endothelial cell proliferation	1	271.8×	0.007	THAP1
endosome organization	1	187.2×	0.009	HOOK3
cytoplasmic microtubule organization	1	172.0×	0.009	HOOK3
endosome to lysosome transport	1	168.5×	0.009	HOOK3
lysosome organization	1	153.2×	0.009	HOOK3
regulation of mitotic cell cycle	1	120.4×	0.011	THAP1
DNA-templated transcription	1	112.3×	0.011	THAP1
protein transport	1	21.9×	0.053	HOOK3
regulation of DNA-templated transcription	1	15.8×	0.069	THAP1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.115	THAP1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	THAP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
THAP1	0	0
HOOK3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	THAP1, HOOK3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THAP1	0	—
HOOK3	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
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation