Torsion dystonia 4

Summary

Torsion dystonia 4 (MONDO:0007493) is a disease caused by TUBB4A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TUBB4A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 55
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001618	Dysphonia	Very frequent (80-99%)
HP:0007325	Generalized dystonia	Very frequent (80-99%)
HP:0012049	Laryngeal dystonia	Very frequent (80-99%)
HP:0000182	Movement abnormality of the tongue	Frequent (30-79%)
HP:0000194	Open mouth	Frequent (30-79%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0003782	Eunuchoid habitus	Frequent (30-79%)
HP:0009938	Sunken cheeks	Frequent (30-79%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002075	Dysdiadochokinesis	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0007351	Upper limb postural tremor	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	torsion dystonia 4
Mondo ID	MONDO:0007493
OMIM	128101
Orphanet	98805
DOID	DOID:0090041
SNOMED CT	719276005
UMLS	C1851943
MedGen	342124
GARD	0010138
Is cancer (heuristic)	no

Also known as: autosomal dominant torsion dystonia-4 · dystonia 4, torsion, autosomal dominant · DYT4 · hereditary whispering dysphonia · torsion dystonia type 4 · whispering dysphonia

Data availability: 55 ClinVar variants · 4 GenCC gene-disease records.

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 › focal, segmental or multifocal dystonia › torsion dystonia 4

Related subtypes (11): torsion dystonia 2, torsion dystonia 13, torsion dystonia 17, dystonia 23, dystonia 24, dystonia 25, dystonia 27, oromandibular dystonia, blepharospasm-oromandibular dystonia syndrome, infantile-onset generalized dyskinesia with orofacial involvement, adult-onset segmental 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

55 retrieved; paginated sample, class counts are floors:

19 benign, 14 uncertain significance, 8 benign/likely benign, 6 pathogenic/likely pathogenic, 3 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
50984	NM_006087.4(TUBB4A):c.4C>G (p.Arg2Gly)	LOC130063295	Pathogenic	no assertion criteria provided
135658	NM_006087.4(TUBB4A):c.1228G>A (p.Glu410Lys)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217025	NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267774	NM_006087.4(TUBB4A):c.533C>T (p.Thr178Met)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267793	NM_006087.4(TUBB4A):c.1172G>A (p.Arg391His)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429952	NM_006087.4(TUBB4A):c.286G>A (p.Gly96Arg)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50985	NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033070	NM_006087.4(TUBB4A):c.854C>A (p.Thr285Lys)	TUBB4A	Likely pathogenic	criteria provided, single submitter
1694453	NM_006087.4(TUBB4A):c.544C>T (p.Pro182Ser)	TUBB4A	Likely pathogenic	criteria provided, single submitter
689794	NM_006087.4(TUBB4A):c.1181T>C (p.Phe394Ser)	TUBB4A	Likely pathogenic	criteria provided, single submitter
212502	NM_006087.4(TUBB4A):c.915G>A (p.Pro305=)	TUBB4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
425158	NM_006087.4(TUBB4A):c.538G>A (p.Val180Met)	TUBB4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893383	NM_006087.4(TUBB4A):c.666C>T (p.Tyr222=)	TUBB4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1697257	NM_006087.4(TUBB4A):c.722G>C (p.Arg241Pro)	TUBB4A	Uncertain significance	criteria provided, single submitter
1698415	NM_006087.4(TUBB4A):c.982G>A (p.Glu328Lys)	TUBB4A	Uncertain significance	criteria provided, single submitter
2442015	NM_006087.4(TUBB4A):c.1289C>A (p.Ala430Asp)	TUBB4A	Uncertain significance	criteria provided, single submitter
330252	NM_006087.4(TUBB4A):c.*440C>T	TUBB4A	Uncertain significance	criteria provided, single submitter
692150	NM_006087.4(TUBB4A):c.238C>T (p.Pro80Ser)	TUBB4A	Uncertain significance	criteria provided, single submitter
893139	NM_006087.4(TUBB4A):c.*304C>T	TUBB4A	Uncertain significance	criteria provided, single submitter
893311	NM_006087.4(TUBB4A):c.*800G>A	TUBB4A	Uncertain significance	criteria provided, single submitter
894152	NM_006087.4(TUBB4A):c.*792C>T	TUBB4A	Uncertain significance	criteria provided, single submitter
894182	NM_006087.4(TUBB4A):c.*86G>A	TUBB4A	Uncertain significance	criteria provided, single submitter
894214	NM_006087.4(TUBB4A):c.630C>T (p.Ile210=)	TUBB4A	Uncertain significance	criteria provided, single submitter
894560	NM_006087.4(TUBB4A):c.*627A>C	TUBB4A	Uncertain significance	criteria provided, multiple submitters, no conflicts
894561	NM_006087.4(TUBB4A):c.*579C>T	TUBB4A	Uncertain significance	criteria provided, single submitter
894619	NM_006087.4(TUBB4A):c.167-12G>C	TUBB4A	Uncertain significance	criteria provided, single submitter
92111	NM_006087.4(TUBB4A):c.811G>A (p.Ala271Thr)	TUBB4A	Uncertain significance	criteria provided, single submitter
330268	NM_006087.4(TUBB4A):c.-62C>T	LOC130063295	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
240288	NM_006087.4(TUBB4A):c.921C>T (p.His307=)	TUBB4A	Benign	criteria provided, multiple submitters, no conflicts
330247	NM_006087.4(TUBB4A):c.*804C>G	TUBB4A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
TUBB4A	Strong	Autosomal dominant	torsion dystonia 4	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB4A	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum
TUBB4A	Orphanet:98805	Primary dystonia, DYT4 type

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
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.

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)
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

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 cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB4A	5,138

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB4A	P04350	92.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.016	TUBB4A
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB4A
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB4A
Gap junction trafficking	1	475.8×	0.016	TUBB4A
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB4A
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB4A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB4A
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB4A
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB4A
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB4A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB4A
HCMV Infection	1	326.3×	0.016	TUBB4A
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB4A
Gap junction assembly	1	292.8×	0.016	TUBB4A
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB4A
Selective autophagy	1	278.5×	0.016	TUBB4A
Protein folding	1	259.6×	0.016	TUBB4A
Centrosome maturation	1	253.8×	0.016	TUBB4A
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB4A
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB4A
Aggrephagy	1	248.3×	0.016	TUBB4A
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB4A
Recycling pathway of L1	1	223.9×	0.016	TUBB4A
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB4A
Post NMDA receptor activation events	1	203.9×	0.016	TUBB4A
Intraflagellar transport	1	200.3×	0.016	TUBB4A
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB4A
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB4A
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB4A
Signaling by Hedgehog	1	184.2×	0.016	TUBB4A

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
negative regulation of microtubule polymerization	1	1296.3×	0.002	TUBB4A
mitotic cell cycle	1	133.8×	0.008	TUBB4A
microtubule cytoskeleton organization	1	121.2×	0.008	TUBB4A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TUBB4A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB4A	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB4A	1,758

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

21 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.

Compound	Max phase	Cohort target (bioactivity)
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB4A
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.