Dystonia 25

Summary

Dystonia 25 (MONDO:0014033) is a disease caused by GNAL (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNAL (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 21
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		28	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0004373	Focal dystonia	Very frequent (80-99%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0002530	Axial dystonia	Frequent (30-79%)
HP:0012049	Laryngeal dystonia	Frequent (30-79%)
HP:0012179	Craniofacial dystonia	Frequent (30-79%)
HP:0031008	Lingual dystonia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 25
Mondo ID	MONDO:0014033
OMIM	615073
Orphanet	329466
DOID	DOID:0090055
UMLS	C4304670
MedGen	930339
GARD	0010667
Is cancer (heuristic)	no

Also known as: dystonia 25 · dystonia type 25 · dystonic disorder caused by mutation in GNAL · DYT25 · GNAL dystonic disorder

Data availability: 21 ClinVar variants · 5 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 › multifocal dystonia › dystonia 25

Related subtypes (2): hemidystonia, dystonia 16

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

21 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 pathogenic, 3 benign, 3 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
39968	NM_182978.4(GNAL):c.1109C>A (p.Ser370Ter)	GNAL	Pathogenic	no assertion criteria provided
39969	NM_182978.4(GNAL):c.694G>A (p.Glu232Lys)	GNAL	Pathogenic	no assertion criteria provided
39970	NM_182978.4(GNAL):c.514dup (p.Ser172fs)	GNAL	Pathogenic	no assertion criteria provided
39971	NM_182978.4(GNAL):c.822dup (p.Arg275fs)	GNAL	Pathogenic	no assertion criteria provided
39972	NM_001369387.1(GNAL):c.61C>T (p.Arg21Ter)	GNAL	Pathogenic	no assertion criteria provided
626333	NM_182978.4(GNAL):c.964C>T (p.Arg322Ter)	GNAL	Pathogenic	criteria provided, multiple submitters, no conflicts
3067873	NM_182978.4(GNAL):c.910G>A (p.Asp304Asn)	GNAL	Likely pathogenic	criteria provided, single submitter
4071949	NM_182978.4(GNAL):c.931G>A (p.Val311Ile)	GNAL	Likely pathogenic	criteria provided, single submitter
4071950	NM_182978.4(GNAL):c.1272C>G (p.Tyr424Ter)	GNAL	Likely pathogenic	criteria provided, single submitter
1806039	NM_182978.4(GNAL):c.311G>A (p.Gly104Asp)	GNAL	Uncertain significance	criteria provided, single submitter
2637618	NM_182978.4(GNAL):c.193C>T (p.Arg65Trp)	GNAL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2920750	NM_182978.4(GNAL):c.377-261G>C	GNAL	Uncertain significance	criteria provided, single submitter
39967	NM_182978.4(GNAL):c.640G>A (p.Val214Met)	GNAL	Uncertain significance	criteria provided, single submitter
4277800	NM_182978.4(GNAL):c.511G>A (p.Val171Ile)	GNAL	Uncertain significance	criteria provided, single submitter
4687938	NM_182978.4(GNAL):c.983A>G (p.Asn328Ser)	GNAL	Uncertain significance	criteria provided, single submitter
626332	NM_182978.4(GNAL):c.505-5T>C	GNAL	Uncertain significance	criteria provided, single submitter
803476	NM_182978.4(GNAL):c.764C>T (p.Thr255Ile)	GNAL	Uncertain significance	criteria provided, single submitter
1246973	NM_182978.4(GNAL):c.-41T>C	GNAL	Benign	criteria provided, multiple submitters, no conflicts
1285298	NM_182978.4(GNAL):c.625-31T>G	GNAL	Benign	criteria provided, multiple submitters, no conflicts
526226	NM_182978.4(GNAL):c.540A>G (p.Pro180=)	GNAL	Likely benign	criteria provided, multiple submitters, no conflicts
626331	NM_182978.4(GNAL):c.1163-7T>G	GNAL	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GNAL	Definitive	Autosomal dominant	dystonia 25	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAL	Orphanet:329466	Autosomal dominant focal dystonia, DYT25 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
GNAL	HGNC:4388	ENSG00000141404	P38405	Guanine nucleotide-binding protein G(olf) subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNAL	Guanine nucleotide-binding protein G(olf) subunit alpha	Guanine nucleotide-binding protein (G protein) involved as transducer in olfactory signal transduction controlled by G protein-coupled receptors (GPCRs).

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)
GNAL	Other/Unknown	no		Gprotein_alpha_S, Gprotein_alpha_su, GproteinA_insert

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
lateral globus pallidus	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAL	274	broad	marker	lateral globus pallidus, lateral nuclear group of thalamus, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAL	2,374

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAL	P38405	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Adenylate cyclase activating pathway	1	1142.0×	0.002	GNAL
Adenylate cyclase inhibitory pathway	1	761.3×	0.002	GNAL
Olfactory Signaling Pathway	1	144.6×	0.007	GNAL

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
response to caffeine	1	2407.4×	0.002	GNAL
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.002	GNAL
sensory perception of chemical stimulus	1	1123.5×	0.002	GNAL
response to amphetamine	1	495.6×	0.004	GNAL
sensory perception of smell	1	156.0×	0.009	GNAL
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.010	GNAL
signal transduction	1	16.1×	0.062	GNAL

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
GNAL	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	GNAL

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)
GNAL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.