Dystonia 16

Summary

Dystonia 16 (MONDO:0012789) is a disease caused by PRKRA (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRKRA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 139
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0002451	Limb dystonia	Very frequent (80-99%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0012514	Lower limb pain	Frequent (30-79%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001249	Intellectual disability	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 16
Mondo ID	MONDO:0012789
MeSH	C567430
OMIM	612067
Orphanet	210571
DOID	DOID:0090048
ICD-11	548945828
NCIT	C168729
SNOMED CT	722435003
UMLS	C2677567
MedGen	436979
GARD	0010539
Is cancer (heuristic)	no

Also known as: dystonia 16 · dystonia type 16 · dystonic disorder caused by mutation in PRKRA · DYT-PRKRA · DYT16 · early-onset dystonia parkinsonism · PRKRA dystonic disorder · Young-onset dystonia-(parkinsonism)

Data availability: 139 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 16

Related subtypes (2): hemidystonia, dystonia 25

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

139 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 40 likely benign, 13 benign, 12 benign/likely benign, 6 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686097	NM_003690.5(PRKRA):c.638G>T (p.Cys213Phe)	CHROMR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6346	NM_003690.5(PRKRA):c.665C>T (p.Pro222Leu)	CHROMR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6347	NM_003690.5(PRKRA):c.267_268del (p.His89fs)	PRKRA	Pathogenic	no assertion criteria provided
1049461	NM_003690.5(PRKRA):c.610-1_610insGAATGCTGCTGAGAAATTTCTTGCCAAATTTAGTAATATTTCTCCAGAGAACCACATTTCTTTA	PRKRA	Likely pathogenic	no assertion criteria provided
3772677	NM_003690.5(PRKRA):c.74A>G (p.Lys25Arg)	PRKRA	Likely pathogenic	no assertion criteria provided
332613	NM_003690.5(PRKRA):c.*313G>A	CHROMR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
332618	NM_003690.5(PRKRA):c.*158A>G	CHROMR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893004	NM_003690.5(PRKRA):c.796G>A (p.Ala266Thr)	CHROMR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893005	NM_003690.5(PRKRA):c.654G>A (p.Leu218=)	CHROMR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893227	NM_003690.5(PRKRA):c.54T>C (p.Ser18=)	PRKRA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
894076	NM_003690.5(PRKRA):c.-14C>T	PRKRA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365242	NM_003690.5(PRKRA):c.795C>A (p.Ser265Arg)	CHROMR	Uncertain significance	criteria provided, single submitter
1436220	NM_003690.5(PRKRA):c.902A>G (p.Asn301Ser)	CHROMR	Uncertain significance	criteria provided, single submitter
1990743	NM_003690.5(PRKRA):c.616G>A (p.Val206Ile)	CHROMR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1996025	NM_003690.5(PRKRA):c.854A>G (p.His285Arg)	CHROMR	Uncertain significance	criteria provided, single submitter
2124843	NM_003690.5(PRKRA):c.861C>A (p.Ser287=)	CHROMR	Uncertain significance	criteria provided, single submitter
2435250	NM_003690.5(PRKRA):c.923T>C (p.Ile308Thr)	CHROMR	Uncertain significance	criteria provided, single submitter
290962	NM_003690.5(PRKRA):c.704G>C (p.Ser235Thr)	CHROMR	Uncertain significance	criteria provided, multiple submitters, no conflicts
332614	NM_003690.5(PRKRA):c.*265A>C	CHROMR	Uncertain significance	criteria provided, single submitter
332616	NM_003690.5(PRKRA):c.*180C>T	CHROMR	Uncertain significance	criteria provided, single submitter
332619	NM_003690.5(PRKRA):c.*151A>T	CHROMR	Uncertain significance	criteria provided, single submitter
332621	NM_003690.5(PRKRA):c.870C>T (p.Ser290=)	CHROMR	Uncertain significance	criteria provided, single submitter
4716044	NM_003690.5(PRKRA):c.785A>G (p.Asp262Gly)	CHROMR	Uncertain significance	criteria provided, single submitter
537331	NM_003690.5(PRKRA):c.766A>G (p.Ile256Val)	CHROMR	Uncertain significance	criteria provided, single submitter
537332	NM_003690.5(PRKRA):c.851G>T (p.Cys284Phe)	CHROMR	Uncertain significance	criteria provided, single submitter
537333	NM_003690.5(PRKRA):c.611C>G (p.Thr204Arg)	CHROMR	Uncertain significance	criteria provided, single submitter
583796	NC_000002.11:g.(?179296804)(179456251_?)dup	CHROMR	Uncertain significance	criteria provided, single submitter
689778	NM_003690.5(PRKRA):c.637T>C (p.Cys213Arg)	CHROMR	Uncertain significance	criteria provided, multiple submitters, no conflicts
894031	NM_003690.5(PRKRA):c.*655T>C	CHROMR	Uncertain significance	criteria provided, multiple submitters, no conflicts
894032	NM_003690.5(PRKRA):c.*576G>A	CHROMR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
PRKRA	Strong	Autosomal recessive	dystonia 16	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKRA	Orphanet:210571	Dystonia 16

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRKRA	HGNC:9438	ENSG00000180228	O75569	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	gencc,clinvar
CHROMR	HGNC:54059	ENSG00000223960		cholesterol induced regulator of metabolism RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKRA	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKRA	Other/Unknown	no		dsRBD_dom, PRKRA_DSRM_1, PRKRA_DSRM_2
CHROMR	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
sperm	1
adenohypophysis	1
adrenal tissue	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKRA	294	ubiquitous	marker	sperm, skeletal muscle tissue of biceps brachii, biceps brachii
CHROMR	183	ubiquitous	marker	adrenal tissue, adenohypophysis, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKRA	2,410
CHROMR	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKRA	O75569	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Small interfering RNA (siRNA) biogenesis	1	1142.0×	0.003	PRKRA
MicroRNA (miRNA) biogenesis	1	456.8×	0.003	PRKRA
PKR-mediated signaling	1	141.0×	0.007	PRKRA

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
regulation of regulatory ncRNA processing	1	5617.3×	0.002	PRKRA
siRNA processing	1	1872.4×	0.002	PRKRA
outer ear morphogenesis	1	1532.0×	0.002	PRKRA
RISC complex assembly	1	1532.0×	0.002	PRKRA
pre-miRNA processing	1	1123.5×	0.002	PRKRA
miRNA processing	1	1053.2×	0.002	PRKRA
middle ear morphogenesis	1	702.2×	0.003	PRKRA
skeletal system morphogenesis	1	495.6×	0.003	PRKRA
positive regulation of intrinsic apoptotic signaling pathway	1	481.5×	0.003	PRKRA
antiviral innate immune response	1	227.7×	0.007	PRKRA
cellular response to oxidative stress	1	154.6×	0.009	PRKRA
response to virus	1	144.0×	0.009	PRKRA
protein stabilization	1	66.9×	0.017	PRKRA
immune response	1	47.1×	0.023	PRKRA
negative regulation of cell population proliferation	1	42.1×	0.024	PRKRA

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
PRKRA	0	0
CHROMR	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	2	PRKRA, CHROMR

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)
PRKRA	0	—
CHROMR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.