Episodic kinesigenic dyskinesia 1

Summary

Episodic kinesigenic dyskinesia 1 (MONDO:0100352) is a disease caused by PRRT2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PRRT2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 55

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	episodic kinesigenic dyskinesia 1
Mondo ID	MONDO:0100352
MeSH	C537180
OMIM	128200
DOID	DOID:0090053
SNOMED CT	609221008
UMLS	C4552000
MedGen	1636366
GARD	0026152
Is cancer (heuristic)	no

Also known as: DYT-PRRT2 · EKD1 · episodic kinesigenic dyskinesia 1 · episodic kinesigenic dyskinesia caused by mutation in PRRT2 · episodic kinesigenic dyskinesia type 1 · PRRT2 episodic kinesigenic dyskinesia · PxMD-PRRT2

Data availability: 55 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › combined dystonia › paroxysmal dystonia › paroxysmal dyskinesia › episodic kinesigenic dyskinesia › episodic kinesigenic dyskinesia 1

Related subtypes (2): episodic kinesigenic dyskinesia 2, episodic kinesigenic dyskinesia 3

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:

16 pathogenic, 11 conflicting classifications of pathogenicity, 9 uncertain significance, 8 pathogenic/likely pathogenic, 4 benign/likely benign, 3 likely pathogenic, 2 benign, 1 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325822	NM_001077350.3(NPRL3):c.922C>T (p.Gln308Ter)	HBA-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
1686101	NM_145239.3(PRRT2):c.1021T>C (p.Ter341Arg)	MVP-DT	Pathogenic	criteria provided, single submitter
2630065	NM_145239.3(PRRT2):c.640del (p.Ala214fs)	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2637572	NM_145239.3(PRRT2):c.741del (p.Ser248fs)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
2682262	NM_145239.3(PRRT2):c.739_740delinsG (p.Pro247fs)	MVP-DT	Pathogenic	criteria provided, single submitter
280888	NM_145239.3(PRRT2):c.324_325del (p.Ser110fs)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
31169	NM_145239.3(PRRT2):c.514_517del (p.Ser172fs)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
31170	NM_145239.3(PRRT2):c.972del (p.Val325fs)	MVP-DT	Pathogenic	no assertion criteria provided
31171	NM_145239.3(PRRT2):c.629dup (p.Ala211fs)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
31174	NM_145239.3(PRRT2):c.718C>T (p.Arg240Ter)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
39752	NM_145239.3(PRRT2):c.649del (p.Arg217fs)	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39754	NM_145239.3(PRRT2):c.629del (p.Pro210fs)	MVP-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
39756	NM_145239.3(PRRT2):c.748C>T (p.Gln250Ter)	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526177	NM_145239.3(PRRT2):c.801_802del (p.Asp267fs)	MVP-DT	Pathogenic	criteria provided, single submitter
4796525	NM_145239.3(PRRT2):c.766del (p.Val256fs)	MVP-DT	Pathogenic	criteria provided, single submitter
522556	NM_145239.3(PRRT2):c.535_538del (p.Gln179fs)	MVP-DT	Pathogenic	criteria provided, single submitter
65758	NM_145239.3(PRRT2):c.649dup (p.Arg217fs)	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813794	NM_145239.3(PRRT2):c.49_50del (p.Pro18fs)	MVP-DT	Pathogenic	criteria provided, single submitter
871891	NM_145239.3(PRRT2):c.971dup (p.Val325fs)	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932548	NM_145239.3(PRRT2):c.880-34G>A	MVP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504178	NM_145239.3(PRRT2):c.640delinsCC (p.Ala214fs)	PRRT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31176	NM_145239.3(PRRT2):c.487C>T (p.Gln163Ter)	PRRT2	Pathogenic	criteria provided, single submitter
3580043	NM_145239.3(PRRT2):c.107_110del (p.Gln36fs)	PRRT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4847055	NC_000016.9:g.(?29823513)(29827203_?)del	PRRT2	Pathogenic	criteria provided, single submitter
1709692	NM_145239.3(PRRT2):c.521_530del (p.Ser174fs)	MVP-DT	Likely pathogenic	criteria provided, single submitter
2584342	NM_145239.3(PRRT2):c.457_458del (p.Lys153fs)	MVP-DT	Likely pathogenic	criteria provided, single submitter
626000	NM_145239.3(PRRT2):c.304del (p.Glu102fs)	MVP-DT	Likely pathogenic	criteria provided, single submitter
917849	NM_032607.3(CREB3L3):c.718G>A (p.Glu240Lys)	CREB3L3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130039	NM_145239.3(PRRT2):c.67G>A (p.Glu23Lys)	MVP-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
206696	NM_145239.3(PRRT2):c.971del (p.Gly324fs)	MVP-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 7 · 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
PRRT2	Strong	Autosomal dominant	episodic kinesigenic dyskinesia 1	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRRT2	Orphanet:306	Self-limited infantile epilepsy
PRRT2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
PRRT2	Orphanet:569	Familial or sporadic hemiplegic migraine
PRRT2	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
PRRT2	Orphanet:98810	Paroxysmal non-kinesigenic dyskinesia
PRRT2	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
CREB3L3	Orphanet:300293	Transient infantile hypertriglyceridemia and hepatosteatosis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRRT2	HGNC:30500	ENSG00000167371	Q7Z6L0	Proline-rich transmembrane protein 2	gencc,clinvar
CREB3L3	HGNC:18855	ENSG00000060566	Q68CJ9	Cyclic AMP-responsive element-binding protein 3-like protein 3	clinvar
MVP-DT	HGNC:56029	ENSG00000238045		MVP divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRRT2	Proline-rich transmembrane protein 2	As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system.
CREB3L3	Cyclic AMP-responsive element-binding protein 3-like protein 3	Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRRT2	Other/Unknown	no		CD225/Dispanin_fam, CD225/Dispanin
CREB3L3	Other/Unknown	no		bZIP, bZIP_sf, CREB_ATF_subfamily
MVP-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
duodenum	1
jejunal mucosa	1
right lobe of liver	1
mucosa of transverse colon	1
oviduct epithelium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRRT2	202	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CREB3L3	119	tissue_specific	marker	right lobe of liver, jejunal mucosa, duodenum
MVP-DT	191		marker	oviduct epithelium, mucosa of transverse colon, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRRT2	1,545
CREB3L3	1,421
MVP-DT	0

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CREB3L3	Q68CJ9	60.26
PRRT2	Q7Z6L0	51.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
CREB3 factors activate genes	1	1268.9×	0.002	CREB3L3
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.002	CREB3L3

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
negative regulation of short-term synaptic potentiation	1	8426.0×	0.001	PRRT2
negative regulation of SNARE complex assembly	1	4213.0×	0.001	PRRT2
regulation of calcium-dependent activation of synaptic vesicle fusion	1	2808.7×	0.001	PRRT2
synaptic vesicle fusion to presynaptic active zone membrane	1	842.6×	0.003	PRRT2
positive regulation of acute inflammatory response	1	702.2×	0.003	CREB3L3
neuromuscular process controlling posture	1	526.6×	0.003	PRRT2
response to unfolded protein	1	150.5×	0.009	CREB3L3
response to endoplasmic reticulum stress	1	83.4×	0.015	CREB3L3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.144	CREB3L3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	CREB3L3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
PRRT2	0	0
CREB3L3	0	0
MVP-DT	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	3	PRRT2, CREB3L3, MVP-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRRT2	0	—
CREB3L3	0	—
MVP-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.