Parkinsonism-dystonia 3, childhood-onset

disease

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Also known as PKDYS3

Summary

Parkinsonism-dystonia 3, childhood-onset (MONDO:0030676) is a disease caused by WARS2 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: WARS2 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	parkinsonism-dystonia 3, childhood-onset
Mondo ID	MONDO:0030676
OMIM	619738
UMLS	C5676913
MedGen	1808365
GARD	0025606
Is cancer (heuristic)	no

Also known as: parkinsonism-dystonia 3, childhood-onset · PKDYS3

Data availability: 11 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › parkinsonism-dystonia, infantile › parkinsonism-dystonia 3, childhood-onset

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

11 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic, 2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1341956	NG_050658.1:g.(5235_69181)_(69440_100126)del	WARS2	Pathogenic	no assertion criteria provided
440916	NM_015836.4(WARS2):c.295CTT[1] (p.Leu100del)	WARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976753	NM_015836.4(WARS2):c.622G>T (p.Glu208Ter)	WARS2	Pathogenic	criteria provided, single submitter
1690649	NM_015836.4(WARS2):c.148G>T (p.Gly50Cys)	WARS2	Likely pathogenic	criteria provided, single submitter
1709258	NM_015836.4(WARS2):c.368T>G (p.Leu123Ter)	WARS2	Likely pathogenic	criteria provided, single submitter
807717	NM_015836.4(WARS2):c.149G>A (p.Gly50Asp)	WARS2	Likely pathogenic	criteria provided, single submitter
440915	NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)	LOC129931299	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029413	NM_015836.4(WARS2):c.404G>A (p.Arg135Gln)	WARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440918	NM_015836.4(WARS2):c.797del (p.Pro266fs)	WARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1806490	NM_015836.4(WARS2):c.882C>A (p.Ser294Arg)	WARS2	Uncertain significance	criteria provided, single submitter
986388	NM_015836.4(WARS2):c.683C>G (p.Ser228Trp)	WARS2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
WARS2	Strong	Autosomal recessive	parkinsonism-dystonia 3, childhood-onset	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WARS2	Orphanet:238455	Infantile dystonia-parkinsonism
WARS2	Orphanet:572798	WARS2-related combined oxidative phosphorylation defect

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
WARS2	HGNC:12730	ENSG00000116874	Q9UGM6	Tryptophan–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WARS2	Tryptophan–tRNA ligase, mitochondrial	Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WARS2	Enzyme (other)	yes	6.1.1.2	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic, Trp-tRNA-ligase

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
bronchial epithelial cell	1
calcaneal tendon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WARS2	226	ubiquitous	marker	primordial germ cell in gonad, bronchial epithelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WARS2	1,970

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WARS2	Q9UGM6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	WARS2
tRNA Aminoacylation	1	285.5×	0.007	WARS2
Translation	1	62.1×	0.021	WARS2
Metabolism of proteins	1	12.4×	0.081	WARS2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial tryptophanyl-tRNA aminoacylation	1	16852.0×	2e-04	WARS2
tRNA aminoacylation for protein translation	1	842.6×	0.002	WARS2
vasculogenesis	1	255.3×	0.005	WARS2
positive regulation of angiogenesis	1	115.4×	0.009	WARS2

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
WARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
WARS2	6.1.1.2	tryptophan-tRNA ligase

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	1	WARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
WARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: WARS2