progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (MONDO:0012241) is a disease caused by TWNK (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TWNK (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 114

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3
Mondo ID	MONDO:0012241
MeSH	C563747
OMIM	609286
DOID	DOID:0111520
UMLS	C1836439
MedGen	373087
GARD	0016499
Is cancer (heuristic)	no

Also known as: PEOA3 · progressive external ophthalmoplegia with mitochondrial DNA deletions caused by mutation in TWNK · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 3 · TWNK progressive external ophthalmoplegia with mitochondrial DNA deletions

Data availability: 114 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions › autosomal dominant progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

Related subtypes (4): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

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

114 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 32 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 pathogenic, 8 pathogenic/likely pathogenic, 6 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1210826	NM_021830.5(TWNK):c.907C>T (p.Arg303Trp)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687171	NM_021830.5(TWNK):c.1433T>G (p.Phe478Cys)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
426104	NM_021830.5(TWNK):c.1374G>T (p.Gln458His)	TWNK	Pathogenic	criteria provided, single submitter
426106	NM_021830.5(TWNK):c.1121G>A (p.Arg374Gln)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277590	NM_021830.5(TWNK):c.1078_1079delinsGG (p.Leu360Gly)	TWNK	Pathogenic	criteria provided, single submitter
4616	NM_021830.5(TWNK):c.1054_1092dup (p.His364_Lys365insLeuSerArgIleLeuArgThrAlaLeuProAlaTrpHis)	TWNK	Pathogenic	no assertion criteria provided
4617	NM_021830.5(TWNK):c.1423G>C (p.Ala475Pro)	TWNK	Pathogenic	no assertion criteria provided
4618	NM_021830.5(TWNK):c.1075G>A (p.Ala359Thr)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4620	NM_021830.5(TWNK):c.944G>T (p.Trp315Leu)	TWNK	Pathogenic	no assertion criteria provided
4621	NM_021830.5(TWNK):c.1061G>C (p.Arg354Pro)	TWNK	Pathogenic	criteria provided, single submitter
4622	NM_021830.5(TWNK):c.1142T>C (p.Leu381Pro)	TWNK	Pathogenic	no assertion criteria provided
4623	NM_021830.5(TWNK):c.1001G>A (p.Arg334Gln)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4624	NM_021830.5(TWNK):c.1106C>A (p.Ser369Tyr)	TWNK	Pathogenic	criteria provided, multiple submitters, no conflicts
4625	NM_021830.5(TWNK):c.955A>G (p.Lys319Glu)	TWNK	Pathogenic	no assertion criteria provided
4629	NM_021830.5(TWNK):c.1120C>T (p.Arg374Trp)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632124	NM_021830.5(TWNK):c.1070G>C (p.Arg357Pro)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975884	NM_021830.5(TWNK):c.649C>T (p.Arg217Ter)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429279	NM_021830.5(TWNK):c.718C>T (p.Arg240Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
2810280	NM_021830.5(TWNK):c.1453T>A (p.Phe485Ile)	TWNK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382359	NM_021830.5(TWNK):c.1399C>T (p.Gln467Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
3898060	NM_021830.5(TWNK):c.945G>T (p.Trp315Cys)	TWNK	Likely pathogenic	criteria provided, single submitter
3898062	NM_021830.5(TWNK):c.997G>A (p.Val333Met)	TWNK	Likely pathogenic	criteria provided, single submitter
3898063	NM_021830.5(TWNK):c.1363A>G (p.Met455Val)	TWNK	Likely pathogenic	criteria provided, single submitter
4292632	NM_021830.5(TWNK):c.1121G>T (p.Arg374Leu)	TWNK	Likely pathogenic	criteria provided, single submitter
4531635	NM_021830.5(TWNK):c.1378G>C (p.Ala460Pro)	TWNK	Likely pathogenic	criteria provided, single submitter
4619	NM_021830.5(TWNK):c.1422G>A (p.Trp474Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
4823902	NM_021830.5(TWNK):c.1436A>G (p.Glu479Gly)	TWNK	Likely pathogenic	criteria provided, single submitter
136587	NM_021830.5(TWNK):c.639C>T (p.Gly213=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136594	NM_021830.5(TWNK):c.1735-14C>A	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683933	NM_021830.5(TWNK):c.1958C>T (p.Ser653Phe)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
TWNK	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome

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
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.

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)
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

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
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TWNK	1,390

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TWNK	Q96RR1	2

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
Strand-asynchronous mitochondrial DNA replication	1	1142.0×	0.003	TWNK
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.007	TWNK
Mitochondrial protein degradation	1	114.2×	0.009	TWNK

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
mitochondrial transcription	1	2407.4×	9e-04	TWNK
mitochondrial DNA replication	1	1532.0×	9e-04	TWNK
protein hexamerization	1	1404.3×	9e-04	TWNK
DNA-templated DNA replication	1	561.7×	0.002	TWNK

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
TWNK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase

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	TWNK
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)
TWNK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.