progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 (MONDO:0020845) is a disease caused by TOP3A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TOP3A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

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 recessive 5
Mondo ID	MONDO:0020845
OMIM	618098
DOID	DOID:0111524
UMLS	C4748184
MedGen	1648331
GARD	0025260
Is cancer (heuristic)	no

Also known as: PEOB5 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 · progressive external ophthalmoplegia, autosomal recessive 5

Data availability: 18 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 › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

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

18 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
3028909	NM_004618.5(TOP3A):c.614A>G (p.Asp205Gly)	TOP3A	Pathogenic	no assertion criteria provided
446285	NM_004618.5(TOP3A):c.298A>G (p.Met100Val)	TOP3A	Pathogenic	criteria provided, single submitter
446286	NM_004618.5(TOP3A):c.403C>T (p.Arg135Ter)	TOP3A	Pathogenic	criteria provided, single submitter
3382278	NM_004618.5(TOP3A):c.865C>T (p.Arg289Ter)	TOP3A	Likely pathogenic	criteria provided, single submitter
636247	NM_004618.5(TOP3A):c.899_900del (p.Tyr300fs)	TOP3A	Likely pathogenic	criteria provided, single submitter
636248	NM_004618.5(TOP3A):c.1723A>G (p.Met575Val)	TOP3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
717059	NM_004618.5(TOP3A):c.2317A>G (p.Asn773Asp)	TOP3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028282	NM_004618.5(TOP3A):c.1982G>A (p.Cys661Tyr)	TOP3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028284	NM_004618.5(TOP3A):c.241-13T>G	TOP3A	Uncertain significance	criteria provided, single submitter
4688010	NM_004618.5(TOP3A):c.2055T>G (p.Cys685Trp)	TOP3A	Uncertain significance	criteria provided, single submitter
1260890	NM_004618.5(TOP3A):c.391-10C>T	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1342247	NM_004618.5(TOP3A):c.2022-39C>A	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1342248	NM_004618.5(TOP3A):c.1527C>T (p.Asp509=)	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1342249	NM_004618.5(TOP3A):c.1468-11G>T	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1342250	NM_004618.5(TOP3A):c.1282-21G>A	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1342251	NM_004618.5(TOP3A):c.916-49G>A	TOP3A	Benign	criteria provided, multiple submitters, no conflicts
1573144	NM_004618.5(TOP3A):c.180+10C>G	TOP3A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
787133	NM_004618.5(TOP3A):c.315-4C>G	TOP3A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TOP3A	Strong	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOP3A	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
TOP3A	Orphanet:508512	Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange 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
TOP3A	HGNC:11992	ENSG00000177302	Q13472	DNA topoisomerase 3-alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOP3A	DNA topoisomerase 3-alpha	Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOP3A	Transcription factor	no		Topo_IA, Topo_IA_2, Topo_IA_DNA-bd_dom

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
blood	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOP3A	134	ubiquitous	yes	blood, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TOP3A	2,753

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TOP3A	Q13472	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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×	0.005	TOP3A
Impaired BRCA2 binding to PALB2	1	456.8×	0.005	TOP3A
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.005	TOP3A
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.005	TOP3A
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.005	TOP3A
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.005	TOP3A
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.005	TOP3A
Impaired BRCA2 binding to RAD51	1	308.6×	0.005	TOP3A
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	TOP3A
HDR through Single Strand Annealing (SSA)	1	292.8×	0.005	TOP3A
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.005	TOP3A
HDR through Homologous Recombination (HRR)	1	190.3×	0.007	TOP3A
Meiotic recombination	1	129.8×	0.009	TOP3A
G2/M DNA damage checkpoint	1	120.2×	0.009	TOP3A
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.009	TOP3A
Processing of DNA double-strand break ends	1	114.2×	0.009	TOP3A

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 DNA metabolic process	1	5617.3×	8e-04	TOP3A
chromosome separation	1	4213.0×	8e-04	TOP3A
resolution of DNA recombination intermediates	1	3370.4×	8e-04	TOP3A
DNA topological change	1	1685.2×	0.001	TOP3A
DNA recombination	1	337.0×	0.005	TOP3A
meiotic cell cycle	1	244.2×	0.005	TOP3A
double-strand break repair via homologous recombination	1	156.0×	0.007	TOP3A
DNA repair	1	63.8×	0.016	TOP3A

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
TOP3A	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	TOP3A

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)
TOP3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.