mitochondrial DNA deletion syndrome with progressive myopathy

Summary

mitochondrial DNA deletion syndrome with progressive myopathy (MONDO:0014062) is a disease caused by DNA2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNA2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000590	Progressive external ophthalmoplegia	Very frequent (80-99%)
HP:0003325	Limb-girdle muscle weakness	Very frequent (80-99%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003737	Mitochondrial myopathy	Frequent (30-79%)
HP:0004673	Decreased facial expression	Frequent (30-79%)
HP:0007970	Congenital ptosis	Frequent (30-79%)
HP:0008331	Elevated creatine kinase after exercise	Frequent (30-79%)
HP:0040013	Decreased mitochondrial number	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001533	Slender build	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA deletion syndrome with progressive myopathy
Mondo ID	MONDO:0014062
OMIM	615156
Orphanet	352470
DOID	DOID:0111519
UMLS	C3554599
MedGen	767513
GARD	0017518
Is cancer (heuristic)	no

Also known as: mitochondrial DNA deletion syndrome with limb-girdle weakness · mtDNA deletion syndrome with limb-girdle weakness · mtDNA deletion syndrome with progressive myopathy · PEOA6 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 6

Data availability: 31 ClinVar variants · 4 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 › mitochondrial DNA deletion syndrome with progressive myopathy

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, 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 5, 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

31 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 6 benign/likely benign, 4 conflicting classifications of pathogenicity, 4 likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4531504	NM_001080449.3(DNA2):c.441+1G>A	DNA2	Likely pathogenic	criteria provided, single submitter
503930	NM_001080449.3(DNA2):c.73_74+10del	DNA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
522960	NM_001080449.3(DNA2):c.3014C>T (p.Thr1005Ile)	DNA2	Likely pathogenic	criteria provided, single submitter
807407	NM_001080449.3(DNA2):c.1919C>T (p.Ser640Leu)	DNA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176875	NM_001080449.3(DNA2):c.662C>G (p.Ala221Gly)	DNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265529	NM_001080449.3(DNA2):c.1644_1647del (p.Asp548fs)	DNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3650985	NM_001080449.3(DNA2):c.1871del (p.Lys624fs)	DNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41477	NM_001080449.3(DNA2):c.593G>A (p.Arg198His)	DNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030090	NM_001080449.3(DNA2):c.2219C>G (p.Ala740Gly)	DNA2	Uncertain significance	criteria provided, single submitter
1031788	NM_001080449.3(DNA2):c.707T>C (p.Met236Thr)	DNA2	Uncertain significance	criteria provided, single submitter
1333505	NM_001080449.3(DNA2):c.411G>C (p.Met137Ile)	DNA2	Uncertain significance	criteria provided, single submitter
1333768	NM_001080449.3(DNA2):c.1450del (p.Arg484fs)	DNA2	Uncertain significance	criteria provided, single submitter
1333770	NM_001080449.3(DNA2):c.2546G>T (p.Gly849Val)	DNA2	Uncertain significance	criteria provided, single submitter
1698835	NM_001080449.3(DNA2):c.1213T>C (p.Tyr405His)	DNA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709661	NM_001080449.3(DNA2):c.876C>A (p.Tyr292Ter)	DNA2	Uncertain significance	criteria provided, single submitter
2575950	NM_001080449.3(DNA2):c.1429A>T (p.Ser477Cys)	DNA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2578140	NM_001080449.3(DNA2):c.3059T>C (p.Leu1020Pro)	DNA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2627764	NM_001080449.3(DNA2):c.1462G>A (p.Val488Ile)	DNA2	Uncertain significance	no assertion criteria provided
2633267	NM_001080449.3(DNA2):c.1655C>T (p.Ser552Leu)	DNA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3233330	NM_001080449.3(DNA2):c.1982_1983del (p.Leu661fs)	DNA2	Uncertain significance	criteria provided, single submitter
41478	NM_001080449.3(DNA2):c.679A>G (p.Lys227Glu)	DNA2	Uncertain significance	criteria provided, single submitter
41479	NM_001080449.3(DNA2):c.1909G>A (p.Val637Ile)	DNA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
257343	NM_001080449.3(DNA2):c.2430C>G (p.Phe810Leu)	DNA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
257346	NM_001080449.3(DNA2):c.507C>A (p.Ala169=)	DNA2	Benign	criteria provided, multiple submitters, no conflicts
381847	NM_001080449.3(DNA2):c.888G>A (p.Pro296=)	DNA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
382984	NM_001080449.3(DNA2):c.295T>C (p.Leu99=)	DNA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
385006	NM_001080449.3(DNA2):c.1649A>G (p.Asn550Ser)	DNA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
429200	NM_001080449.3(DNA2):c.2697+13del	DNA2	Benign	criteria provided, multiple submitters, no conflicts
516414	NM_001080449.3(DNA2):c.1057+19del	DNA2	Benign	criteria provided, multiple submitters, no conflicts
559218	NM_001080449.3(DNA2):c.720-4del	DNA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
DNA2	Strong	Autosomal dominant	mitochondrial DNA deletion syndrome with progressive myopathy	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNA2	Orphanet:352470	DNA2-related mitochondrial DNA deletion syndrome
DNA2	Orphanet:715635	Rothmund-Thomson syndrome type 4
DNA2	Orphanet:808	Seckel 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
DNA2	HGNC:2939	ENSG00000138346	P51530	DNA replication ATP-dependent helicase/nuclease DNA2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNA2	DNA replication ATP-dependent helicase/nuclease DNA2	Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNA2	Other/Unknown	no		PDDEXK-like_dom_sf, DNA_replication_fac_Dna2_N, Dna2/JHS1_DEXXQ-box

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
Brodmann (1909) area 10	1
primordial germ cell in gonad	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNA2	192	ubiquitous	marker	secondary oocyte, primordial germ cell in gonad, Brodmann (1909) area 10

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNA2	2,792

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNA2	P51530	1

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
Removal of the Flap Intermediate	1	815.7×	0.005	DNA2
Removal of the Flap Intermediate from the C-strand	1	634.4×	0.005	DNA2
Impaired BRCA2 binding to PALB2	1	456.8×	0.005	DNA2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.005	DNA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.005	DNA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.005	DNA2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.005	DNA2
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.005	DNA2
Impaired BRCA2 binding to RAD51	1	308.6×	0.005	DNA2
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	DNA2
HDR through Single Strand Annealing (SSA)	1	292.8×	0.005	DNA2
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.005	DNA2
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	DNA2
G2/M DNA damage checkpoint	1	120.2×	0.009	DNA2
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.009	DNA2
Processing of DNA double-strand break ends	1	114.2×	0.009	DNA2

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
DNA replication, Okazaki fragment processing	1	16852.0×	9e-04	DNA2
mitotic telomere maintenance via semi-conservative replication	1	5617.3×	0.001	DNA2
DNA replication, removal of RNA primer	1	4213.0×	0.001	DNA2
replication fork reversal	1	3370.4×	0.001	DNA2
telomere maintenance via semi-conservative replication	1	2808.7×	0.001	DNA2
mitochondrial DNA repair	1	2407.4×	0.001	DNA2
DNA geometric change	1	2106.5×	0.001	DNA2
DNA double-strand break processing	1	1532.0×	0.001	DNA2
mitochondrial DNA replication	1	1532.0×	0.001	DNA2
t-circle formation	1	1404.3×	0.001	DNA2
DNA replication checkpoint signaling	1	1296.3×	0.001	DNA2
positive regulation of DNA replication	1	581.1×	0.002	DNA2
base-excision repair	1	468.1×	0.002	DNA2
telomere maintenance	1	267.5×	0.004	DNA2
DNA replication	1	165.2×	0.006	DNA2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DNA2	23	Binding:23

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	DNA2

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)
DNA2	23	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.