mitochondrial DNA depletion syndrome 11

Summary

mitochondrial DNA depletion syndrome 11 (MONDO:0014039) is a disease caused by MGME1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MGME1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000590	Progressive external ophthalmoplegia	Very frequent (80-99%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0001644	Dilated cardiomyopathy	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003306	Spinal rigidity	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Frequent (30-79%)
HP:0008443	Spinal deformities	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0040013	Decreased mitochondrial number	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0000651	Diplopia	Excluded (0%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000815	Hypergonadotropic hypogonadism	Very rare (<1-4%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0001272	Cerebellar atrophy	Very rare (<1-4%)
HP:0002014	Diarrhea	Very rare (<1-4%)
HP:0011675	Arrhythmia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 11
Mondo ID	MONDO:0014039
OMIM	615084
Orphanet	352447
DOID	DOID:0080129
UMLS	C3554462
MedGen	767376
GARD	0017517
Is cancer (heuristic)	no

Also known as: MGME1 mitochondrial DNA depletion syndrome · mitochondrial DNA depletion syndrome 11 · mitochondrial DNA depletion syndrome caused by mutation in MGME1 · mitochondrial DNA depletion syndrome type 11 · mitochondrial DNA maintenance syndrome due to MGME1 deficiency · mtDNA maintenance syndrome due to MGME1 deficiency · MTDPS11 · PEO-myopathy-emaciation syndrome

Data availability: 16 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial DNA depletion syndrome › mitochondrial DNA depletion syndrome 11

Related subtypes (20): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA deletion syndrome with progressive myopathy, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial DNA depletion syndrome, encephalomyopathic form, mitochondrial dna depletion syndrome 16B (neuroophthalmic type), mitochondrial DNA depletion syndrome 20 (mngie type), mitochondrial DNA depletion syndrome 16 (hepatic type), mitochondrial DNA depletion syndrome 17, mitochondrial DNA depletion syndrome 18, mitochondrial DNA depletion syndrome 19, mitochondrial DNA depletion syndrome, hepatocerebral form, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 21, mitochondrial dna depletion syndrome 14A (encephalomyopathic type)

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

16 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
40051	NM_052865.4(MGME1):c.456G>A (p.Trp152Ter)	LOC126862983	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428588	NM_052865.4(MGME1):c.359del (p.Pro120fs)	LOC126862983	Pathogenic	no assertion criteria provided
3362549	NM_052865.4(MGME1):c.589_590del (p.Arg196_Asp197insTer)	MGME1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40052	NM_052865.4(MGME1):c.698A>G (p.Tyr233Cys)	MGME1	Pathogenic	no assertion criteria provided
4845682	NM_052865.4(MGME1):c.102_103del (p.Cys35fs)	LOC126862983	Likely pathogenic	criteria provided, single submitter
711756	NM_052865.4(MGME1):c.242C>G (p.Pro81Arg)	LOC126862983	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445604	NM_052865.4(MGME1):c.532C>T (p.Arg178Trp)	MGME1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433744	NM_052865.4(MGME1):c.203C>G (p.Thr68Ser)	LOC126862983	Uncertain significance	criteria provided, single submitter
2523822	NM_052865.4(MGME1):c.383A>C (p.Asn128Thr)	LOC126862983	Uncertain significance	criteria provided, multiple submitters, no conflicts
3391050	NM_052865.4(MGME1):c.203C>T (p.Thr68Ile)	LOC126862983	Uncertain significance	criteria provided, single submitter
4279673	NM_052865.4(MGME1):c.241C>A (p.Pro81Thr)	LOC126862983	Uncertain significance	criteria provided, single submitter
984721	NM_052865.4(MGME1):c.55_57del (p.Ser19del)	LOC126862983	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029042	NM_052865.4(MGME1):c.1018C>A (p.Pro340Thr)	MGME1	Uncertain significance	criteria provided, single submitter
1368309	NM_052865.4(MGME1):c.659G>A (p.Arg220Gln)	MGME1	Uncertain significance	criteria provided, multiple submitters, no conflicts
235425	NM_052865.4(MGME1):c.794C>T (p.Thr265Ile)	MGME1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
380041	NM_052865.4(MGME1):c.43A>T (p.Ser15Cys)	MGME1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
MGME1	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 11	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MGME1	Orphanet:352447	Progressive external ophthalmoplegia-myopathy-emaciation 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
MGME1	HGNC:16205	ENSG00000125871	Q9BQP7	Mitochondrial genome maintenance exonuclease 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MGME1	Mitochondrial genome maintenance exonuclease 1	Metal-dependent single-stranded DNA (ssDNA) exonuclease involved in mitochondrial genome maintenance.

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)
MGME1	Other/Unknown	no		Restrct_endonuc-II-like, PDDEXK-like_dom_sf, PDDEXK_AddAB-type

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MGME1	250	ubiquitous	marker	upper arm skin, left ventricle myocardium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MGME1	1,121

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MGME1	Q9BQP7	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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×	0.002	MGME1
DNA Replication	1	237.9×	0.004	MGME1

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 repair	1	2407.4×	7e-04	MGME1
mitochondrial DNA replication	1	1532.0×	7e-04	MGME1

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
MGME1	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	MGME1

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)
MGME1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.