Autosomal dominant mitochondrial myopathy with exercise intolerance

Summary

Autosomal dominant mitochondrial myopathy with exercise intolerance (MONDO:0014532) is a disease caused by CHCHD10 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CHCHD10 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 224
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003722	Neck flexor weakness	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0012240	Increased intramyocellular lipid droplets	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0040014	Increased mitochondrial number	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant mitochondrial myopathy with exercise intolerance
Mondo ID	MONDO:0014532
OMIM	616209
Orphanet	457050
DOID	DOID:0081357
UMLS	C4015513
MedGen	863950
GARD	0017794
Is cancer (heuristic)	no

Also known as: IMMD · myopathy, isolated mitochondrial, autosomal dominant

Data availability: 224 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › autosomal dominant mitochondrial myopathy with exercise intolerance

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

224 retrieved; paginated sample, class counts are floors:

115 uncertain significance, 78 likely benign, 11 conflicting classifications of pathogenicity, 8 benign/likely benign, 6 benign, 4 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
180222	NM_213720.2(CHCHD10):c.[43C>A ;172G>C]		Pathogenic	no assertion criteria provided
140745	NM_213720.3(CHCHD10):c.176C>T (p.Ser59Leu)	CHCHD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452852	NM_213720.3(CHCHD10):c.44_45delinsTT (p.Arg15Leu)	CHCHD10	Pathogenic	criteria provided, single submitter
180220	NM_213720.3(CHCHD10):c.44G>T (p.Arg15Leu)	CHCHD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180221	NM_213720.3(CHCHD10):c.197G>T (p.Gly66Val)	CHCHD10	Pathogenic	criteria provided, single submitter
242618	NM_213720.3(CHCHD10):c.172G>C (p.Gly58Arg)	CHCHD10	Pathogenic	no assertion criteria provided
1080264	NM_213720.3(CHCHD10):c.42-5C>T	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446575	NM_213720.3(CHCHD10):c.42-5C>G	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204292	NM_213720.3(CHCHD10):c.239C>T (p.Pro80Leu)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2061695	NM_213720.3(CHCHD10):c.261+10_261+11delinsAG	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2922669	NM_213720.3(CHCHD10):c.215C>T (p.Ala72Val)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473421	NM_213720.3(CHCHD10):c.214G>A (p.Ala72Thr)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540611	NM_213720.3(CHCHD10):c.274G>A (p.Ala92Thr)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
565755	NM_213720.3(CHCHD10):c.312C>G (p.Tyr104Ter)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567906	NM_213720.3(CHCHD10):c.276T>A (p.Ala92=)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640736	NM_213720.3(CHCHD10):c.224G>A (p.Gly75Glu)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
655998	NM_213720.3(CHCHD10):c.196G>A (p.Gly66Ser)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665651	NC_000022.10:g.(?24108011)(24110169_?)dup	C22orf15	Uncertain significance	criteria provided, single submitter
831034	NC_000022.11:g.(?23765824)(23767603_?)del	C22orf15	Uncertain significance	criteria provided, single submitter
1000426	NM_213720.3(CHCHD10):c.2T>G (p.Met1Arg)	CHCHD10	Uncertain significance	criteria provided, single submitter
1003466	NM_213720.3(CHCHD10):c.8G>C (p.Arg3Pro)	CHCHD10	Uncertain significance	criteria provided, single submitter
1021740	NM_213720.3(CHCHD10):c.235G>A (p.Glu79Lys)	CHCHD10	Uncertain significance	criteria provided, single submitter
1026524	NM_213720.3(CHCHD10):c.409+1G>A	CHCHD10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1036655	NM_213720.3(CHCHD10):c.263C>A (p.Ala88Asp)	CHCHD10	Uncertain significance	criteria provided, single submitter
1040911	NM_213720.3(CHCHD10):c.55C>T (p.Pro19Ser)	CHCHD10	Uncertain significance	criteria provided, single submitter
1043025	NC_000022.10:g.(?24109541)(24110081_?)del	CHCHD10	Uncertain significance	criteria provided, single submitter
1043375	NM_213720.3(CHCHD10):c.42-2A>G	CHCHD10	Uncertain significance	criteria provided, single submitter
1052112	NM_213720.3(CHCHD10):c.302C>T (p.Pro101Leu)	CHCHD10	Uncertain significance	criteria provided, single submitter
1313416	NM_213720.3(CHCHD10):c.211G>A (p.Gly71Arg)	CHCHD10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1352828	NM_213720.3(CHCHD10):c.350G>A (p.Ser117Asn)	CHCHD10	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
CHCHD10	Strong	Autosomal dominant	autosomal dominant mitochondrial myopathy with exercise intolerance	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHCHD10	Orphanet:275872	Frontotemporal dementia with motor neuron disease
CHCHD10	Orphanet:276435	Lower motor neuron syndrome with late-adult onset
CHCHD10	Orphanet:457050	Autosomal dominant mitochondrial myopathy with exercise intolerance
CHCHD10	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHCHD10	HGNC:15559	ENSG00000250479	Q8WYQ3	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	gencc,clinvar
C22orf15	HGNC:15558	ENSG00000169314	Q8WYQ4	Uncharacterized protein C22orf15	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHCHD10	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHCHD10	Other/Unknown	no		CHCH, CHCHD2/10-like
C22orf15	Other/Unknown	no		CXorf65-like

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart left ventricle	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHCHD10	133	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle
C22orf15	123		marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHCHD10	1,344
C22orf15	152

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHCHD10	Q8WYQ3	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C22orf15	Q8WYQ4	76.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 protein import	1	167.9×	0.006	CHCHD10

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 membrane organization	1	2407.4×	0.001	CHCHD10
inner mitochondrial membrane organization	1	842.6×	0.002	CHCHD10
mitochondrion organization	1	151.8×	0.007	CHCHD10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
CHCHD10	0	0
C22orf15	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CHCHD10, C22orf15

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CHCHD10	0	—
C22orf15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.