mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant

Summary

mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (MONDO:0014959) is a disease caused by SLC25A4 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: SLC25A4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant
Mondo ID	MONDO:0014959
OMIM	617184
DOID	DOID:0080130
UMLS	C4310676
MedGen	934643
GARD	0025039
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD · mitochondrial DNA depletion syndrome 12a (cardiomyopathic type), autosomal dominant · mitochondrial DNA depletion syndrome 12a (cardiomyopathic type), autosomal dominant; MTDPS12A · MTDPS12A

Data availability: 27 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 12A (cardiomyopathic type), autosomal dominant

Related subtypes (20): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 11, 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, 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

27 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
253037	NM_001151.4(SLC25A4):c.239G>A (p.Arg80His)	SLC25A4	Pathogenic	criteria provided, multiple submitters, no conflicts
253038	NM_001151.4(SLC25A4):c.703C>G (p.Arg235Gly)	SLC25A4	Pathogenic	no assertion criteria provided
3778708	NM_001151.4(SLC25A4):c.599-11_621del	SLC25A4	Likely pathogenic	criteria provided, single submitter
635018	NM_001151.4(SLC25A4):c.238C>G (p.Arg80Gly)	SLC25A4	Likely pathogenic	criteria provided, single submitter
16638	NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4277472	NM_001151.4(SLC25A4):c.238C>T (p.Arg80Cys)	SLC25A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033744	NM_001151.4(SLC25A4):c.874G>C (p.Asp292His)	SLC25A4	Uncertain significance	criteria provided, single submitter
1308141	NM_001151.4(SLC25A4):c.331C>A (p.Arg111Ser)	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
215173	NM_001151.4(SLC25A4):c.755C>T (p.Thr252Met)	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236732	NM_001151.4(SLC25A4):c.448G>A (p.Ala150Thr)	SLC25A4	Uncertain significance	criteria provided, single submitter
3382544	NM_001151.4(SLC25A4):c.149A>C (p.Gln50Pro)	SLC25A4	Uncertain significance	criteria provided, single submitter
348258	NM_001151.4(SLC25A4):c.*824C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
348264	NM_001151.4(SLC25A4):c.*1163G>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
348277	NM_001151.4(SLC25A4):c.*2592C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
348281	NM_001151.4(SLC25A4):c.*2824G>C	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
348285	NM_001151.4(SLC25A4):c.*3276C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
348286	NM_001151.4(SLC25A4):c.*3277G>A	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
900372	NM_001151.4(SLC25A4):c.*151T>C	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
900427	NM_001151.4(SLC25A4):c.*2616C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
901524	NM_001151.4(SLC25A4):c.*994G>A	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
902042	NM_001151.4(SLC25A4):c.-65C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
902158	NM_001151.4(SLC25A4):c.*3195T>C	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
902159	NM_001151.4(SLC25A4):c.*3229A>G	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
902161	NM_001151.4(SLC25A4):c.*3317G>A	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
902981	NM_001151.4(SLC25A4):c.*2475C>T	SLC25A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
402541	NM_000085.5(CLCNKB):c.1877G>A (p.Cys626Tyr)	CLCNKB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
704300	NM_001151.4(SLC25A4):c.252C>T (p.Thr84=)	SLC25A4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 8 · 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
SLC25A4	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3
EDNRB	Orphanet:388	Hirschsprung disease
EDNRB	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc,clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	clinvar
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1
adult mammalian kidney	1
metanephros cortex	1
renal medulla	1
lateral globus pallidus	1
lower lobe of lung	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A4	3,085
EDNRB	2,415
CLCNKB	767

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDNRB	P24530	18

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A4	P12235	92.07
CLCNKB	P51801	87.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial Uncoupling	1	1903.3×	0.008	SLC25A4
Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization	1	1268.9×	0.008	SLC25A4
Interactions of Vpr with host cellular proteins	1	475.8×	0.014	SLC25A4
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	317.2×	0.016	SLC25A4
Host Interactions of HIV factors	1	112.0×	0.036	SLC25A4
Transport of vitamins, nucleosides, and related molecules	1	90.6×	0.037	SLC25A4
Protein localization	1	63.4×	0.039	SLC25A4
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.039	EDNRB
Mitochondrial protein import	1	56.0×	0.039	SLC25A4
Stimuli-sensing channels	1	45.3×	0.044	CLCNKB
HIV Infection	1	39.6×	0.045	SLC25A4
Aerobic respiration and respiratory electron transport	1	29.5×	0.056	SLC25A4
Peptide ligand-binding receptors	1	24.7×	0.061	EDNRB
SLC-mediated transmembrane transport	1	19.7×	0.069	SLC25A4
G alpha (q) signalling events	1	19.1×	0.069	EDNRB
Viral Infection Pathways	1	10.3×	0.118	SLC25A4
Transport of small molecules	1	8.4×	0.129	SLC25A4
Infectious disease	1	8.3×	0.129	SLC25A4
Disease	1	4.4×	0.223	SLC25A4
Metabolism	1	3.9×	0.237	SLC25A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal sodium ion absorption	2	660.9×	2e-04	CLCNKB, EDNRB
enteric smooth muscle cell differentiation	1	5617.3×	0.003	EDNRB
response to endothelin	1	5617.3×	0.003	EDNRB
posterior midgut development	1	2808.7×	0.003	EDNRB
negative regulation of neuron maturation	1	2808.7×	0.003	EDNRB
regulation of fever generation	1	2808.7×	0.003	EDNRB
aldosterone metabolic process	1	2808.7×	0.003	EDNRB
positive regulation of penile erection	1	1872.4×	0.004	EDNRB
chordate pharynx development	1	1872.4×	0.004	EDNRB
renin secretion into blood stream	1	1404.3×	0.004	EDNRB
vein smooth muscle contraction	1	1404.3×	0.004	EDNRB
renal sodium excretion	1	1404.3×	0.004	EDNRB
renal albumin absorption	1	1123.5×	0.004	EDNRB
neuroblast migration	1	1123.5×	0.004	EDNRB
mitochondrial ADP transmembrane transport	1	1123.5×	0.004	SLC25A4
heparin proteoglycan metabolic process	1	936.2×	0.004	EDNRB
ADP transport	1	702.2×	0.004	SLC25A4
epithelial fluid transport	1	702.2×	0.004	EDNRB
developmental pigmentation	1	702.2×	0.004	EDNRB
negative regulation of protein metabolic process	1	702.2×	0.004	EDNRB
transepithelial chloride transport	1	624.1×	0.004	CLCNKB
mitochondrial ATP transmembrane transport	1	624.1×	0.004	SLC25A4
renal absorption	1	561.7×	0.004	CLCNKB
endothelin receptor signaling pathway	1	561.7×	0.004	EDNRB
response to sodium phosphate	1	561.7×	0.004	EDNRB
regulation of pH	1	468.1×	0.005	EDNRB
negative regulation of adenylate cyclase activity	1	468.1×	0.005	EDNRB
regulation of mitochondrial membrane permeability	1	468.1×	0.005	SLC25A4
podocyte differentiation	1	468.1×	0.005	EDNRB
positive regulation of urine volume	1	432.1×	0.005	EDNRB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
EDNRB	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
SLC25A4	0	0
CLCNKB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EDNRB	270	Binding:229, Functional:41
SLC25A4	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EDNRB	270

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

16 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.

Compound	Max phase	Cohort target (bioactivity)
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EDNRB
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	SLC25A4, CLCNKB

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)
SLC25A4	1	—
CLCNKB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.