mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive

Summary

mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive (MONDO:0014175) is a disease caused by SLC25A4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SLC25A4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive
Mondo ID	MONDO:0014175
OMIM	615418
DOID	DOID:0080335
NCIT	C129977
UMLS	C3809443
MedGen	815773
GARD	0015961
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 12 · mitochondrial DNA depletion syndrome 12 (cardiomyopathic type) · mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR · mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), AR · mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive · mitochondrial DNA depletion syndrome type 12 · MTDPS12 · MTDPS12B

Data availability: 30 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 12B (cardiomyopathic type), autosomal recessive

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 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

30 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
18249	NM_001151.4(SLC25A4):c.368C>A (p.Ala123Asp)	SLC25A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215174	NM_001151.4(SLC25A4):c.523del (p.Gln175fs)	SLC25A4	Pathogenic	criteria provided, multiple submitters, no conflicts
268149	NM_001151.4(SLC25A4):c.116_137del (p.Gln39fs)	SLC25A4	Pathogenic	no assertion criteria provided
268150	NM_001151.4(SLC25A4):c.707G>C (p.Arg236Pro)	SLC25A4	Pathogenic	no assertion criteria provided
3340703	NM_001151.4(SLC25A4):c.390del (p.Phe130fs)	SLC25A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66011	NM_001151.4(SLC25A4):c.111+1G>A	SLC25A4	Pathogenic	no assertion criteria provided
3572858	NM_001151.4(SLC25A4):c.46_47del (p.Gly16fs)	SLC25A4	Likely pathogenic	criteria provided, single submitter
3767159	NM_001151.4(SLC25A4):c.423G>C (p.Leu141Phe)	SLC25A4	Likely pathogenic	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
2671903	NM_001151.4(SLC25A4):c.706C>T (p.Arg236Cys)	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
3775292	NM_001151.4(SLC25A4):c.112-16C>G	SLC25A4	Uncertain significance	criteria provided, single submitter
3775600	NM_001151.4(SLC25A4):c.265T>C (p.Phe89Leu)	SLC25A4	Uncertain significance	criteria provided, single submitter
3775855	NM_001151.4(SLC25A4):c.597G>T (p.Lys199Asn)	SLC25A4	Uncertain significance	criteria provided, single submitter
562200	NM_001151.4(SLC25A4):c.515G>T (p.Gly172Val)	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
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: 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
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

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
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc,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.

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)
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane

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
apex of heart	1
heart right ventricle	1
left ventricle myocardium	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A4	3,085

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A4	P12235	92.07

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
Mitochondrial Uncoupling	1	5710.0×	0.002	SLC25A4
Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization	1	3806.7×	0.002	SLC25A4
Interactions of Vpr with host cellular proteins	1	1427.5×	0.004	SLC25A4
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	951.7×	0.004	SLC25A4
Host Interactions of HIV factors	1	335.9×	0.010	SLC25A4
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.010	SLC25A4
Protein localization	1	190.3×	0.012	SLC25A4
Mitochondrial protein import	1	167.9×	0.012	SLC25A4
HIV Infection	1	119.0×	0.015	SLC25A4
Aerobic respiration and respiratory electron transport	1	88.5×	0.018	SLC25A4
SLC-mediated transmembrane transport	1	59.2×	0.025	SLC25A4
Viral Infection Pathways	1	30.8×	0.043	SLC25A4
Transport of small molecules	1	25.1×	0.046	SLC25A4
Infectious disease	1	24.8×	0.046	SLC25A4
Disease	1	13.1×	0.082	SLC25A4
Metabolism	1	11.6×	0.086	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 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 ADP transmembrane transport	1	3370.4×	0.001	SLC25A4
ADP transport	1	2106.5×	0.001	SLC25A4
mitochondrial ATP transmembrane transport	1	1872.4×	0.001	SLC25A4
regulation of mitochondrial membrane permeability	1	1404.3×	0.001	SLC25A4
positive regulation of mitophagy	1	1123.5×	0.001	SLC25A4
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	1053.2×	0.001	SLC25A4
adaptive thermogenesis	1	1053.2×	0.001	SLC25A4
negative regulation of necroptotic process	1	991.3×	0.001	SLC25A4
apoptotic mitochondrial changes	1	887.0×	0.001	SLC25A4
generation of precursor metabolites and energy	1	343.9×	0.003	SLC25A4

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
SLC25A4	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
SLC25A4	1	Binding:1

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	SLC25A4

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)
SLC25A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.