Developmental and epileptic encephalopathy, 39

Summary

Developmental and epileptic encephalopathy, 39 (MONDO:0013056) is a disease caused by SLC25A12 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC25A12 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33

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

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 39
Mondo ID	MONDO:0013056
MeSH	C567847
OMIM	612949
Orphanet	353217
DOID	DOID:0080349
SNOMED CT	726702005
UMLS	C2751855
MedGen	414492
GARD	0017532
Is cancer (heuristic)	no

Also known as: AGC1 deficiency · DEE39 · early infantile epileptic encephalopathy caused by mutation in SLC25A12 · EIEE39 · epileptic encephalopathy with global cerebral demyelination · epileptic encephalopathy, early infantile, 39 · mitochondrial aspartate-glutamate carrier 1 deficiency · SLC25A12 early infantile epileptic encephalopathy

Data availability: 33 ClinVar variants · 4 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 membrane transport disorder › mitochondrial substrate carrier disorder › developmental and epileptic encephalopathy, 39

Related subtypes (4): Sengers syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 28, sideroblastic anemia 3

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

33 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 7 pathogenic, 5 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1712506	NM_003705.5(SLC25A12):c.1295C>T (p.Ala432Val)	SLC25A12	Pathogenic	no assertion criteria provided
1712507	NM_003705.5(SLC25A12):c.1447-2_1447-1del	SLC25A12	Pathogenic	no assertion criteria provided
2150869	NM_003705.5(SLC25A12):c.1057C>T (p.Arg353Ter)	SLC25A12	Pathogenic	criteria provided, multiple submitters, no conflicts
2579196	GRCh38/hg38 2q31.1(chr2:171833866-171844606)x0	SLC25A12	Pathogenic	criteria provided, single submitter
3338991	NM_003705.5(SLC25A12):c.693del (p.Val232fs)	SLC25A12	Pathogenic	criteria provided, single submitter
6148	NM_003705.5(SLC25A12):c.1769A>G (p.Gln590Arg)	SLC25A12	Pathogenic	no assertion criteria provided
813326	GRCh37/hg19 2q31.1(chr2:172644081-172644457)	SLC25A12	Pathogenic	criteria provided, single submitter
1341560	NM_003705.5(SLC25A12):c.410T>C (p.Phe137Ser)	SLC25A12	Likely pathogenic	no assertion criteria provided
4076175	NM_003705.5(SLC25A12):c.1747C>T (p.Arg583Ter)	SLC25A12	Likely pathogenic	criteria provided, single submitter
488597	NM_003705.5(SLC25A12):c.1618G>A (p.Asp540Asn)	SLC25A12	Likely pathogenic	criteria provided, single submitter
804390	NM_003705.5(SLC25A12):c.326-2A>C	SLC25A12	Likely pathogenic	criteria provided, single submitter
982872	NM_003705.5(SLC25A12):c.225del (p.Glu76fs)	SLC25A12	Likely pathogenic	criteria provided, single submitter
1700200	NM_003705.5(SLC25A12):c.1490T>A (p.Ile497Asn)	SLC25A12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
253136	NM_003705.5(SLC25A12):c.1058G>A (p.Arg353Gln)	SLC25A12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406559	NM_003705.5(SLC25A12):c.2015del (p.Ala672fs)	SLC25A12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546880	NM_003705.5(SLC25A12):c.1654G>A (p.Ala552Thr)	SLC25A12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
793468	NM_003705.5(SLC25A12):c.1548G>A (p.Val516=)	SLC25A12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501512	NM_003705.5(SLC25A12):c.1469G>A (p.Arg490Gln)	SLC25A12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1524654	NM_003705.5(SLC25A12):c.870G>C (p.Glu290Asp)	SLC25A12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585292	NM_003705.5(SLC25A12):c.101T>A (p.Met34Lys)	SLC25A12	Uncertain significance	criteria provided, single submitter
3391365	NM_003705.5(SLC25A12):c.274_276del (p.Ile92del)	SLC25A12	Uncertain significance	criteria provided, single submitter
3731374	NM_003705.5(SLC25A12):c.622G>A (p.Gly208Arg)	SLC25A12	Uncertain significance	criteria provided, single submitter
4076174	NM_003705.5(SLC25A12):c.1282G>C (p.Ala428Pro)	SLC25A12	Uncertain significance	criteria provided, single submitter
585055	NM_003705.5(SLC25A12):c.125G>A (p.Arg42His)	SLC25A12	Uncertain significance	criteria provided, multiple submitters, no conflicts
626170	NM_003705.5(SLC25A12):c.67-6T>A	SLC25A12	Uncertain significance	criteria provided, single submitter
644015	NM_003705.5(SLC25A12):c.930+3dup	SLC25A12	Uncertain significance	criteria provided, multiple submitters, no conflicts
917534	NM_003705.5(SLC25A12):c.325G>A (p.Glu109Lys)	SLC25A12	Uncertain significance	no assertion criteria provided
1332979	NM_003705.5(SLC25A12):c.210-21A>G	SLC25A12	Benign	criteria provided, multiple submitters, no conflicts
1604199	NM_003705.5(SLC25A12):c.13-16del	SLC25A12	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
332338	NM_003705.5(SLC25A12):c.1458G>A (p.Ala486=)	SLC25A12	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SLC25A12	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 39	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A12	Orphanet:353217	Epileptic encephalopathy with global cerebral demyelination

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
SLC25A12	HGNC:10982	ENSG00000115840	O75746	Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A12	Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial	Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A12	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair

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
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A12	295	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A12	1,645

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC25A12	O75746	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Malate-aspartate shuttle	1	1268.9×	0.004	SLC25A12
Aspartate and asparagine metabolism	1	1038.2×	0.004	SLC25A12
Protein localization	1	190.3×	0.012	SLC25A12
Mitochondrial protein import	1	167.9×	0.012	SLC25A12
Respiratory electron transport	1	95.2×	0.015	SLC25A12
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SLC25A12
Metabolism of amino acids and derivatives	1	67.6×	0.017	SLC25A12
Metabolism	1	11.6×	0.086	SLC25A12

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
malate-aspartate shuttle	1	1872.4×	0.001	SLC25A12
aspartate transmembrane transport	1	1404.3×	0.001	SLC25A12
L-glutamate transmembrane transport	1	802.5×	0.002	SLC25A12
response to calcium ion	1	318.0×	0.003	SLC25A12

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
SLC25A12	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	1	SLC25A12
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
SLC25A12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.