Developmental and epileptic encephalopathy, 3

Summary

Developmental and epileptic encephalopathy, 3 (MONDO:0012245) is a disease caused by SLC25A22 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: SLC25A22 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 3
Mondo ID	MONDO:0012245
OMIM	609304
DOID	DOID:0080440
UMLS	C5574665
MedGen	1801135
GARD	0015456
Is cancer (heuristic)	no

Also known as: DEE3 · developmental and epileptic encephalopathy 3 · early infantile epileptic encephalopathy caused by mutation in SLC25A22 · EIEE3 · epileptic encephalopathy, early infantile, 3 · epileptic encephalopathy, early infantile, type 3 · SLC25A22 early infantile epileptic encephalopathy

Data availability: 33 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 3

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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:

23 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
120308	NM_001191061.2(SLC25A22):c.328G>C (p.Gly110Arg)	SLC25A22	Pathogenic	no assertion criteria provided
1775	NM_001191061.2(SLC25A22):c.617C>T (p.Pro206Leu)	SLC25A22	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1776	NM_001191061.2(SLC25A22):c.706G>T (p.Gly236Trp)	SLC25A22	Pathogenic	no assertion criteria provided
530429	NM_001191061.2(SLC25A22):c.271C>T (p.Arg91Ter)	SLC25A22	Pathogenic	criteria provided, multiple submitters, no conflicts
2664234	NM_145886.4(PIDD1):c.2044C>T (p.Arg682Cys)	PIDD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139139	NM_001191061.2(SLC25A22):c.570C>T (p.Leu190=)	SLC25A22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139145	NM_001191061.2(SLC25A22):c.876G>A (p.Ala292=)	SLC25A22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207161	NM_001191061.2(SLC25A22):c.140C>T (p.Thr47Met)	SLC25A22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278341	NM_001191061.2(SLC25A22):c.-184GCG[6]	PANO1	Uncertain significance	criteria provided, single submitter
1018607	NM_001191061.2(SLC25A22):c.88G>A (p.Asp30Asn)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021665	NM_001191061.2(SLC25A22):c.871C>T (p.Arg291Cys)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033642	NM_001191061.2(SLC25A22):c.658GAG[1] (p.Glu221del)	SLC25A22	Uncertain significance	criteria provided, single submitter
1448420	NM_001191061.2(SLC25A22):c.365C>T (p.Thr122Met)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1878637	NM_001191061.2(SLC25A22):c.581T>G (p.Leu194Arg)	SLC25A22	Uncertain significance	criteria provided, single submitter
1976562	NM_001191061.2(SLC25A22):c.52G>A (p.Ala18Thr)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
207169	NM_001191061.2(SLC25A22):c.562A>G (p.Lys188Glu)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435993	NM_001191061.2(SLC25A22):c.955C>T (p.Gln319Ter)	SLC25A22	Uncertain significance	criteria provided, single submitter
2435994	NM_001191061.2(SLC25A22):c.674T>G (p.Phe225Cys)	SLC25A22	Uncertain significance	criteria provided, single submitter
2435995	NM_001191061.2(SLC25A22):c.200G>T (p.Arg67Leu)	SLC25A22	Uncertain significance	criteria provided, single submitter
2500932	NM_001191061.2(SLC25A22):c.191G>T (p.Gly64Val)	SLC25A22	Uncertain significance	criteria provided, single submitter
2585604	NM_001191061.2(SLC25A22):c.94G>C (p.Ala32Pro)	SLC25A22	Uncertain significance	criteria provided, single submitter
2690004	NM_001191061.2(SLC25A22):c.407G>A (p.Arg136His)	SLC25A22	Uncertain significance	criteria provided, single submitter
3319203	NM_001191061.2(SLC25A22):c.715G>A (p.Ala239Thr)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362674	NM_001191061.2(SLC25A22):c.737G>A (p.Cys246Tyr)	SLC25A22	Uncertain significance	criteria provided, single submitter
392861	NM_001191061.2(SLC25A22):c.190G>A (p.Gly64Ser)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
4080072	NM_001191061.2(SLC25A22):c.445C>T (p.Gln149Ter)	SLC25A22	Uncertain significance	criteria provided, single submitter
4278301	NM_001191061.2(SLC25A22):c.819G>T (p.Arg273Ser)	SLC25A22	Uncertain significance	criteria provided, single submitter
546116	NM_001191061.2(SLC25A22):c.524G>A (p.Arg175His)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
883624	NM_001191061.2(SLC25A22):c.199C>T (p.Arg67Trp)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts
940821	NM_001191061.2(SLC25A22):c.178G>A (p.Glu60Lys)	SLC25A22	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
SLC25A22	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A22	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC25A22	Orphanet:293181	Epilepsy of infancy with migrating focal seizures

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
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	gencc,clinvar
PIDD1	HGNC:16491	ENSG00000177595	C0HMD6	PIDD1 alternative open reading frame protein	clinvar
PANO1	HGNC:51237	ENSG00000288675	I0J062	Proapoptotic nucleolar protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
PANO1	Proapoptotic nucleolar protein 1	Apoptosis-inducing protein that modulates the tumor suppressor function of CDKN2A/p14ARF.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	25.9×	0.114
Protease	1	12.2×	0.120
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
PIDD1	Protease	yes		Death_dom, ZU5_dom, Leu-rich_rpt
PANO1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	3
cerebellar hemisphere	2
cerebellar cortex	1
apex of heart	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A22	228	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PIDD1	189	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, right uterine tube
PANO1	126			male germ line stem cell (sensu Vertebrata) in testis, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A22	1,483
PANO1	54
PIDD1	4

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIDD1	C0HMD6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A22	Q9H936	78.48
PANO1	I0J062	51.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (2 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 2 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	634.4×	0.003	SLC25A22
TP53 Regulates Transcription of Caspase Activators and Caspases	1	475.8×	0.003	PIDD1
SLC-mediated transport of neurotransmitters	1	203.9×	0.005	SLC25A22

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
malate-aspartate shuttle	1	624.1×	0.012	SLC25A22
aspartate transmembrane transport	1	468.1×	0.012	SLC25A22
positive regulation of apoptotic process	2	37.8×	0.012	PIDD1, PANO1
L-glutamate transmembrane transport	1	267.5×	0.013	SLC25A22
apoptotic process	2	19.1×	0.013	PIDD1, PANO1
protein autoprocessing	1	216.1×	0.013	PIDD1
regulation of canonical NF-kappaB signal transduction	1	160.5×	0.013	PIDD1
extrinsic apoptotic signaling pathway via death domain receptors	1	133.8×	0.013	PIDD1
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.013	PANO1
regulation of insulin secretion	1	130.6×	0.013	SLC25A22
DNA damage response, signal transduction by p53 class mediator	1	119.5×	0.013	PIDD1
monoatomic ion transport	1	52.0×	0.027	SLC25A22
regulation of protein stability	1	41.9×	0.031	PANO1
DNA damage response	1	17.8×	0.067	PIDD1
intracellular signal transduction	1	12.7×	0.087	PIDD1
negative regulation of apoptotic process	1	11.6×	0.089	PIDD1
signal transduction	1	5.3×	0.176	PIDD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
SLC25A22	0	0
PIDD1	0	0
PANO1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	PIDD1
D	Druggable family + AlphaFold only, no drug	1	SLC25A22
E	Difficult family or no structure, no drug	1	PANO1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A22	0	—
PIDD1	0	—
PANO1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.