Developmental and epileptic encephalopathy, 13

Summary

Developmental and epileptic encephalopathy, 13 (MONDO:0013801) is a disease caused by SCN8A (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: SCN8A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 253
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 13
Mondo ID	MONDO:0013801
OMIM	614558
DOID	DOID:0080445
SNOMED CT	765170001
UMLS	C3281191
MedGen	482821
GARD	0013085
Is cancer (heuristic)	no

Also known as: DEE13 · developmental and epileptic encephalopathy 13 · early infantile epileptic encephalopathy caused by mutation in SCN8A · early infantile epileptic encephalopathy-13 · EIEE13 · epileptic encephalopathy, early infantile, 13 · epileptic encephalopathy, early infantile, type 13 · SCN8A early infantile epileptic encephalopathy · SCN8A encephalopathy · SCN8A epilepsy

Data availability: 253 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy › developmental and epileptic encephalopathy, 13

Related subtypes (15): developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 45, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

253 retrieved; paginated sample, class counts are floors:

81 uncertain significance, 56 likely pathogenic, 39 conflicting classifications of pathogenicity, 33 pathogenic, 22 pathogenic/likely pathogenic, 9 benign, 8 not provided, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
426363	NM_001182.5(ALDH7A1):c.589C>T (p.Pro197Ser)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1029253	NM_001330260.2(SCN8A):c.4409A>G (p.Gln1470Arg)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068482	NM_001330260.2(SCN8A):c.3943G>A (p.Val1315Met)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
1164029	NM_001330260.2(SCN8A):c.4064del (p.Tyr1355fs)	SCN8A	Pathogenic	no assertion criteria provided
1299336	NM_001330260.2(SCN8A):c.2706del (p.Glu903fs)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320055	NM_001330260.2(SCN8A):c.3995T>C (p.Leu1332Pro)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342316	NM_001330260.2(SCN8A):c.2901+2T>C	SCN8A	Pathogenic	criteria provided, single submitter
135651	NM_001330260.2(SCN8A):c.2549G>A (p.Arg850Gln)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385042	NM_001330260.2(SCN8A):c.1226T>C (p.Val409Ala)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399415	NM_001330260.2(SCN8A):c.632T>G (p.Val211Gly)	SCN8A	Pathogenic	criteria provided, single submitter
1465027	NM_001330260.2(SCN8A):c.424A>G (p.Ile142Val)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1472032	NM_001330260.2(SCN8A):c.3967G>T (p.Ala1323Ser)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156106	NM_001330260.2(SCN8A):c.4850G>A (p.Arg1617Gln)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
156107	NM_001330260.2(SCN8A):c.4398C>A (p.Asn1466Lys)	SCN8A	Pathogenic	no assertion criteria provided
156108	NM_001330260.2(SCN8A):c.4397A>C (p.Asn1466Thr)	SCN8A	Pathogenic	no assertion criteria provided
1699202	NM_001330260.2(SCN8A):c.971G>A (p.Cys324Tyr)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
192317	NM_001330260.2(SCN8A):c.2952C>G (p.Asn984Lys)	SCN8A	Pathogenic	criteria provided, single submitter
192318	NM_001330260.2(SCN8A):c.4351G>A (p.Gly1451Ser)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
195688	NM_001330260.2(SCN8A):c.3967G>A (p.Ala1323Thr)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207119	NM_001330260.2(SCN8A):c.4423G>A (p.Gly1475Arg)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207120	NM_001330260.2(SCN8A):c.4435A>G (p.Ile1479Val)	SCN8A	Pathogenic	criteria provided, single submitter
207131	NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
208500	NM_001330260.2(SCN8A):c.2300C>T (p.Thr767Ile)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2129007	NM_001330260.2(SCN8A):c.2266G>A (p.Asp756Asn)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499548	NM_001330260.2(SCN8A):c.5284A>C (p.Ile1762Leu)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253195	NM_001330260.2(SCN8A):c.4447G>A (p.Glu1483Lys)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
253277	NM_014191.4(SCN8A):c.643A>G (p.Asn215Asp)	SCN8A	Pathogenic	criteria provided, single submitter
253279	NM_001330260.2(SCN8A):c.779T>C (p.Phe260Ser)	SCN8A	Pathogenic	criteria provided, single submitter
253284	NM_001330260.2(SCN8A):c.2537T>C (p.Phe846Ser)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
253287	NM_001330260.2(SCN8A):c.2879T>A (p.Val960Asp)	SCN8A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · 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
SCN8A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 13	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SASH1	Orphanet:231040	Familial generalized lentiginosis
SASH1	Orphanet:447961	Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome
ALDH7A1	Orphanet:3006	Pyridoxine-dependent-developmental and epileptic encephalopathy

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
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	gencc,clinvar
SASH1	HGNC:19182	ENSG00000111961	O94885	SAM and SH3 domain-containing protein 1	clinvar
ALDH7A1	HGNC:877	ENSG00000164904	P49419	Alpha-aminoadipic semialdehyde dehydrogenase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
SASH1	SAM and SH3 domain-containing protein 1	Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation.
ALDH7A1	Alpha-aminoadipic semialdehyde dehydrogenase	Aldehyde dehydrogenase enzyme that mediates important protective effects.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · 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
Ion channel	1	37.2×	0.080
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SASH1	Transcription factor	no		SH3_domain, SAM, SAM/pointed_sf
ALDH7A1	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH/histidinol_DH, Ald_DH_N

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
postcentral gyrus	1
lateral globus pallidus	1
skin of hip	1
synovial joint	1
left ovary	1
right lobe of liver	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SASH1	293	ubiquitous	marker	synovial joint, lateral globus pallidus, skin of hip
ALDH7A1	255	ubiquitous	marker	right lobe of liver, ventricular zone, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH7A1	4,544
SCN8A	2,120
SASH1	879

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH7A1	P49419	20
SCN8A	Q9UQD0	7
SASH1	O94885	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Choline catabolism	1	713.8×	0.011	ALDH7A1
Lysine catabolism	1	571.0×	0.011	ALDH7A1
Interaction between L1 and Ankyrins	1	184.2×	0.017	SCN8A
Phase 0 - rapid depolarisation	1	173.0×	0.017	SCN8A
L1CAM interactions	1	60.1×	0.037	SCN8A
Cardiac conduction	1	54.4×	0.037	SCN8A
Muscle contraction	1	38.6×	0.044	SCN8A
Metabolism of amino acids and derivatives	1	33.8×	0.044	ALDH7A1
Axon guidance	1	22.6×	0.055	SCN8A
Nervous system development	1	21.5×	0.055	SCN8A
Developmental Biology	1	7.2×	0.146	SCN8A
Metabolism	1	5.8×	0.165	ALDH7A1

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
L-lysine catabolic process	1	5617.3×	0.001	ALDH7A1
regulation of protein K63-linked ubiquitination	1	5617.3×	0.001	SASH1
regulation of protein autoubiquitination	1	5617.3×	0.001	SASH1
negative regulation of endosome to plasma membrane protein transport	1	5617.3×	0.001	ALDH7A1
obsolete glycine betaine biosynthetic process from choline	1	2808.7×	0.002	ALDH7A1
choline catabolic process	1	1404.3×	0.003	ALDH7A1
regulation of epithelial cell migration	1	936.2×	0.004	SASH1
negative regulation of Golgi to plasma membrane protein transport	1	936.2×	0.004	ALDH7A1
obsolete lysine catabolic process	1	802.5×	0.004	ALDH7A1
positive regulation of lipopolysaccharide-mediated signaling pathway	1	510.7×	0.005	SASH1
plasma membrane to endosome transport	1	510.7×	0.005	ALDH7A1
aldehyde metabolic process	1	432.1×	0.005	ALDH7A1
positive regulation of JUN kinase activity	1	432.1×	0.005	SASH1
Golgi to endosome transport	1	351.1×	0.006	ALDH7A1
negative regulation of ferroptosis	1	267.5×	0.007	ALDH7A1
cardiac muscle cell action potential involved in contraction	1	234.1×	0.008	SCN8A
positive regulation of p38MAPK cascade	1	208.1×	0.008	SASH1
peripheral nervous system development	1	193.7×	0.008	SCN8A
action potential	1	119.5×	0.013	SCN8A
endosome to lysosome transport	1	112.3×	0.013	ALDH7A1
sodium ion transport	1	90.6×	0.014	SCN8A
energy homeostasis	1	90.6×	0.014	ALDH7A1
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.014	SASH1
positive regulation of endothelial cell migration	1	83.8×	0.014	SASH1
myelination	1	83.8×	0.014	SCN8A
sodium ion transmembrane transport	1	67.7×	0.016	SCN8A
protein polyubiquitination	1	38.5×	0.027	SASH1
positive regulation of angiogenesis	1	38.5×	0.027	SASH1
sensory perception of sound	1	33.6×	0.029	ALDH7A1

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
SCN8A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN8A	25	4
SASH1	0	0
ALDH7A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN8A
SERTINDOLE	4	SCN8A
PIMOZIDE	4	SCN8A
NIFEDIPINE	4	SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	SCN8A
HALOPERIDOL	4	SCN8A
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A
AMIODARONE	4	SCN8A
CHLORPROMAZINE	4	SCN8A
TETRACAINE	4	SCN8A
TEDISAMIL	3	SCN8A
NITRENDIPINE	3	SCN8A
AJMALINE	3	SCN8A
VIXOTRIGINE	3	SCN8A
ELECLAZINE	3	SCN8A
TETRODOTOXIN	3	SCN8A
CIFENLINE	2	SCN8A
PF-05089771	2	SCN8A
FUNAPIDE	2	SCN8A
DS-1971	2	SCN8A
ZANDATRIGINE	2	SCN8A
PF-05150122	1	SCN8A
PF-05186462	1	SCN8A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
ALDH7A1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH7A1	1.2.1.3, 1.2.1.31	aldehyde dehydrogenase (NAD+), L-aminoadipate-semialdehyde dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN8A	173

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

25 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)
IMIPRAMINE	4	SCN8A
SERTINDOLE	4	SCN8A
PIMOZIDE	4	SCN8A
NIFEDIPINE	4	SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	SCN8A
HALOPERIDOL	4	SCN8A
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A
AMIODARONE	4	SCN8A
CHLORPROMAZINE	4	SCN8A
TETRACAINE	4	SCN8A
TEDISAMIL	3	SCN8A
NITRENDIPINE	3	SCN8A
AJMALINE	3	SCN8A
VIXOTRIGINE	3	SCN8A
ELECLAZINE	3	SCN8A
TETRODOTOXIN	3	SCN8A
CIFENLINE	2	SCN8A
PF-05089771	2	SCN8A
FUNAPIDE	2	SCN8A
DS-1971	2	SCN8A
ZANDATRIGINE	2	SCN8A
PF-05150122	1	SCN8A
PF-05186462	1	SCN8A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN8A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH7A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SASH1

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)
SASH1	0	—
ALDH7A1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05818553	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE)