early-infantile DEE

Summary

early-infantile DEE (MONDO:0800491) is a disease with 13 cohort genes and 4 clinical trials. The dominant Reactome pathway is Interaction between L1 and Ankyrins (4 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Japan) [Orphanet-validated]
• Cohort genes: 13
• ClinVar variants: 13,977
• Phenotypes (HPO): 63
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	Japan	Validated
Prevalence at birth	1-9 / 100 000	2	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

63 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Obligate (100%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002123	Generalized myoclonic seizure	Very frequent (80-99%)
HP:0011153	Focal motor seizure	Very frequent (80-99%)
HP:0200134	Epileptic encephalopathy	Very frequent (80-99%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010851	EEG with burst suppression	Frequent (30-79%)
HP:0011167	Focal tonic seizure	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002131	Episodic ataxia	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0007204	Diffuse white matter abnormalities	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0010818	Generalized tonic seizure	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010850	EEG with spike-wave complexes	Occasional (5-29%)
HP:0011169	Generalized clonic seizure	Occasional (5-29%)
HP:0011190	Uni- and bilateral multifocal epileptiform discharges	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)
HP:0000054	Micropenis	Very rare (<1-4%)
HP:0000070	Ureterocele	Very rare (<1-4%)
HP:0000110	Renal dysplasia	Very rare (<1-4%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0000252	Microcephaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-infantile DEE
Mondo ID	MONDO:0800491
Orphanet	1934, 1935
DOID	DOID:0050709, DOID:2481, DOID:308
ICD-11	1877241469
NCIT	C116593
SNOMED CT	230429005, 44423001
UMLS	C0393706
MedGen	97959
GARD	0027299
MedDRA	10071545
Is cancer (heuristic)	no

Also known as: early infantile epileptic encephalopathy · early infantile epileptic encephalopathy with suppression-bursts · early myoclonic encephalopathy · early myoclonic encephalopathy with suppression-bursts · early-infantile developmental and epileptic encephalopathy syndrome · EIDEE · EIEE · EME · epileptic encephalopathy, early infantile · epileptic encephalopathy, infantile · epileptic seizures - myoclonic · epileptic seizures, myoclonic · infantile epileptic encephalopathy · myoclonia epileptica · myoclonic epilepsy · myoclonic seizure · myoclonic seizure disorder · myoclonus epilepsy · Ohtahara syndrome

Data availability: 13,977 ClinVar variants · 15 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › developmental and epileptic encephalopathy › early-infantile DEE

Related subtypes (2): genetic developmental and epileptic encephalopathy, acquired developmental and epileptic encephalopathy

Subtypes (3): developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 41

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

600 retrieved; paginated sample, class counts are floors:

379 uncertain significance, 93 pathogenic, 41 conflicting classifications of pathogenicity, 36 likely pathogenic, 31 likely benign, 18 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070772	NM_006030.4(CACNA2D2):c.97_103dup (p.Arg35fs)	CACNA2D2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074184	NM_006030.4(CACNA2D2):c.235dup (p.Gln79fs)	CACNA2D2	Pathogenic	criteria provided, single submitter
1012170	NM_020988.3(GNAO1):c.136A>G (p.Lys46Glu)	GNAO1	Pathogenic	criteria provided, single submitter
1016767	NM_020988.3(GNAO1):c.759dup (p.Ile254fs)	GNAO1	Pathogenic	criteria provided, single submitter
1074847	NM_021072.4(HCN1):c.1172G>T (p.Gly391Val)	HCN1	Pathogenic	criteria provided, single submitter
100784	NM_139318.5(KCNH5):c.980G>A (p.Arg327His)	KCNH5	Pathogenic	criteria provided, multiple submitters, no conflicts
1042182	NM_139318.5(KCNH5):c.998G>A (p.Arg333His)	KCNH5	Pathogenic	criteria provided, multiple submitters, no conflicts
1020770	NM_172107.4(KCNQ2):c.560C>T (p.Ser187Phe)	KCNQ2	Pathogenic	criteria provided, single submitter
1022468	NM_172107.4(KCNQ2):c.1720G>A (p.Gly574Ser)	KCNQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066055	NM_172107.4(KCNQ2):c.917C>A (p.Ala306Glu)	KCNQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066163	NM_172107.4(KCNQ2):c.1024-2A>C	KCNQ2	Pathogenic	criteria provided, single submitter
1068430	NM_172107.4(KCNQ2):c.1749G>C (p.Lys583Asn)	KCNQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069909	NM_172107.4(KCNQ2):c.2568_2574del (p.Thr857fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1070673	NM_172107.4(KCNQ2):c.1006_1009dup (p.Ala337fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1071234	NM_172107.4(KCNQ2):c.1966del (p.Glu656fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1071549	NM_172107.4(KCNQ2):c.1114dup (p.Tyr372fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1071682	NM_172107.4(KCNQ2):c.699_709del (p.Thr234fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1072506	NM_172107.4(KCNQ2):c.653G>A (p.Trp218Ter)	KCNQ2	Pathogenic	criteria provided, single submitter
1073519	NM_172107.4(KCNQ2):c.1118+2T>G	KCNQ2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073802	NM_172107.4(KCNQ2):c.2305G>T (p.Glu769Ter)	KCNQ2	Pathogenic	criteria provided, single submitter
1074630	NM_172107.4(KCNQ2):c.1064A>G (p.Asp355Gly)	KCNQ2	Pathogenic	criteria provided, single submitter
1074752	NM_172107.4(KCNQ2):c.734T>C (p.Leu245Pro)	KCNQ2	Pathogenic	criteria provided, single submitter
1074881	NM_172107.4(KCNQ2):c.1056_1057delinsCG (p.Arg353Gly)	KCNQ2	Pathogenic	criteria provided, single submitter
1075006	NM_172107.4(KCNQ2):c.195_196del (p.Lys66fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1076179	NM_172107.4(KCNQ2):c.1217+2_1217+3delinsAG	KCNQ2	Pathogenic	criteria provided, single submitter
1076431	NM_172107.4(KCNQ2):c.1113del (p.Met371fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1076678	NM_172107.4(KCNQ2):c.792C>A (p.Tyr264Ter)	KCNQ2	Pathogenic	criteria provided, single submitter
1076681	NM_172107.4(KCNQ2):c.493dup (p.Arg165fs)	KCNQ2	Pathogenic	criteria provided, single submitter
1024963	NM_001165963.4(SCN1A):c.5020G>A (p.Gly1674Ser)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1024964	NM_001165963.4(SCN1A):c.3862G>A (p.Asp1288Asn)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
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
ST3GAL3	Orphanet:697734	ST3GAL3-CDG
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
SLC25A22	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC25A22	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
GNAO1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
GNAO1	Orphanet:592564	GNAO1-related developmental delay-seizures-movement disorder spectrum
HCN1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
HCN1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
KCNH5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy

Cohort genes → proteins

13 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
ST3GAL3	HGNC:10866	ENSG00000126091	Q11203	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
CACNA2D2	HGNC:1400	ENSG00000007402	Q9NY47	Voltage-dependent calcium channel subunit alpha-2/delta-2	clinvar
ARHGEF15	HGNC:15590	ENSG00000198844	O94989	Rho guanine nucleotide exchange factor 15	clinvar
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	clinvar
GNAO1	HGNC:4389	ENSG00000087258	P09471	Guanine nucleotide-binding protein G(o) subunit alpha	clinvar
HCN1	HGNC:4845	ENSG00000164588	O60741	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar
KCNH5	HGNC:6254	ENSG00000140015	Q8NCM2	Voltage-gated delayed rectifier potassium channel KCNH5	clinvar
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
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…
ST3GAL3	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
CACNA2D2	Voltage-dependent calcium channel subunit alpha-2/delta-2	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
ARHGEF15	Rho guanine nucleotide exchange factor 15	Guanine nucleotide exchange factor (GEF) that activates RhoA, playing a role in the regulation of actin cytoskeleton organization.
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
GNAO1	Guanine nucleotide-binding protein G(o) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
HCN1	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.
KCNH5	Voltage-gated delayed rectifier potassium channel KCNH5	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.

Protein-family classification

Druggable: 7 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.54

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	5	42.9×	3e-07
Transporter	1	6.0×	0.387
Scaffold/PPI	1	1.3×	0.847
Enzyme (other)	1	0.9×	0.847
Other/Unknown	5	0.7×	0.938

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
ST3GAL3	Enzyme (other)	yes	2.4.99.2	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
CACNA2D2	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
ARHGEF15	Other/Unknown	no		DH_dom, PH-like_dom_sf, DBL_dom_sf
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
GNAO1	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
HCN1	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
SCN1A-AS1	Other/Unknown	no
KCNH5	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

13 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	4
cerebellar cortex	3
cerebellar hemisphere	3
right hemisphere of cerebellum	3
lateral nuclear group of thalamus	2
primary visual cortex	2
middle temporal gyrus	2
male germ line stem cell (sensu Vertebrata) in testis	2
postcentral gyrus	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
cerebellar vermis	1
lower lobe of lung	1
superior vestibular nucleus	1
apex of heart	1
omental fat pad	1
peritoneum	1
cortical plate	1
entorhinal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
ST3GAL3	178	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
CACNA2D2	218	broad	marker	lower lobe of lung, cerebellar vermis, superior vestibular nucleus
ARHGEF15	198	broad	marker	apex of heart, omental fat pad, peritoneum
SLC25A22	228	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GNAO1	261	broad	marker	cortical plate, superficial temporal artery, entorhinal cortex
HCN1	147	broad	marker	endothelial cell, Brodmann (1909) area 23, primary visual cortex
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
KCNH5	83	tissue_specific	marker	buccal mucosa cell, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAO1	3,437
KCNQ2	3,388
SPTAN1	3,083
STXBP1	3,003
SCN1A	2,287
SCN8A	2,120
SLC25A22	1,483
CACNA2D2	1,458
KCNH5	921
ST3GAL3	891

Intra-cohort edges

A	B	Sources
KCNH5	KCNQ2	string_interaction
KCNQ2	SCN1A	string_interaction
KCNQ2	SCN8A	string_interaction
KCNQ2	SLC25A22	string_interaction
KCNQ2	STXBP1	string_interaction
SCN1A	SLC25A22	string_interaction
SCN1A	STXBP1	string_interaction
SLC25A22	SPTAN1	string_interaction
SLC25A22	STXBP1	string_interaction
SPTAN1	STXBP1	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAO1	P09471	86
KCNQ2	O43526	39
HCN1	O60741	17
SCN8A	Q9UQD0	7
SPTAN1	Q13813	7
KCNH5	Q8NCM2	6
SCN1A	P35498	1
STXBP1	P61764	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ST3GAL3	Q11203	90.87
CACNA2D2	Q9NY47	81.48
SLC25A22	Q9H936	78.48
ARHGEF15	O94989	62.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 107. Enrichment computed across 13 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	4	122.8×	2e-06	SCN1A, SCN8A, SPTAN1, KCNQ2
L1CAM interactions	4	40.1×	1e-04	SCN1A, SCN8A, SPTAN1, KCNQ2
Phase 0 - rapid depolarisation	3	86.5×	2e-04	SCN1A, SCN8A, CACNA2D2
Axon guidance	4	15.1×	0.002	SCN1A, SCN8A, SPTAN1, KCNQ2
Neuronal System	4	14.8×	0.002	STXBP1, CACNA2D2, KCNH5, KCNQ2
Nervous system development	4	14.3×	0.002	SCN1A, SCN8A, SPTAN1, KCNQ2
Cardiac conduction	3	27.2×	0.002	SCN1A, SCN8A, CACNA2D2
Muscle contraction	3	19.3×	0.006	SCN1A, SCN8A, CACNA2D2
Sensory processing of sound	2	51.4×	0.008	SPTAN1, CACNA2D2
Voltage gated Potassium channels	2	40.5×	0.011	KCNH5, KCNQ2
Regulation of insulin secretion	2	36.6×	0.013	STXBP1, CACNA2D2
Integration of energy metabolism	2	29.3×	0.018	STXBP1, CACNA2D2
Sensory processing of sound by inner hair cells of the cochlea	2	27.2×	0.019	SPTAN1, CACNA2D2
Potassium Channels	2	22.4×	0.026	KCNH5, KCNQ2
HCN channels	1	237.9×	0.030	HCN1
Sensory Perception	2	15.9×	0.045	SPTAN1, CACNA2D2
Developmental Biology	4	4.8×	0.045	SCN1A, SCN8A, SPTAN1, KCNQ2
Defective ST3GAL3 causes MCT12 and EIEE15	1	119.0×	0.048	ST3GAL3
Maturation of protein 3a	1	105.7×	0.048	ST3GAL3
Malate-aspartate shuttle	1	105.7×	0.048	SLC25A22
Blood group systems biosynthesis	1	95.2×	0.051	ST3GAL3
Presynaptic depolarization and calcium channel opening	1	79.3×	0.056	CACNA2D2
Caspase-mediated cleavage of cytoskeletal proteins	1	79.3×	0.056	SPTAN1
Translation of Structural Proteins	1	73.2×	0.057	ST3GAL3
Diseases associated with glycosaminoglycan metabolism	1	63.4×	0.057	ST3GAL3
Phase 2 - plateau phase	1	63.4×	0.057	CACNA2D2
Acetylcholine Neurotransmitter Release Cycle	1	56.0×	0.057	STXBP1
Lewis blood group biosynthesis	1	56.0×	0.057	ST3GAL3
Serotonin Neurotransmitter Release Cycle	1	52.9×	0.057	STXBP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion transmembrane transport	3	50.8×	0.002	SCN1A, SCN8A, HCN1
cardiac muscle cell action potential involved in contraction	2	117.0×	0.003	SCN1A, SCN8A
obsolete vesicle docking involved in exocytosis	2	112.3×	0.003	STXBP1, GNAO1
potassium ion transmembrane transport	3	34.0×	0.003	HCN1, KCNH5, KCNQ2
neuronal action potential	2	80.2×	0.005	SCN1A, HCN1
obsolete positive regulation of vesicle docking	1	1404.3×	0.008	STXBP1
positive regulation of membrane hyperpolarization	1	1404.3×	0.008	HCN1
regulation of acrosomal vesicle exocytosis	1	1404.3×	0.008	STXBP1
action potential	2	59.8×	0.008	SCN8A, KCNQ2
sodium ion transport	2	45.3×	0.009	SCN1A, SCN8A
regulation of membrane potential	2	38.5×	0.011	HCN1, KCNH5
positive regulation of glutamate secretion, neurotransmission	1	702.2×	0.012	STXBP1
axon target recognition	1	468.1×	0.015	STXBP1
negative regulation of synapse maturation	1	468.1×	0.015	ARHGEF15
negative regulation of synaptic transmission, GABAergic	1	351.1×	0.016	STXBP1
negative regulation of action potential	1	351.1×	0.016	HCN1
rhythmic synaptic transmission	1	351.1×	0.016	CACNA2D2
presynaptic dense core vesicle exocytosis	1	351.1×	0.016	STXBP1
platelet degranulation	1	280.9×	0.016	STXBP1
developmental process involved in reproduction	1	280.9×	0.016	STXBP1
general adaptation syndrome, behavioral process	1	280.9×	0.016	HCN1
retina vasculature morphogenesis in camera-type eye	1	280.9×	0.016	ARHGEF15
regulation of SA node cell action potential	1	234.1×	0.019	HCN1
regulation of synaptic vesicle fusion to presynaptic active zone membrane	1	175.5×	0.021	STXBP1
regulation of membrane depolarization	1	156.0×	0.021	HCN1
G protein-coupled dopamine receptor signaling pathway	1	156.0×	0.021	GNAO1
synaptic vesicle maturation	1	156.0×	0.021	STXBP1
malate-aspartate shuttle	1	156.0×	0.021	SLC25A22
adenylate cyclase-inhibiting serotonin receptor signaling pathway	1	140.4×	0.021	GNAO1
regulation of synaptic vesicle priming	1	140.4×	0.021	STXBP1

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 8

Druggability breadth: 10 of 13 evidence-associated genes (77%) 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
SCN1A	MEXILETINE HYDROCHLORIDE
SCN8A	IMIPRAMINE
CACNA2D2	NIMODIPINE
KCNQ2	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
SCN8A	25	4
KCNQ2	4	4
CACNA2D2	3	4
SPTAN1	1	2
ST3GAL3	0	0
STXBP1	0	0
ARHGEF15	0	0
SLC25A22	0	0
GNAO1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A, SCN8A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A, SCN8A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A, SCN8A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

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
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
HCN1	21	Binding:12, Functional:8, ADMET:1
KCNH5	21	Binding:20, Toxicity:1
CACNA2D2	17	Binding:17
GNAO1	12	Functional:10, Binding:2
SPTAN1	7	Binding:7
ST3GAL3	2	Binding:2
STXBP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ST3GAL3	2.4.99.2, 2.4.99.6	beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminide alpha-2,3-sialyltransferase, N-acetyllactosaminide alpha-2,3-sialyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149
SCN8A	173
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A, SCN8A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A, SCN8A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A, SCN8A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SCN1A, SCN8A, CACNA2D2, KCNQ2
B	Phased (≥1) drug, not yet approved	1	SPTAN1
C	Druggable family + PDB, no drug	2	HCN1, KCNH5
D	Druggable family + AlphaFold only, no drug	2	ST3GAL3, SLC25A22
E	Difficult family or no structure, no drug	4	STXBP1, ARHGEF15, GNAO1, SCN1A-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNH5	21	KCNQ2
ST3GAL3	2	—
STXBP1	1	—
ARHGEF15	0	—
SLC25A22	0	—
GNAO1	12	—
HCN1	21	—
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT00006191	Not specified	COMPLETED	Effect of Levetiracetam on Brain Excitability
NCT02960347	Not specified	COMPLETED	Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures