Developmental and epileptic encephalopathy

Summary

Developmental and epileptic encephalopathy (MONDO:0100620) is a disease with 68 cohort genes and 22 clinical trials. The dominant Reactome pathway is Interaction between L1 and Ankyrins (7 cohort genes). Top therapeutic interventions include vigabatrin, cannabidiol, and corticotropin.

At a glance

• Cohort genes: 68
• ClinVar variants: 982
• Clinical trials: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy
Mondo ID	MONDO:0100620
UMLS	C5779964
MedGen	1830477
GARD	0027373
Is cancer (heuristic)	no

Also known as: DEE · developmental and epileptic encephalopathy · infantile spasm

Data availability: 982 ClinVar variants · 1 GenCC gene-disease record · 2 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

Related subtypes (12): extratemporal epilepsy, focal epilepsy, epilepsy syndrome, monogenic epilepsy, reflex epilepsy, post-traumatic epilepsy, immune epilepsy, metabolic epilepsy, structural epilepsy, infantile-onset epilepsy, generalized epilepsy, epilepsy, unknown whether focal or generalized

Subtypes (3): genetic developmental and epileptic encephalopathy, acquired developmental and epileptic encephalopathy, early-infantile DEE

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:

315 uncertain significance, 163 pathogenic, 39 likely benign, 37 likely pathogenic, 25 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 4 benign, 1 pathogenic/likely pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426640	NC_000016.9:g.(?56226148)(58768132_?)del	ADGRG1	Pathogenic	criteria provided, single submitter
3245119	NC_000009.11:g.(?130374683)(131329276_?)del	AK1	Pathogenic	criteria provided, single submitter
1456135	NC_000003.11:g.(?49547968)(50685477_?)del	AMIGO3	Pathogenic	criteria provided, single submitter
3067131	NM_001286615.2(ANO4):c.1688T>A (p.Met563Lys)	ANO4	Pathogenic	criteria provided, single submitter
3067132	NM_001286615.2(ANO4):c.1674C>A (p.Asn558Lys)	ANO4	Pathogenic	criteria provided, single submitter
3067133	NM_001286615.2(ANO4):c.1684A>T (p.Ile562Phe)	ANO4	Pathogenic	criteria provided, single submitter
3067134	NM_001286615.2(ANO4):c.1807A>G (p.Asn603Asp)	ANO4	Pathogenic	criteria provided, single submitter
3067135	NM_001286615.2(ANO4):c.387C>G (p.Asn129Lys)	ANO4	Pathogenic	criteria provided, single submitter
2427488	NC_000020.10:g.(?61471874)(62078210_?)del	ARFGAP1	Pathogenic	criteria provided, single submitter
3247692	NC_000001.10:g.(?44201934)(44482805_?)del	ARTN	Pathogenic	criteria provided, single submitter
1320140	NM_001205293.3(CACNA1E):c.1042G>C (p.Gly348Arg)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344625	NM_001205293.3(CACNA1E):c.2098G>A (p.Ala700Thr)	CACNA1E	Pathogenic	criteria provided, single submitter
1344627	NM_001205293.3(CACNA1E):c.4264A>T (p.Ile1422Phe)	CACNA1E	Pathogenic	criteria provided, single submitter
1344628	NM_001205293.3(CACNA1E):c.4274C>A (p.Thr1425Asn)	CACNA1E	Pathogenic	criteria provided, single submitter
265066	NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
390468	NM_001205293.3(CACNA1E):c.1807A>C (p.Ile603Leu)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452392	NM_001205293.3(CACNA1E):c.683T>C (p.Leu228Pro)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457005	NC_000003.11:g.(?50513539)(50540854_?)del	CACNA2D2	Pathogenic	criteria provided, single submitter
1069868	NC_000020.10:g.(?61977556)(62039909_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
1069869	NC_000020.10:g.(?61977556)(62078210_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
1458699	NC_000020.10:g.(?61978090)(62055579_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
2427472	NC_000020.10:g.(?61978090)(62076207_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
2427484	NC_000020.10:g.(?61978090)(62324656_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
2427487	NC_000020.10:g.(?61978090)(62039909_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
3248244	NC_000020.10:g.(?61978090)(62062742_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
1056169	NC_000009.11:g.(?129376729)(131016993_?)del	CIZ1	Pathogenic	criteria provided, single submitter
2500127	NM_004408.4(DNM1):c.850C>T (p.Gln284Ter)	DNM1	Pathogenic	criteria provided, multiple submitters, no conflicts
3572927	NM_004408.4(DNM1):c.194C>A (p.Thr65Asn)	DNM1	Pathogenic	criteria provided, single submitter
2423787	NC_000009.11:g.(?131329020)(131419005_?)del	DYNC2I2	Pathogenic	criteria provided, single submitter
2424102	NC_000020.10:g.(?62075992)(62324656_?)del	EEF1A2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 94 · 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
GRIN2A	Strong	Autosomal dominant	early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIN2A	Orphanet:163721	Rolandic epilepsy-speech dyspraxia syndrome
GRIN2A	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GRIN2A	Orphanet:289266	Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
GRIN2A	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
GRIN2A	Orphanet:98818	Landau-Kleffner syndrome
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
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
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
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SEC24C	Orphanet:567	22q11.2 deletion syndrome
ST3GAL3	Orphanet:697734	ST3GAL3-CDG
SLC32A1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC32A1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
SLC12A5	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
CACNA1E	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PIGQ	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5

Cohort genes → proteins

68 cohort genes, 66 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	68

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	gencc
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	clinvar
SEC24C	HGNC:10705	ENSG00000176986	P53992	Protein transport protein Sec24C	clinvar
ST3GAL3	HGNC:10866	ENSG00000126091	Q11203	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	clinvar
SLC32A1	HGNC:11018	ENSG00000101438	Q9H598	Vesicular inhibitory amino acid transporter	clinvar
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
SRMS	HGNC:11298	ENSG00000125508	Q9H3Y6	Tyrosine-protein kinase Srms	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
SLC12A5	HGNC:13818	ENSG00000124140	Q9H2X9	Solute carrier family 12 member 5	clinvar
CACNA1E	HGNC:1392	ENSG00000198216	Q15878	Voltage-dependent R-type calcium channel subunit alpha-1E	clinvar
CACNA2D2	HGNC:1400	ENSG00000007402	Q9NY47	Voltage-dependent calcium channel subunit alpha-2/delta-2	clinvar
PIGQ	HGNC:14135	ENSG00000007541	Q9BRB3	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q	clinvar
ARHGEF15	HGNC:15590	ENSG00000198844	O94989	Rho guanine nucleotide exchange factor 15	clinvar
ADRM1	HGNC:15759	ENSG00000130706	Q16186	Proteasomal ubiquitin receptor ADRM1	clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar
ARFGAP1	HGNC:15852	ENSG00000101199	Q8N6T3	ADP-ribosylation factor GTPase-activating protein 1	clinvar
MRGBP	HGNC:15866	ENSG00000101189	Q9NV56	MRG/MORF4L-binding protein	clinvar
ABHD16B	HGNC:16128	ENSG00000183260	Q9H3Z7	ABHD16B	clinvar
PPDPF	HGNC:16142	ENSG00000125534	Q9H3Y8	Pancreatic progenitor cell differentiation and proliferation factor	clinvar
CIZ1	HGNC:16744	ENSG00000148337	Q9ULV3	Cip1-interacting zinc finger protein	clinvar
MAST3	HGNC:19036	ENSG00000099308	O60307	Microtubule-associated serine/threonine-protein kinase 3	clinvar
CHD2	HGNC:1917	ENSG00000173575	O14647	ATP-dependent chromatin remodeler CHD2	clinvar
TNK2	HGNC:19297	ENSG00000061938	Q07912	Activated CDC42 kinase 1	clinvar
CUX2	HGNC:19347	ENSG00000111249	O14529	Homeobox protein cut-like 2	clinvar
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	clinvar
ANO4	HGNC:23837	ENSG00000151572	Q32M45	Anoctamin-4	clinvar
AMIGO3	HGNC:24075	ENSG00000176020	Q86WK7	Amphoterin-induced protein 3	clinvar
CEND1	HGNC:24153	ENSG00000184524	Q8N111	Cell cycle exit and neuronal differentiation protein 1	clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	clinvar
B4GALNT4	HGNC:26315	ENSG00000182272	Q76KP1	N-acetyl-beta-glucosaminyl-glycoprotein 4-beta-N-acetylgalactosaminyltransferase 1	clinvar
AK8	HGNC:26526	ENSG00000165695	Q96MA6	Adenylate kinase 8	clinvar
DYNC2I2	HGNC:28296	ENSG00000119333	Q96EX3	Cytoplasmic dynein 2 intermediate chain 2	clinvar
SZT2	HGNC:29040	ENSG00000198198	Q5T011	KICSTOR complex protein SZT2	clinvar
DNM1	HGNC:2972	ENSG00000106976	Q05193	Dynamin-1	clinvar
HELZ2	HGNC:30021	ENSG00000130589	Q9BYK8	3’-5’ exoribonuclease HELZ2	clinvar
PIGP	HGNC:3046	ENSG00000185808	P57054	Phosphatidylinositol N-acetylglucosaminyltransferase subunit P	clinvar
CSRNP3	HGNC:30729	ENSG00000178662	Q8WYN3	Cysteine/serine-rich nuclear protein 3	clinvar
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	clinvar
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	clinvar
LRRC37A2	HGNC:32404	ENSG00000238083	A6NM11	Leucine-rich repeat-containing protein 37A2	clinvar
ANXA2R	HGNC:33463	ENSG00000177721	Q3ZCQ2	Annexin-2 receptor	clinvar
AK1	HGNC:361	ENSG00000106992	P00568	Adenylate kinase isoenzyme 1	clinvar
FGF10	HGNC:3666	ENSG00000070193	O15520	Fibroblast growth factor 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
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.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN3A	Sodium channel protein type 3 subunit alpha	Pore-forming subunit of Nav1.3, 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…
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SEC24C	Protein transport protein Sec24C	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
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.
SLC32A1	Vesicular inhibitory amino acid transporter	Antiporter that exchanges vesicular protons for cytosolic 4-aminobutanoate or to a lesser extend glycine, thus allowing their secretion from nerve terminals.
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
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.
SRMS	Tyrosine-protein kinase Srms	Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
SLC12A5	Solute carrier family 12 member 5	Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis.
CACNA1E	Voltage-dependent R-type calcium channel subunit alpha-1E	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.
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.
PIGQ	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
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.
ADRM1	Proteasomal ubiquitin receptor ADRM1	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
ARFGAP1	ADP-ribosylation factor GTPase-activating protein 1	GTPase-activating protein (GAP) for the ADP ribosylation factor 1 (ARF1).
MRGBP	MRG/MORF4L-binding protein	Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A.
ABHD16B	ABHD16B	Hydrolyzes the sn-1 position of glycerophospholipids with high specificity towards phosphatidylserine (PS), PS-PLA1 enzyme.
PPDPF	Pancreatic progenitor cell differentiation and proliferation factor	Probable regulator of exocrine pancreas development.
CIZ1	Cip1-interacting zinc finger protein	May regulate the subcellular localization of CIP/WAF1.
CHD2	ATP-dependent chromatin remodeler CHD2	ATP-dependent chromatin-remodeling factor that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3.
TNK2	Activated CDC42 kinase 1	Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation.
CUX2	Homeobox protein cut-like 2	Transcription factor involved in the control of neuronal proliferation and differentiation in the brain.
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
ANO4	Anoctamin-4	Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide.
AMIGO3	Amphoterin-induced protein 3	May mediate heterophilic cell-cell interaction.
CEND1	Cell cycle exit and neuronal differentiation protein 1	Involved in neuronal differentiation.
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
B4GALNT4	N-acetyl-beta-glucosaminyl-glycoprotein 4-beta-N-acetylgalactosaminyltransferase 1	Transfers N-acetylgalactosamine (GalNAc) from UDP-GalNAc to N-acetylglucosamine-beta-benzyl with a beta-1,4-linkage to form N,N’-diacetyllactosediamine, GalNAc-beta-1,4-GlcNAc structures in N-linked glycans and probably O-linked glycans.
AK8	Adenylate kinase 8	Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates.
DYNC2I2	Cytoplasmic dynein 2 intermediate chain 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
SZT2	KICSTOR complex protein SZT2	As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.
DNM1	Dynamin-1	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission and participates in many forms of endocytosis, such as clathrin-mediated endocytosis or synaptic vesicle endocytosis as well as rapid endocytosis (RE).
HELZ2	3’-5’ exoribonuclease HELZ2	Can degrade highly structured RNAs through its concerted ATP-dependent RNA helicase and 3’ to 5’ exoribonuclease activities.
PIGP	Phosphatidylinositol N-acetylglucosaminyltransferase subunit P	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
CSRNP3	Cysteine/serine-rich nuclear protein 3	Binds to the consensus sequence 5’-AGAGTG-3’ and has transcriptional activator activity.
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
ANXA2R	Annexin-2 receptor	May act as a receptor for annexin II on marrow stromal cells to induce osteoclast formation.
AK1	Adenylate kinase isoenzyme 1	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.
FGF10	Fibroblast growth factor 10	Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation.
AKR1A1	Aldo-keto reductase family 1 member A1	Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols.
GABRA2	Gamma-aminobutyric acid receptor subunit alpha-2	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

Protein-family classification

Druggable: 28 · Difficult: 7 · Unknown: 33 · Druggable fraction: 0.41

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	11	18.0×	2e-10
Kinase	5	2.0×	0.333
Enzyme (other)	9	1.6×	0.333
Transporter	1	1.1×	0.972
Other/Unknown	33	0.9×	0.972
Scaffold/PPI	3	0.8×	0.972
Transcription factor	4	0.5×	0.972
Antibody/Immunoglobulin	1	0.4×	0.972
GPCR	1	0.3×	0.972

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SEC24C	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
ST3GAL3	Enzyme (other)	yes	2.4.99.2	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SLC32A1	Other/Unknown	no		AA_transpt_TM
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
SRMS	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
SLC12A5	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
CACNA1E	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_R_a1su
CACNA2D2	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
PIGQ	Enzyme (other)	yes	2.4.1.198	PigQ/GPI1
ARHGEF15	Other/Unknown	no		DH_dom, PH-like_dom_sf, DBL_dom_sf
ADRM1	Other/Unknown	no		Rpn13/ADRM1, RPN13_DEUBAD, RPN13_DEUBAD_sf
BSCL2	Other/Unknown	no		Seipin
ARFGAP1	Other/Unknown	no		ArfGAP_dom, ARFGAP/RecO, ArfGAP_dom_sf
MRGBP	Other/Unknown	no		Eaf7/MRGBP
ABHD16B	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
PPDPF	Other/Unknown	no		PPDPF
CIZ1	Transcription factor	no		Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type
MAST3	Kinase	yes		Prot_kinase_dom, AGC-kinase_C, PDZ
CHD2	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
TNK2	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, SH3_domain
CUX2	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
ANO4	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
AMIGO3	Antibody/Immunoglobulin	yes		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, Ig_sub2
CEND1	Other/Unknown	no		Cend1
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
B4GALNT4	Enzyme (other)	yes	2.4.1.244	Chond_GalNAc, PA14_dom, Nucleotide-diphossugar_trans
AK8	Enzyme (other)	yes	2.7.4.3	Adenylat/UMP-CMP_kin, P-loop_NTPase, ADK_active_lid_dom_sf
DYNC2I2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
SZT2	Other/Unknown	no		SZT2
DNM1	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
HELZ2	Transcription factor	no		Znf_CCCH, RNase_II/R, NA-bd_OB-fold
PIGP	Enzyme (other)	yes	2.4.1.198	PIG-P, PIG-P_GPI19, GPI_Anchor_Biosynth
CSRNP3	Other/Unknown	no		Cys/Ser-rich_nuc_prot, CSRNP_N
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
LRRC37A2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRRC37
ANXA2R	Other/Unknown	no		ANXA2R
AK1	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, AK1/5, P-loop_NTPase
FGF10	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

Expression context

Cohort genes with no expression data: 0.

59 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)	68
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	12
cerebellar hemisphere	11
middle temporal gyrus	9
right hemisphere of cerebellum	9
cortical plate	6
cerebellar cortex	6
right uterine tube	6
hindlimb stylopod muscle	5
primary visual cortex	4
sural nerve	4
gastrocnemius	4
apex of heart	4
right testis	4
calcaneal tendon	4
granulocyte	4
endothelial cell	3
postcentral gyrus	3
mucosa of transverse colon	3
frontal pole	3
left testis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
SEC24C	290	ubiquitous	marker	lower esophagus mucosa, esophagus squamous epithelium, epithelium of esophagus
ST3GAL3	178	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
SLC32A1	69	broad	marker	nucleus accumbens, putamen, prefrontal cortex
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SRMS	115		yes	mucosa of transverse colon, pancreatic ductal cell, spleen
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
SLC12A5	205	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CACNA1E	144	broad	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
CACNA2D2	218	broad	marker	lower lobe of lung, cerebellar vermis, superior vestibular nucleus
PIGQ	186	broad	marker	right lobe of thyroid gland, right uterine tube, left lobe of thyroid gland
ARHGEF15	198	broad	marker	apex of heart, omental fat pad, peritoneum
ADRM1	269	ubiquitous	marker	gastrocnemius, right testis, left testis
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
ARFGAP1	265	ubiquitous	marker	adenohypophysis, pituitary gland, mucosa of stomach
MRGBP	249	ubiquitous	yes	sperm, left testis, right testis
ABHD16B	106		yes	right testis, left testis, testis
PPDPF	262	ubiquitous	marker	lower esophagus mucosa, right coronary artery, mucosa of transverse colon
CIZ1	281	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, right ovary
MAST3	256	ubiquitous	marker	frontal pole, Brodmann (1909) area 10, middle frontal gyrus
CHD2	268	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
TNK2	276	ubiquitous	marker	right hemisphere of cerebellum, right frontal lobe, cerebellar hemisphere
CUX2	144	broad	marker	middle temporal gyrus, buccal mucosa cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 48.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GOT2	4,357
FGF10	4,233
DNM1	3,614
AK1	3,526
GNAO1	3,437
KCNQ2	3,388
SLC32A1	3,331
GRIN2A	3,146
HELZ2	3,126
SPTAN1	3,083

Intra-cohort edges

A	B	Sources
ALG13	CDKL5	string_interaction
AMIGO3	KCNB1	biogrid_interaction
ARFGAP1	ARFGAP3	biogrid_interaction
BSCL2	CHRNA4	biogrid_interaction
CACNA1E	CACNA2D2	string_interaction
CACNA1E	HCN1	intact
CDHR5	SLC25A22	string_interaction
CDKL5	KCNQ2	string_interaction
CDKL5	SCN1A	string_interaction
CDKL5	SCN2A	string_interaction
CDKL5	SLC25A22	string_interaction
CDKL5	STXBP1	string_interaction
CHRNA4	KCNQ2	string_interaction
CSRNP3	SCN3A	string_interaction
DYNC2I2	TTC21B	string_interaction
GABRA2	GRIA3	string_interaction
GRIA3	STXBP1	string_interaction
GRIN2A	SLC12A5	string_interaction
HCN1	KCNB1	string_interaction
HCN1	SCN2A	intact
HCN1	SCN3A	intact
HCN1	SCN9A	intact
KCNB1	KCNH5	string_interaction
KCNB1	SCN8A	string_interaction
KCNB1	SNAP25	biogrid_interaction
KCNC2	SCN1A	string_interaction
KCNC2	SCN2A	string_interaction
KCNC2	SCN3A	string_interaction
KCNH5	KCNQ2	string_interaction
KCNQ2	SCN1A	string_interaction
KCNQ2	SCN2A	string_interaction
KCNQ2	SCN3A	string_interaction
KCNQ2	SCN8A	string_interaction
KCNQ2	SLC25A22	string_interaction
KCNQ2	STXBP1	string_interaction
PIGP	PIGQ	biogrid_interaction, intact, string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN1A	SLC25A22	string_interaction
SCN1A	STXBP1	string_interaction
SCN2A	SCN3A	intact
SCN2A	SCN9A	intact
SCN2A	SLC25A22	string_interaction
SCN2A	STXBP1	string_interaction
SLC12A5	SLC32A1	string_interaction
SLC25A22	SPTAN1	string_interaction
SLC25A22	STXBP1	string_interaction
SNAP25	STXBP1	biogrid_interaction, intact
SPTAN1	STXBP1	string_interaction

Structural data

PDB: 42 · AlphaFold-only: 24 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAO1	P09471	86
SCN9A	Q15858	43
KCNQ2	O43526	39
GRIN2A	Q12879	37
DNM1	Q05193	22
ADRM1	Q16186	21
TNK2	Q07912	18
HCN1	O60741	17
SNAP25	P60880	14
CHRNA4	P43681	12
SZT2	Q5T011	9
GABRA2	P47869	8
SCN8A	Q9UQD0	7
SPTAN1	Q13813	7
KCNB1	Q14721	6
KCNH5	Q8NCM2	6
SCN2A	Q99250	5
CACNA1E	Q15878	5
AK1	P00568	5
ARTN	Q5T4W7	5
DYNC2I2	Q96EX3	4
ITPA	Q9BY32	4
SEC24C	P53992	3
CDKL5	O76039	3
CUX2	O14529	3
TTC21B	Q7Z4L5	3
GOT2	P00505	3
SCN3A	Q9NY46	2
SLC12A5	Q9H2X9	2
ARFGAP1	Q8N6T3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ST3GAL3	Q11203	90.87
GALNT3	Q14435	89.88
AK8	Q96MA6	87.47
ABHD16B	Q9H3Z7	86.64
SRMS	Q9H3Y6	83.99
GRIA3	P42263	83.98
PIGP	P57054	82.42
CACNA2D2	Q9NY47	81.48
ANO4	Q32M45	79.27
SLC32A1	Q9H598	78.69
SLC25A22	Q9H936	78.48
AMIGO3	Q86WK7	73.90
B4GALNT4	Q76KP1	70.89
KCNC2	Q96PR1	68.26
PIGQ	Q9BRB3	64.70
ARHGEF15	O94989	62.96
CEND1	Q8N111	60.87
CHD2	O14647	60.81
PPDPF	Q9H3Y8	60.64
CSRNP3	Q8WYN3	60.42
ANXA2R	Q3ZCQ2	55.65
ALG13	Q9NP73	54.42
LRRC37A2	A6NM11	42.32
HELZ2	Q9BYK8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 376. Enrichment computed across 68 evidence-associated genes (51 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 51 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	7	50.6×	2e-08	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, SPTAN1, KCNQ2
Phase 0 - rapid depolarisation	6	40.7×	1e-06	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, CACNA2D2
Regulation of insulin secretion	6	25.8×	1e-05	SNAP25, STXBP1, CACNA1E, CACNA2D2, KCNB1, KCNC2
L1CAM interactions	7	16.5×	2e-05	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, SPTAN1, KCNQ2
Integration of energy metabolism	6	20.7×	3e-05	SNAP25, STXBP1, CACNA1E, CACNA2D2, KCNB1, KCNC2
Axon guidance	9	8.0×	9e-05	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, SPTAN1, ADRM1, KCNQ2 (+1 more)
Neuronal System	9	7.8×	1e-04	SNAP25, STXBP1, CACNA1E, CACNA2D2, CHRNA4, KCNB1, KCNC2, KCNH5 (+1 more)
Nervous system development	9	7.6×	1e-04	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, SPTAN1, ADRM1, KCNQ2 (+1 more)
Cardiac conduction	6	12.8×	3e-04	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, CACNA2D2
Sensory Perception	6	11.2×	5e-04	SCN2A, SCN3A, SCN9A, SNAP25, SPTAN1, CACNA2D2
Muscle contraction	6	9.1×	0.002	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, CACNA2D2
Voltage gated Potassium channels	4	19.1×	0.002	KCNB1, KCNC2, KCNH5, KCNQ2
GABA synthesis, release, reuptake and degradation	3	37.3×	0.002	SLC32A1, SNAP25, STXBP1
Metabolism	14	3.2×	0.002	SEC24C, ST3GAL3, SNAP25, STXBP1, CACNA1E, CACNA2D2, ADRM1, AK8 (+6 more)
Asparagine N-linked glycosylation	6	7.1×	0.005	SEC24C, ST3GAL3, SPTAN1, ARFGAP1, ALG13, ARFGAP3
Sensory perception of taste	3	19.8×	0.011	SCN2A, SCN3A, SCN9A
Sensory processing of sound	3	18.2×	0.012	SNAP25, SPTAN1, CACNA2D2
Potassium Channels	4	10.5×	0.012	KCNB1, KCNC2, KCNH5, KCNQ2
ER to Golgi Anterograde Transport	4	10.4×	0.012	SEC24C, SPTAN1, ARFGAP1, ARFGAP3
Metabolism of nucleotides	3	17.7×	0.012	AK8, AK1, ITPA
Malate-aspartate shuttle	2	49.8×	0.012	SLC25A22, GOT2
Sensory perception of sweet, bitter, and umami (glutamate) taste	3	16.4×	0.014	SCN2A, SCN3A, SCN9A
Presynaptic depolarization and calcium channel opening	2	37.3×	0.021	CACNA1E, CACNA2D2
Transport to the Golgi and subsequent modification	4	8.1×	0.023	SEC24C, SPTAN1, ARFGAP1, ARFGAP3
Acetylcholine Neurotransmitter Release Cycle	2	26.3×	0.038	SNAP25, STXBP1
Synthesis of glycosylphosphatidylinositol (GPI)	2	24.9×	0.038	PIGQ, PIGP
Serotonin Neurotransmitter Release Cycle	2	24.9×	0.038	SNAP25, STXBP1
Norepinephrine Neurotransmitter Release Cycle	2	24.9×	0.038	SNAP25, STXBP1
Unblocking of NMDA receptors, glutamate binding and activation	2	21.3×	0.047	GRIA3, GRIN2A
Synaptic adhesion-like molecules	2	21.3×	0.047	GRIA3, GRIN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 63 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell action potential involved in contraction	5	55.7×	6e-06	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
sodium ion transmembrane transport	7	22.6×	6e-06	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, GRIN2A, HCN1
action potential	5	28.5×	1e-04	SCN8A, CHRNA4, KCNB1, KCNC2, KCNQ2
neuronal action potential	4	30.6×	0.001	SCN1A, SCN2A, SCN9A, HCN1
glutamate receptor signaling pathway	3	44.6×	0.004	GRIA3, GRIN2A, KCNB1
presynaptic dense core vesicle exocytosis	2	133.8×	0.006	SNAP25, STXBP1
obsolete vesicle docking involved in exocytosis	3	32.1×	0.006	STXBP1, GNAO1, KCNB1
sodium ion transport	4	17.3×	0.006	SCN1A, SCN2A, SCN3A, SCN8A
potassium ion transmembrane transport	5	10.8×	0.006	HCN1, KCNB1, KCNC2, KCNH5, KCNQ2
chemical synaptic transmission	6	7.4×	0.008	SNAP25, SLC12A5, CACNA1E, CHRNA4, GRIN2A, KCNQ2
malate-aspartate shuttle	2	59.4×	0.022	SLC25A22, GOT2
membrane depolarization during action potential	2	53.5×	0.022	SCN1A, SCN3A
response to L-glutamate	2	53.5×	0.022	HCN1, KCNB1
sensory perception of pain	3	17.8×	0.022	SCN9A, CHRNA4, GRIN2A
monoatomic ion transport	4	9.9×	0.023	SLC32A1, SLC12A5, CHRNA4, SLC25A22
positive regulation of calcium ion-dependent exocytosis	2	41.1×	0.032	STXBP1, KCNB1
ITP catabolic process	1	267.5×	0.037	ITPA
deoxyribonucleoside triphosphate catabolic process	1	267.5×	0.037	ITPA
cerebellar granular layer maturation	1	267.5×	0.037	CEND1
radial glia guided migration of cerebellar granule cell	1	267.5×	0.037	CEND1
embryonic genitalia morphogenesis	1	267.5×	0.037	FGF10
regulation of activin receptor signaling pathway	1	267.5×	0.037	FGF10
urothelial cell proliferation	1	267.5×	0.037	FGF10
positive regulation of urothelial cell proliferation	1	267.5×	0.037	FGF10
bronchiole morphogenesis	1	267.5×	0.037	FGF10
mesenchymal-epithelial cell signaling involved in lung development	1	267.5×	0.037	FGF10
fibroblast growth factor receptor signaling pathway involved in mammary gland specification	1	267.5×	0.037	FGF10
submandibular salivary gland formation	1	267.5×	0.037	FGF10
semicircular canal fusion	1	267.5×	0.037	FGF10
lung proximal/distal axis specification	1	267.5×	0.037	FGF10

Therapeutics

Drug target analysis

Approved (phase 4): 18 · Phase ≥3: 18 · Phased (≥1): 19 · Undrugged: 49

Druggability breadth: 37 of 68 evidence-associated genes (54%) 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
GRIN2A	MEMANTINE HYDROCHLORIDE
SCN1A	MEXILETINE HYDROCHLORIDE
SCN2A	BEPRIDIL
SCN3A	BEPRIDIL
SCN8A	IMIPRAMINE
SCN9A	IMIPRAMINE
SRMS	FEDRATINIB
CDKL5	FEDRATINIB
CACNA1E	NIMODIPINE
CACNA2D2	NIMODIPINE
ADRM1	BORTEZOMIB
TNK2	VEMURAFENIB
CHRNA4	VARENICLINE
DNM1	CETRIMIDE
AKR1A1	VALPROIC ACID
GABRA2	ENZALUTAMIDE
GRIA3	PERAMPANEL
KCNQ2	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
CHRNA4	64	4
TNK2	51	4
GABRA2	46	4
GRIN2A	37	4
SCN9A	36	4
SCN8A	25	4
SRMS	19	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEMANTINE HYDROCHLORIDE	4	GRIN2A
ESKETAMINE	4	GRIN2A
DEXTROMETHORPHAN	4	GRIN2A
PENTAMIDINE	4	GRIN2A
AMANTADINE	4	GRIN2A
KETAMINE	4	GRIN2A
CYCLOSERINE	4	GRIN2A
MEMANTINE	4	GRIN2A
TACRINE	4	CACNA1E, CACNA2D2, GRIN2A
LEVORPHANOL	4	GRIN2A, SCN1A, SCN2A, SCN3A
CHLORPROMAZINE	4	GRIN2A, SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A
QUINIDINE	4	SCN1A, SCN2A, SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

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

Symbol	Assays	Type breakdown
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
GABRA2	385	Binding:327, Functional:52, ADMET:3, Toxicity:3
TNK2	348	Binding:346, Functional:2
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SRMS	179	Binding:178, Functional:1
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
GRIA3	126	Binding:113, Functional:13
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
CDKL5	74	Binding:74
ADRM1	60	Binding:60
MAST3	38	Binding:38
KCNC2	32	Binding:31, Toxicity:1
KCNB1	28	Binding:27, Toxicity:1
AKR1A1	26	Binding:25, ADMET:1
HCN1	21	Binding:12, Functional:8, ADMET:1
KCNH5	21	Binding:20, Toxicity:1
CACNA2D2	17	Binding:17
CACNA1E	14	Binding:14
GNAO1	12	Functional:10, Binding:2
DNM1	11	Binding:11
EEF1A2	8	Binding:8
ITPA	8	Binding:8
SPTAN1	7	Binding:7
SLC12A5	6	Functional:4, Binding:2
GOT2	4	Binding:4
AK1	3	Binding:3
ADGRG1	3	Binding:3
ST3GAL3	2	Binding:2
ARFGAP1	2	Binding:2
SEC24C	1	Binding:1
STXBP1	1	Binding:1
GALNT3	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
SRMS	2.7.10.2	non-specific protein-tyrosine kinase
CDKL5	2.7.11.22	cyclin-dependent kinase
PIGQ	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
TNK2	2.7.10.2	non-specific protein-tyrosine kinase
B4GALNT4	2.4.1.244, 2.4.1.92	N-acetyl-beta-glucosaminyl-glycoprotein 4-beta-N-acetylgalactosaminyltransferase, (N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase
AK8	2.7.4.3	adenylate kinase
DNM1	3.6.5.5	dynamin GTPase
PIGP	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
AK1	2.7.4.3	adenylate kinase
AKR1A1	1.1.1.2	alcohol dehydrogenase (NADP+)
GALNT3	2.4.1.41	polypeptide N-acetylgalactosaminyltransferase
GOT2	2.6.1.1	aspartate transaminase
ITPA	3.6.1.66, 3.6.1.9	XTP/dITP diphosphatase, nucleotide diphosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRIN2A	324
SCN1A	149
SCN2A	203
SCN3A	102
SCN8A	173
SCN9A	428
SRMS	179
TNK2	348
CHRNA4	624
GABRA2	385
GRIA3	126
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 66; 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)
MEMANTINE HYDROCHLORIDE	4	GRIN2A
ESKETAMINE	4	GRIN2A
DEXTROMETHORPHAN	4	GRIN2A
PENTAMIDINE	4	GRIN2A
AMANTADINE	4	GRIN2A
KETAMINE	4	GRIN2A
CYCLOSERINE	4	GRIN2A
MEMANTINE	4	GRIN2A
TACRINE	4	CACNA1E, CACNA2D2, GRIN2A
LEVORPHANOL	4	GRIN2A, SCN1A, SCN2A, SCN3A
CHLORPROMAZINE	4	GRIN2A, SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A
QUINIDINE	4	SCN1A, SCN2A, SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	18	GRIN2A, SCN1A, SCN2A, SCN3A, SCN8A, SCN9A, SRMS, CDKL5, CACNA1E, CACNA2D2 (+8 more)
B	Phased (≥1) drug, not yet approved	1	SPTAN1
C	Druggable family + PDB, no drug	8	MAST3, AK1, GOT2, ADGRG1, HCN1, ITPA, KCNB1, KCNH5
D	Druggable family + AlphaFold only, no drug	9	ST3GAL3, PIGQ, SLC25A22, AMIGO3, B4GALNT4, AK8, PIGP, GALNT3, KCNC2
E	Difficult family or no structure, no drug	32	SEC24C, SLC32A1, SNAP25, STXBP1, SLC12A5, ARHGEF15, BSCL2, ARFGAP1, MRGBP, ABHD16B (+22 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A22	0	CDKL5
KCNC2	32	SCN3A, SCN1A, SCN2A
KCNH5	21	KCNQ2
SEC24C	1	—
ST3GAL3	2	—
SLC32A1	0	—
SNAP25	0	—
STXBP1	1	—
SLC12A5	6	—
PIGQ	0	—
ARHGEF15	0	—
BSCL2	0	—
ARFGAP1	2	—
MRGBP	0	—
ABHD16B	0	—
PPDPF	0	—
CIZ1	0	—
MAST3	38	—
CHD2	0	—
CUX2	0	—
ANO4	0	—
AMIGO3	0	—
CEND1	0	—
TTC21B	0	—
B4GALNT4	0	—
AK8	0	—
DYNC2I2	0	—
SZT2	0	—
HELZ2	0	—
PIGP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 22.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE3	4
PHASE2/PHASE3	2
PHASE2	2
PHASE1/PHASE2	2
PHASE1	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VIGABATRIN	4	3
CANNABIDIOL	4	1
CORTICOTROPIN	4	1
FENFLURAMINE	4	1
GLYCEROL PHENYLBUTYRATE	4	1
TRICAPRILIN	3	1
BEXICASERIN	2	1