Epilepsy syndrome

Summary

Epilepsy syndrome (MONDO:0015650) is a disease (an umbrella term covering 8 Mondo subtypes) with 7 cohort genes and 6 clinical trials. Top therapeutic interventions include ezogabine.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 9
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy syndrome
Mondo ID	MONDO:0015650
Orphanet	166463
UMLS	C4505072
MedGen	1371141
GARD	0020083
Is cancer (heuristic)	no

Also known as: epileptic syndrome · syndromic epilepsy

Data availability: 9 ClinVar variants.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome

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

Subtypes (8): adolescence-adult electroclinical syndrome, benign focal seizures of adolescence, neonatal epilepsy syndrome, infantile epilepsy syndrome, childhood-onset epilepsy syndrome, neonatal/infantile epilepsy syndrome, myoclonic epilepsy, variable age epilepsy syndrome

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

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic, 1 pathogenic, low penetrance, 1 uncertain risk allele, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3062345	GRCh38/hg38 16p11.2(chr16:29642391-30204353)	ALDOA	Pathogenic, low penetrance	no assertion criteria provided
3062346	GRCh38/hg38 22q12.2-12.3(chr22:31684443-31987722)	DEPDC5	Pathogenic	no assertion criteria provided
39599	NM_020822.3(KCNT1):c.1193G>A (p.Arg398Gln)	KCNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062343	GRCh38/hg38 1p34.2(chr1:42278946-43598390)	PPIH	Pathogenic	no assertion criteria provided
3064268	NC_000014.9:g.(?87933020)(87956057_?)del	GALC	Uncertain risk allele	no assertion criteria provided
3062342	NC_000008.11:g.(?67476661)(67485906_?)del	ARFGEF1-DT	Uncertain significance	criteria provided, single submitter
3062361	GRCh38/hg38 Xp22.33(chrX:335525-805472)	CNE-3	Uncertain significance	no assertion criteria provided
3062344	GRCh38/hg38 13q21.32(chr13:65630901-67257385)	LINC01052	Uncertain significance	no assertion criteria provided
3062340	NC_000005.10:g.(?66758973)(67006046_?)del	LOC123493325	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
KCNT1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNT1	Orphanet:98784	Sleep-related hypermotor epilepsy
GALC	Orphanet:206436	Infantile Krabbe disease
GALC	Orphanet:206443	Late-infantile/juvenile Krabbe disease
GALC	Orphanet:206448	Adult Krabbe disease
ALDOA	Orphanet:57	Glycogen storage disease due to aldolase A deficiency

Cohort genes → proteins

7 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPIH	HGNC:14651	ENSG00000171960	O43447	Peptidyl-prolyl cis-trans isomerase H	clinvar
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	clinvar
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	clinvar
GALC	HGNC:4115	ENSG00000054983	P54803	Galactocerebrosidase	clinvar
ALDOA	HGNC:414	ENSG00000149925	P04075	Fructose-bisphosphate aldolase A	clinvar
LINC01052	HGNC:49046	ENSG00000234767		long intergenic non-protein coding RNA 1052	clinvar
ARFGEF1-DT	HGNC:55237	ENSG00000271966		ARFGEF1 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPIH	Peptidyl-prolyl cis-trans isomerase H	PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding.
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
GALC	Galactocerebrosidase	Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine.
ALDOA	Fructose-bisphosphate aldolase A	Catalyzes the reversible conversion of beta-D-fructose 1,6-bisphosphate (FBP) into two triose phosphate and plays a key role in glycolysis and gluconeogenesis.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.57

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
Enzyme (other)	3	5.1×	0.047
Ion channel	1	15.9×	0.092
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPIH	Enzyme (other)	yes	5.2.1.8	Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-type_PPIase
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
GALC	Enzyme (other)	yes	3.2.1.46	Glyco_hydro_59, Aldolase_TIM, GH_hydrolase_sf
ALDOA	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
LINC01052	Other/Unknown	no
ARFGEF1-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
embryo	1
ventricular zone	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adrenal tissue	1
bronchial epithelial cell	1
jejunal mucosa	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
bone marrow	1
bone marrow cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPIH	293	ubiquitous	marker	embryo, ventricular zone, ganglionic eminence
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
KCNT1	153	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GALC	295	ubiquitous	marker	adrenal tissue, bronchial epithelial cell, jejunal mucosa
ALDOA	134	ubiquitous	marker	skeletal muscle tissue, gastrocnemius, hindlimb stylopod muscle
LINC01052	42		yes	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
ARFGEF1-DT	127		yes	bone marrow cell, bone marrow, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDOA	3,591
PPIH	3,315
KCNT1	1,562
DEPDC5	1,273
GALC	1,154
LINC01052	0
ARFGEF1-DT	0

Intra-cohort edges

A	B	Sources
DEPDC5	KCNT1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPIH	O43447	11
DEPDC5	O75140	11
ALDOA	P04075	8
KCNT1	Q5JUK3	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GALC	P54803	94.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 7 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glucose metabolism	1	219.6×	0.047	ALDOA
Gluconeogenesis	1	109.8×	0.047	ALDOA
Glycosphingolipid catabolism	1	73.2×	0.047	GALC
Glycolysis	1	71.4×	0.047	ALDOA
SARS-CoV-1 activates/modulates innate immune responses	1	68.0×	0.047	PPIH
Amino acids regulate mTORC1	1	50.1×	0.053	DEPDC5
Response to elevated platelet cytosolic Ca2+	1	40.8×	0.056	ALDOA
Metabolism of carbohydrates and carbohydrate derivatives	1	30.1×	0.066	ALDOA
Platelet activation, signaling and aggregation	1	26.4×	0.066	ALDOA
Platelet degranulation	1	22.0×	0.072	ALDOA
mRNA Splicing - Major Pathway	1	13.7×	0.104	PPIH
Hemostasis	1	9.0×	0.142	ALDOA
Innate Immune System	1	6.4×	0.182	ALDOA
Neutrophil degranulation	1	5.8×	0.186	ALDOA
Immune System	1	3.2×	0.293	ALDOA
Metabolism	1	2.9×	0.302	ALDOA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein homotetramerization	2	94.9×	0.004	KCNT1, ALDOA
galactosylceramide catabolic process	1	1685.2×	0.007	GALC
fructose 1,6-bisphosphate metabolic process	1	421.3×	0.016	ALDOA
fructose metabolic process	1	337.0×	0.016	ALDOA
glycosphingolipid catabolic process	1	306.4×	0.016	GALC
ATP biosynthetic process	1	198.3×	0.020	ALDOA
striated muscle contraction	1	168.5×	0.020	ALDOA
canonical glycolysis	1	140.4×	0.021	ALDOA
muscle cell cellular homeostasis	1	129.6×	0.021	ALDOA
positive regulation of viral genome replication	1	116.2×	0.021	PPIH
binding of sperm to zona pellucida	1	84.3×	0.025	ALDOA
glycolytic process	1	76.6×	0.025	ALDOA
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	74.9×	0.025	ALDOA
negative regulation of TORC1 signaling	1	64.8×	0.025	DEPDC5
cellular response to amino acid starvation	1	63.6×	0.025	DEPDC5
myelination	1	50.3×	0.030	GALC
positive regulation of autophagy	1	41.6×	0.034	DEPDC5
potassium ion transmembrane transport	1	27.2×	0.048	KCNT1
regulation of cell shape	1	24.6×	0.049	ALDOA
actin filament organization	1	23.7×	0.049	ALDOA
protein-containing complex assembly	1	22.8×	0.049	PPIH
protein folding	1	20.7×	0.052	PPIH
mRNA splicing, via spliceosome	1	18.3×	0.056	PPIH
intracellular signal transduction	1	7.6×	0.124	DEPDC5

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 4 of 7 evidence-associated genes (57%) 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
KCNT1	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNT1	2	4
ALDOA	1	2
PPIH	0	0
DEPDC5	0	0
GALC	0	0
LINC01052	0	0
ARFGEF1-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNT1
QUINIDINE	4	KCNT1
MOLIBRESIB	2	ALDOA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
KCNT1	24	Binding:24
ALDOA	9	Binding:9
GALC	3	Binding:2, Functional:1
PPIH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPIH	5.2.1.8	peptidylprolyl isomerase
GALC	3.2.1.46	galactosylceramidase
ALDOA	4.1.2.13	fructose-bisphosphate aldolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
BEPRIDIL	4	KCNT1
QUINIDINE	4	KCNT1
MOLIBRESIB	2	ALDOA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNT1
B	Phased (≥1) drug, not yet approved	1	ALDOA
C	Druggable family + PDB, no drug	1	PPIH
D	Druggable family + AlphaFold only, no drug	1	GALC
E	Difficult family or no structure, no drug	3	DEPDC5, LINC01052, ARFGEF1-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PPIH	1	—
DEPDC5	0	—
GALC	3	—
LINC01052	0	—
ARFGEF1-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04639310	PHASE3	TERMINATED	XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
NCT04912856	PHASE3	TERMINATED	An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE
NCT04048213	Not specified	UNKNOWN	The Becoming of Children With Doose Syndrome
NCT05097742	Not specified	COMPLETED	Cognitive Impairments in Children With Epilepsy
NCT06222840	Not specified	COMPLETED	Electro-clinical Features and Functional Connectivity Analysis in SYN1 Gene Mutation-related Epilepsy
NCT06223334	Not specified	UNKNOWN	Epileptic Syndromes in Infants and Early Childhood

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EZOGABINE	4	2