Epilepsy with generalized tonic-clonic seizures

Summary

Epilepsy with generalized tonic-clonic seizures (MONDO:0005754) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy with generalized tonic-clonic seizures
Mondo ID	MONDO:0005754
EFO	EFO:0007262
MeSH	D004830
Orphanet	698005
DOID	DOID:7725
NCIT	C3022
SNOMED CT	352818000
UMLS	C0014549
MedGen	4987
GARD	0024228
Is cancer (heuristic)	no

Also known as: EGTCA · epilepsy with generalized tonic-clonic seizures alone · grand Mal epilepsy · tonic-clonic epilepsy

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › hereditary generalized epilepsy › idiopathic generalized epilepsy › variable-age onset idiopathic generalized epilepsy syndrome › epilepsy with generalized tonic-clonic seizures

Related subtypes (3): juvenile myoclonic epilepsy, juvenile absence epilepsy, epilepsy, idiopathic generalized 20

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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
208672	NM_130811.4(SNAP25):c.142G>T (p.Val48Phe)	SNAP25	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3896751	NM_001376.5(DYNC1H1):c.6341A>G (p.Glu2114Gly)	DYNC1H1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellum	1
pons	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
SNAP25	163

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
SNAP25	P60880	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Toxicity of botulinum toxin type C (botC)	1	1903.3×	0.011	SNAP25
Toxicity of botulinum toxin type E (botE)	1	1903.3×	0.011	SNAP25
Toxicity of botulinum toxin type A (botA)	1	1427.5×	0.011	SNAP25
Neurotoxicity of clostridium toxins	1	713.8×	0.015	SNAP25
Uptake and actions of bacterial toxins	1	407.9×	0.015	SNAP25
Acetylcholine Neurotransmitter Release Cycle	1	335.9×	0.015	SNAP25
Serotonin Neurotransmitter Release Cycle	1	317.2×	0.015	SNAP25
Norepinephrine Neurotransmitter Release Cycle	1	317.2×	0.015	SNAP25
GABA synthesis, release, reuptake and degradation	1	317.2×	0.015	SNAP25
Neutrophil degranulation	2	23.1×	0.015	SNAP25, DYNC1H1
Dopamine Neurotransmitter Release Cycle	1	248.3×	0.016	SNAP25
Other interleukin signaling	1	237.9×	0.016	SNAP25
Glutamate Neurotransmitter Release Cycle	1	228.4×	0.016	SNAP25
Neurotransmitter release cycle	1	219.6×	0.016	SNAP25
Bacterial Infection Pathways	1	167.9×	0.019	SNAP25
Sensory processing of sound	1	154.3×	0.019	SNAP25
Aggrephagy	1	124.1×	0.023	DYNC1H1
Regulation of insulin secretion	1	109.8×	0.024	SNAP25
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.024	DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.025	DYNC1H1
Integration of energy metabolism	1	87.8×	0.025	SNAP25
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.025	SNAP25
Loss of Nlp from mitotic centrosomes	1	79.3×	0.025	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.025	DYNC1H1
AURKA Activation by TPX2	1	76.1×	0.025	DYNC1H1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.027	DYNC1H1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.028	DYNC1H1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.028	DYNC1H1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.028	DYNC1H1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.028	DYNC1H1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
presynaptic dense core vesicle exocytosis	1	2106.5×	0.004	SNAP25
regulation of metaphase plate congression	1	1685.2×	0.004	DYNC1H1
establishment of spindle localization	1	1404.3×	0.004	DYNC1H1
positive regulation of spindle assembly	1	1053.2×	0.004	DYNC1H1
synaptic vesicle fusion to presynaptic active zone membrane	1	842.6×	0.004	SNAP25
positive regulation of intracellular transport	1	842.6×	0.004	DYNC1H1
retrograde axonal transport	1	766.0×	0.004	DYNC1H1
neurotransmitter uptake	1	702.2×	0.004	SNAP25
obsolete synaptic vesicle docking	1	648.1×	0.004	SNAP25
P-body assembly	1	526.6×	0.005	DYNC1H1
regulation of mitotic spindle organization	1	421.3×	0.005	DYNC1H1
synaptic vesicle priming	1	401.2×	0.005	SNAP25
synaptic vesicle exocytosis	1	383.0×	0.005	SNAP25
nuclear migration	1	366.4×	0.005	DYNC1H1
stress granule assembly	1	300.9×	0.006	DYNC1H1
associative learning	1	240.7×	0.007	SNAP25
regulation of neuron projection development	1	216.1×	0.007	SNAP25
regulation of insulin secretion	1	195.9×	0.007	SNAP25
cytoplasmic microtubule organization	1	172.0×	0.008	DYNC1H1
long-term synaptic potentiation	1	140.4×	0.009	SNAP25
mitotic spindle organization	1	135.9×	0.009	DYNC1H1
locomotory behavior	1	89.6×	0.013	SNAP25
positive regulation of cold-induced thermogenesis	1	81.8×	0.014	DYNC1H1
exocytosis	1	75.9×	0.014	SNAP25
chemical synaptic transmission	1	38.6×	0.027	SNAP25
cell division	1	23.1×	0.043	DYNC1H1

Therapeutics

Drugs indicated or in trials for this disease

2 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Lamotrigine	Approved (phase 4)
Levetiracetam	Approved (phase 4)

5 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Azetukalner	Phase 3
Clonazepam	Phase 3
Perampanel	Phase 3
Pregabalin	Phase 3
Topiramate	Phase 3

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYNC1H1	1	2
SNAP25	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DYNC1H1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DYNC1H1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	DYNC1H1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DYNC1H1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SNAP25

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SNAP25	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.