Generalized epilepsy with febrile seizures plus, type 2

Summary

Generalized epilepsy with febrile seizures plus, type 2 (MONDO:0011461) is a disease caused by SCN1A (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SCN1A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 425

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized epilepsy with febrile seizures plus, type 2
Mondo ID	MONDO:0011461
MeSH	C565810
OMIM	604403
DOID	DOID:0111294
UMLS	C1858673
MedGen	388117
GARD	0018661
Is cancer (heuristic)	no

Also known as: febrile seizures, familial caused by mutation in SCN1A · GEFS+, type 2 · GEFSP2 · generalized epilepsy with febrile seizures plus, type 2 · SCN1A febrile seizures, familial

Data availability: 425 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › febrile seizures, familial › generalized epilepsy with febrile seizures plus, type 2

Related subtypes (12): febrile seizures, familial, 1, febrile seizures, familial, 2, febrile seizures, familial, 4, febrile seizures, familial, 8, febrile seizures, familial, 6, febrile seizures, familial, 5, febrile seizures, familial, 7, familial febrile seizures 9, febrile seizures, familial, 10, febrile seizures, familial, 11, febrile seizures, familial, 3a, febrile seizures, familial, 3b

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

425 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 108 pathogenic, 90 conflicting classifications of pathogenicity, 51 likely pathogenic, 36 pathogenic/likely pathogenic, 21 benign/likely benign, 7 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1210335	NM_001165963.4(SCN1A):c.4999del (p.Leu1667fs)	LOC102724058	Pathogenic	criteria provided, single submitter
12882	NM_001165963.4(SCN1A):c.4943G>A (p.Arg1648His)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
12885	NM_001165963.4(SCN1A):c.4057G>C (p.Val1353Leu)	LOC102724058	Pathogenic	no assertion criteria provided
12886	NM_001165963.4(SCN1A):c.4968C>G (p.Ile1656Met)	LOC102724058	Pathogenic	criteria provided, single submitter
12887	NM_001165963.4(SCN1A):c.3610T>C (p.Trp1204Arg)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
12895	NM_001165963.4(SCN1A):c.4831G>T (p.Val1611Phe)	LOC102724058	Pathogenic	no assertion criteria provided
1454054	NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167639	NM_001165963.4(SCN1A):c.3733C>T (p.Arg1245Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
1686139	NM_001165963.4(SCN1A):c.5318_5324del (p.Ser1773fs)	LOC102724058	Pathogenic	criteria provided, single submitter
1686143	NM_001165963.4(SCN1A):c.4284+2del	LOC102724058	Pathogenic	criteria provided, single submitter
1686144	NM_001165963.4(SCN1A):c.4112G>A (p.Gly1371Asp)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686145	NM_001165963.4(SCN1A):c.3950C>G (p.Thr1317Arg)	LOC102724058	Pathogenic	criteria provided, single submitter
1700151	NM_001165963.4(SCN1A):c.3550+2T>G	LOC102724058	Pathogenic	criteria provided, single submitter
189870	NM_001165963.4(SCN1A):c.4906C>T (p.Arg1636Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189881	NM_001165963.4(SCN1A):c.5536_5539del (p.Lys1846fs)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189896	NM_001165963.4(SCN1A):c.5674C>T (p.Arg1892Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189921	NM_001165963.4(SCN1A):c.4933C>T (p.Arg1645Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189990	NM_001165963.4(SCN1A):c.4055T>C (p.Leu1352Pro)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
206811	NM_001165963.4(SCN1A):c.3850T>C (p.Trp1284Arg)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206837	NM_001165963.4(SCN1A):c.4547C>A (p.Ser1516Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
224116	NM_001165963.4(SCN1A):c.4002+2451G>C	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
2584345	NM_001165963.4(SCN1A):c.4620_4627del (p.Arg1540fs)	LOC102724058	Pathogenic	criteria provided, single submitter
381568	NM_001165963.4(SCN1A):c.4913T>A (p.Ile1638Asn)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4056328	NM_001165963.4(SCN1A):c.4970G>C (p.Arg1657Pro)	LOC102724058	Pathogenic	criteria provided, single submitter
4819944	NM_001165963.4(SCN1A):c.5343C>G (p.Tyr1781Ter)	LOC102724058	Pathogenic	criteria provided, single submitter
68533	NM_001165963.4(SCN1A):c.3734G>A (p.Arg1245Gln)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68551	NM_001165963.4(SCN1A):c.4633A>G (p.Ile1545Val)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68553	NM_001165963.4(SCN1A):c.4786C>T (p.Arg1596Cys)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68558	NM_001165963.4(SCN1A):c.4934G>A (p.Arg1645Gln)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68559	NM_001165963.4(SCN1A):c.4970G>A (p.Arg1657His)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 9 · 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
SCN1A	Definitive	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 2	20

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
RELN	Orphanet:101046	Epilepsy with auditory features
RELN	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc,clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar
RELN	HGNC:9957	ENSG00000189056	P78509	Reelin	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.
RELN	Reelin	Extracellular matrix serine protease secreted by pioneer neurons that plays a role in layering of neurons in the cerebral cortex and cerebellum by coordinating cell positioning during neurodevelopment.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN1A-AS1	Other/Unknown	no
RELN	Other/Unknown	no		EGF, Reeler_dom, EGF_extracell

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
primary visual cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1
cerebellar vermis	1
cerebellum	1
olfactory bulb	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
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
RELN	254	broad	marker	olfactory bulb, cerebellar vermis, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RELN	2,305
SCN1A	2,287
SCN1A-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1A	P35498	1
RELN	P78509	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reelin signalling pathway	1	951.7×	0.009	RELN
Interaction between L1 and Ankyrins	1	184.2×	0.017	SCN1A
Phase 0 - rapid depolarisation	1	173.0×	0.017	SCN1A
L1CAM interactions	1	60.1×	0.033	SCN1A
Cardiac conduction	1	54.4×	0.033	SCN1A
Muscle contraction	1	38.6×	0.039	SCN1A
Axon guidance	1	22.6×	0.052	SCN1A
Nervous system development	1	21.5×	0.052	SCN1A
Developmental Biology	1	7.2×	0.134	SCN1A

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
spinal cord patterning	1	8426.0×	0.003	RELN
positive regulation of lateral motor column neuron migration	1	8426.0×	0.003	RELN
lateral motor column neuron migration	1	2808.7×	0.005	RELN
cerebral cortex tangential migration	1	2106.5×	0.005	RELN
regulation of synaptic activity	1	2106.5×	0.005	RELN
NMDA glutamate receptor clustering	1	1685.2×	0.005	RELN
postsynaptic density protein 95 clustering	1	1404.3×	0.005	RELN
positive regulation of small GTPase mediated signal transduction	1	1053.2×	0.005	RELN
receptor localization to synapse	1	1053.2×	0.005	RELN
ventral spinal cord development	1	936.2×	0.005	RELN
positive regulation of synapse maturation	1	936.2×	0.005	RELN
postsynaptic density assembly	1	936.2×	0.005	RELN
membrane depolarization during action potential	1	842.6×	0.005	SCN1A
radial glial cell differentiation	1	766.0×	0.005	RELN
interneuron migration	1	766.0×	0.005	RELN
neuronal action potential propagation	1	702.2×	0.005	SCN1A
regulation of behavior	1	702.2×	0.005	RELN
reelin-mediated signaling pathway	1	601.9×	0.005	RELN
layer formation in cerebral cortex	1	561.7×	0.005	RELN
detection of mechanical stimulus involved in sensory perception of pain	1	561.7×	0.005	SCN1A
neuromuscular process controlling posture	1	526.6×	0.005	SCN1A
nerve development	1	468.1×	0.005	SCN1A
glial cell differentiation	1	443.5×	0.005	RELN
response to pain	1	443.5×	0.005	RELN
positive regulation of dendritic spine morphogenesis	1	443.5×	0.005	RELN
protein localization to synapse	1	383.0×	0.006	RELN
regulation of neuron differentiation	1	366.4×	0.006	RELN
cardiac muscle cell action potential involved in contraction	1	351.1×	0.006	SCN1A
positive regulation of long-term synaptic potentiation	1	337.0×	0.006	RELN
positive regulation of synaptic transmission, glutamatergic	1	312.1×	0.006	RELN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
SCN1A-AS1	0	0
RELN	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
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
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
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): 0.

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

Symbol	Assays	Type breakdown
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149

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

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
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
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
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)	1	SCN1A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SCN1A-AS1, RELN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCN1A-AS1	0	—
RELN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.