Epilepsy, familial temporal lobe, 1

Summary

Epilepsy, familial temporal lobe, 1 (MONDO:0700090) is a disease caused by LGI1 (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: LGI1 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 161

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, familial temporal lobe, 1
Mondo ID	MONDO:0700090
OMIM	600512
DOID	DOID:0060748
NCIT	C141441
GARD	0026356
Is cancer (heuristic)	no

Also known as: ADLTE · ADPEAF · epilepsy, familial temporal lobe, type 1 · epilepsy, lateral temporal lobe, autosomal dominant · epilepsy, partial, with auditory features · ETL1

Data availability: 161 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › temporal lobe epilepsy › epilepsy, familial temporal lobe, 1

Related subtypes (5): familial temporal lobe epilepsy 2, familial temporal lobe epilepsy 4, familial temporal lobe epilepsy 7, familial temporal lobe epilepsy 8, familial mesial temporal lobe epilepsy

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

161 retrieved; paginated sample, class counts are floors:

57 conflicting classifications of pathogenicity, 42 uncertain significance, 18 benign/likely benign, 15 pathogenic, 13 likely pathogenic, 6 likely benign, 4 benign, 3 not provided, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
833253	NC_000010.11:g.(?93161309)(93797823_?)del	CEP55	Pathogenic	criteria provided, single submitter
39001	NM_012330.4(KAT6B):c.4205_4206del (p.Ser1402fs)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
1455204	NM_005097.4(LGI1):c.988C>T (p.Arg330Ter)	LGI1	Pathogenic	criteria provided, multiple submitters, no conflicts
1527920	NM_005097.4(LGI1):c.1442del (p.Pro481fs)	LGI1	Pathogenic	criteria provided, single submitter
208125	NM_005097.4(LGI1):c.1013T>C (p.Phe338Ser)	LGI1	Pathogenic	criteria provided, single submitter
208478	NM_005097.4(LGI1):c.1420C>T (p.Arg474Ter)	LGI1	Pathogenic	criteria provided, single submitter
208479	NC_000010.11:g.(93704377_?)_(?_93785620)del	LGI1	Pathogenic	no assertion criteria provided
208480	NM_005097.4(LGI1):c.1418C>T (p.Ser473Leu)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5430	NM_005097.4(LGI1):c.1148A>C (p.Glu383Ala)	LGI1	Pathogenic	no assertion criteria provided
5431	NM_005097.4(LGI1):c.611del (p.Pro204fs)	LGI1	Pathogenic	no assertion criteria provided
5432	NM_005097.4(LGI1):c.360-3C>A	LGI1	Pathogenic	no assertion criteria provided
5433	NM_005097.4(LGI1):c.136T>C (p.Cys46Arg)	LGI1	Pathogenic	criteria provided, single submitter
5435	NM_005097.4(LGI1):c.953T>G (p.Phe318Cys)	LGI1	Pathogenic	no assertion criteria provided
5437	NM_005097.4(LGI1):c.695T>C (p.Leu232Pro)	LGI1	Pathogenic	no assertion criteria provided
5438	NM_005097.4(LGI1):c.406C>T (p.Arg136Trp)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5439	NM_005097.4(LGI1):c.365T>A (p.Ile122Lys)	LGI1	Pathogenic	no assertion criteria provided
641538	NM_005097.4(LGI1):c.1580_1581del (p.His527fs)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1525979	NM_022765.4(MICAL1):c.-43-1G>A	MICAL1	Pathogenic	no assertion criteria provided
1028856	NM_005097.4(LGI1):c.287+1G>A	LGI1	Likely pathogenic	criteria provided, single submitter
1683626	NM_005097.4(LGI1):c.1095del (p.Asn365fs)	LGI1	Likely pathogenic	criteria provided, single submitter
2627607	NM_005097.4(LGI1):c.187del (p.Arg63fs)	LGI1	Likely pathogenic	criteria provided, single submitter
2664977	NM_005097.4(LGI1):c.701_702dup (p.Gln235fs)	LGI1	Likely pathogenic	criteria provided, single submitter
2691875	NM_005097.4(LGI1):c.682_683del (p.Lys228fs)	LGI1	Likely pathogenic	criteria provided, single submitter
3383206	NM_005097.4(LGI1):c.953T>C (p.Phe318Ser)	LGI1	Likely pathogenic	criteria provided, single submitter
3770199	NM_005097.4(LGI1):c.749dup (p.Val251fs)	LGI1	Likely pathogenic	criteria provided, single submitter
3770200	NM_005097.4(LGI1):c.794G>A (p.Trp265Ter)	LGI1	Likely pathogenic	criteria provided, single submitter
3901090	NM_005097.4(LGI1):c.856T>G (p.Cys286Gly)	LGI1	Likely pathogenic	criteria provided, single submitter
5436	NM_005097.4(LGI1):c.431+1G>A	LGI1	Likely pathogenic	criteria provided, single submitter
982819	NM_005097.4(LGI1):c.4G>T (p.Glu2Ter)	LGI1	Likely pathogenic	criteria provided, single submitter
996744	NM_005097.4(LGI1):c.215+2T>A	LGI1	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 12 · 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
LGI1	Definitive	Autosomal dominant	autosomal dominant epilepsy with auditory features	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LGI1	Orphanet:101046	Epilepsy with auditory features
CEP55	Orphanet:500135	Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
MICAL1	Orphanet:101046	Epilepsy with auditory features
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
RELN	Orphanet:101046	Epilepsy with auditory features
RELN	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LGI1	HGNC:6572	ENSG00000108231	O95970	Leucine-rich glioma-inactivated protein 1	gencc,clinvar
CEP55	HGNC:1161	ENSG00000138180	Q53EZ4	Centrosomal protein of 55 kDa	clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
MICAL1	HGNC:20619	ENSG00000135596	Q8TDZ2	[F-actin]-monooxygenase MICAL1	clinvar
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	clinvar
SLC26A5-AS1	HGNC:55680	ENSG00000234715		SLC26A5 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)
LGI1	Leucine-rich glioma-inactivated protein 1	Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1.
CEP55	Centrosomal protein of 55 kDa	Plays a role in mitotic exit and cytokinesis.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
MICAL1	[F-actin]-monooxygenase MICAL1	Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization.
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+).
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: 0 · Difficult: 2 · Unknown: 5 · 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
Transcription factor	2	2.4×	0.332
Other/Unknown	5	1.3×	0.332

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LGI1	Other/Unknown	no		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
CEP55	Other/Unknown	no		EABR, CEP55
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
MICAL1	Transcription factor	no	1.14.13.225	CH_dom, Znf_LIM, FAD-bd
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
SLC26A5-AS1	Other/Unknown	no
RELN	Other/Unknown	no		EGF, Reeler_dom, EGF_extracell

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
Brodmann (1909) area 23	2
endothelial cell	2
secondary oocyte	2
ventricular zone	2
pons	1
primordial germ cell in gonad	1
cortical plate	1
sural nerve	1
granulocyte	1
left coronary artery	1
right coronary artery	1
middle temporal gyrus	1
colonic epithelium	1
oocyte	1
cerebellar vermis	1
cerebellum	1
olfactory bulb	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LGI1	195	broad	marker	pons, Brodmann (1909) area 23, endothelial cell
CEP55	189	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, secondary oocyte
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
MICAL1	234	ubiquitous	marker	right coronary artery, granulocyte, left coronary artery
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
SLC26A5-AS1	111		yes	colonic epithelium, secondary oocyte, oocyte
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
GRIN2A	3,146
CEP55	2,662
RELN	2,305
KAT6B	2,214
MICAL1	1,045
LGI1	1,038
SLC26A5-AS1	0

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2A	Q12879	37
MICAL1	Q8TDZ2	11
LGI1	O95970	9
CEP55	Q53EZ4	4
KAT6B	Q8WYB5	3
RELN	P78509	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 7 evidence-associated genes (5 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 5 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	380.7×	0.022	RELN
LGI-ADAM interactions	1	163.1×	0.022	LGI1
MECP2 regulates neuronal receptors and channels	1	120.2×	0.022	GRIN2A
Unblocking of NMDA receptors, glutamate binding and activation	1	108.8×	0.022	GRIN2A
Synaptic adhesion-like molecules	1	108.8×	0.022	GRIN2A
Negative regulation of NMDA receptor-mediated neuronal transmission	1	108.8×	0.022	GRIN2A
Long-term potentiation	1	95.2×	0.022	GRIN2A
Assembly and cell surface presentation of NMDA receptors	1	50.8×	0.037	GRIN2A
Neurexins and neuroligins	1	39.4×	0.042	GRIN2A
Chromatin organization	1	16.3×	0.084	KAT6B
HATs acetylate histones	1	15.9×	0.084	KAT6B
Chromatin modifying enzymes	1	14.5×	0.084	KAT6B
Factors involved in megakaryocyte development and platelet production	1	13.3×	0.084	MICAL1
Hemostasis	1	7.2×	0.141	MICAL1
Developmental Biology	1	2.9×	0.301	LGI1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of synaptic transmission, glutamatergic	2	208.1×	0.003	GRIN2A, RELN
positive regulation of excitatory postsynaptic potential	2	175.5×	0.003	GRIN2A, RELN
long-term synaptic potentiation	2	93.6×	0.006	GRIN2A, RELN
spinal cord patterning	1	2808.7×	0.007	RELN
positive regulation of lateral motor column neuron migration	1	2808.7×	0.007	RELN
sulfur oxidation	1	1404.3×	0.010	MICAL1
regulation of regulated secretory pathway	1	1404.3×	0.010	MICAL1
directional locomotion	1	936.2×	0.011	GRIN2A
lateral motor column neuron migration	1	936.2×	0.011	RELN
protein localization to postsynaptic membrane	1	936.2×	0.011	GRIN2A
cerebral cortex tangential migration	1	702.2×	0.012	RELN
regulation of synaptic activity	1	702.2×	0.012	RELN
NMDA glutamate receptor clustering	1	561.7×	0.013	RELN
axon guidance	2	30.2×	0.013	LGI1, RELN
postsynaptic density protein 95 clustering	1	468.1×	0.013	RELN
sleep	1	401.2×	0.013	GRIN2A
regulation of developmental process	1	401.2×	0.013	KAT6B
positive regulation of small GTPase mediated signal transduction	1	351.1×	0.013	RELN
receptor localization to synapse	1	351.1×	0.013	RELN
regulation of monoatomic cation transmembrane transport	1	351.1×	0.013	GRIN2A
ventral spinal cord development	1	312.1×	0.013	RELN
positive regulation of synapse maturation	1	312.1×	0.013	RELN
postsynaptic density assembly	1	312.1×	0.013	RELN
brain development	2	26.5×	0.013	GRIN2A, RELN
serotonin metabolic process	1	280.9×	0.013	GRIN2A
radial glial cell differentiation	1	255.3×	0.013	RELN
calcium ion transmembrane import into cytosol	1	255.3×	0.013	GRIN2A
regulation of hemopoiesis	1	255.3×	0.013	KAT6B
interneuron migration	1	255.3×	0.013	RELN
regulation of behavior	1	234.1×	0.014	RELN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 2 of 7 evidence-associated genes (29%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIN2A	37	4
LGI1	0	0
CEP55	0	0
KAT6B	0	0
MICAL1	0	0
SLC26A5-AS1	0	0
RELN	0	0

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	GRIN2A
LEVORPHANOL	4	GRIN2A
CHLORPROMAZINE	4	GRIN2A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
ESMETHADONE	3	GRIN2A
DALZANEMDOR	3	GRIN2A
LATREPIRDINE	3	GRIN2A
GLUTAMIC ACID	3	GRIN2A
DEXOXADROL	2	GRIN2A
DEXTRORPHAN	2	GRIN2A
LEVOMETHADONE	2	GRIN2A
ALPHAMETHADOL	2	GRIN2A
BETAMETHADOL	2	GRIN2A
DIMEMORFAN	2	GRIN2A
PHENCYCLIDINE	2	GRIN2A
DIZOCILPINE	2	GRIN2A
ETOXADROL	2	GRIN2A
IFENPRODIL	2	GRIN2A
TEZAMPANEL ANHYDROUS	2	GRIN2A
TRAXOPRODIL	2	GRIN2A
RADIPRODIL	2	GRIN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
KAT6B	22	Binding:20, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase
MICAL1	1.14.13.225	F-actin monooxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRIN2A	324

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	GRIN2A
LEVORPHANOL	4	GRIN2A
CHLORPROMAZINE	4	GRIN2A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
ESMETHADONE	3	GRIN2A
DALZANEMDOR	3	GRIN2A
LATREPIRDINE	3	GRIN2A
GLUTAMIC ACID	3	GRIN2A
DEXOXADROL	2	GRIN2A
DEXTRORPHAN	2	GRIN2A
LEVOMETHADONE	2	GRIN2A
ALPHAMETHADOL	2	GRIN2A
BETAMETHADOL	2	GRIN2A
DIMEMORFAN	2	GRIN2A
PHENCYCLIDINE	2	GRIN2A
DIZOCILPINE	2	GRIN2A
ETOXADROL	2	GRIN2A
IFENPRODIL	2	GRIN2A
TEZAMPANEL ANHYDROUS	2	GRIN2A
TRAXOPRODIL	2	GRIN2A
RADIPRODIL	2	GRIN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIN2A
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	6	LGI1, CEP55, KAT6B, MICAL1, SLC26A5-AS1, RELN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LGI1	0	—
CEP55	0	—
KAT6B	22	—
MICAL1	0	—
SLC26A5-AS1	0	—
RELN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.