Autosomal dominant epilepsy with auditory features

Summary

Autosomal dominant epilepsy with auditory features (MONDO:0010898) is a disease caused by LGI1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: LGI1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 411
• Phenotypes (HPO): 19

Clinical features

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0007359	Focal-onset seizure	Very frequent (80-99%)
HP:0008765	Auditory hallucinations	Very frequent (80-99%)
HP:0011185	EEG with focal epileptiform discharges	Very frequent (80-99%)
HP:0002381	Aphasia	Frequent (30-79%)
HP:0011182	Interictal epileptiform activity	Frequent (30-79%)
HP:0002349	Focal aware seizure	Occasional (5-29%)
HP:0002367	Visual hallucinations	Occasional (5-29%)
HP:0011154	Focal autonomic seizure	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)
HP:0031951	Nocturnal seizures	Occasional (5-29%)
HP:0001249	Intellectual disability	Excluded (0%)
HP:0410263	Brain imaging abnormality	Excluded (0%)
HP:0000708	Atypical behavior	Very rare (<1-4%)
HP:0000716	Depression	Very rare (<1-4%)
HP:0002069	Bilateral tonic-clonic seizure	Very rare (<1-4%)
HP:0002076	Migraine	Very rare (<1-4%)
HP:0002197	Generalized-onset seizure	Very rare (<1-4%)
HP:0007334	Bilateral tonic-clonic seizure with focal onset	Very rare (<1-4%)
HP:0100710	Impulsivity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant epilepsy with auditory features
Mondo ID	MONDO:0010898
MeSH	C537297
Orphanet	101046
ICD-11	832717248
UMLS	C1838062
MedGen	325326
GARD	0002257
Is cancer (heuristic)	no

Also known as: ADEAF · ADLTE · adolescent/adult onset autosomal dominant epilepsy with auditory features · ADPEAF · Autosomal dominant epilepsy with auditory features · autosomal dominant epilepsy with auditory features · autosomal dominant lateral temporal lobe epilepsy · autosomal dominant partial epilepsy with auditory features · autosomal dominant partial/lateral temporal epilepsy with auditory features · partial epilepsy with auditory aura · partial epilepsy with auditory features

Data availability: 411 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

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 › autosomal dominant epilepsy with auditory features

Related subtypes (6): familial sleep-related hypermotor epilepsy, temporal lobe epilepsy, self-limited epilepsy with centrotemporal spikes, generalized epilepsy-paroxysmal dyskinesia syndrome, familial focal epilepsy with variable foci, mesial temporal lobe epilepsy with hippocampal sclerosis

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

411 retrieved; paginated sample, class counts are floors:

188 uncertain significance, 144 likely benign, 30 conflicting classifications of pathogenicity, 27 pathogenic, 6 likely pathogenic, 6 benign/likely benign, 5 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
833253	NC_000010.11:g.(?93161309)(93797823_?)del	CEP55	Pathogenic	criteria provided, single submitter
1069952	NM_005097.4(LGI1):c.446_449del (p.Asn149fs)	LGI1	Pathogenic	criteria provided, single submitter
1071970	NC_000010.10:g.(?95517882)(95537394_?)del	LGI1	Pathogenic	criteria provided, single submitter
1075145	NM_005097.4(LGI1):c.795G>A (p.Trp265Ter)	LGI1	Pathogenic	criteria provided, single submitter
1075701	NM_005097.4(LGI1):c.1118T>A (p.Leu373Ter)	LGI1	Pathogenic	criteria provided, single submitter
1076005	NM_005097.4(LGI1):c.108del (p.Lys36fs)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365772	NM_005097.4(LGI1):c.1252C>T (p.Gln418Ter)	LGI1	Pathogenic	criteria provided, single submitter
1410458	NM_005097.4(LGI1):c.1599dup (p.Asn534Ter)	LGI1	Pathogenic	criteria provided, single submitter
1455204	NM_005097.4(LGI1):c.988C>T (p.Arg330Ter)	LGI1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458021	NM_005097.4(LGI1):c.443dup (p.Asn148fs)	LGI1	Pathogenic	criteria provided, single submitter
2000198	NM_005097.4(LGI1):c.1396C>T (p.Gln466Ter)	LGI1	Pathogenic	criteria provided, single submitter
208478	NM_005097.4(LGI1):c.1420C>T (p.Arg474Ter)	LGI1	Pathogenic	criteria provided, single submitter
208480	NM_005097.4(LGI1):c.1418C>T (p.Ser473Leu)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425295	NC_000010.10:g.(?95517902)(95518136_?)del	LGI1	Pathogenic	criteria provided, single submitter
2735458	NM_005097.4(LGI1):c.598del (p.Cys200fs)	LGI1	Pathogenic	criteria provided, single submitter
2746608	NM_005097.4(LGI1):c.1104C>A (p.Tyr368Ter)	LGI1	Pathogenic	criteria provided, single submitter
2756254	NM_005097.4(LGI1):c.600C>A (p.Cys200Ter)	LGI1	Pathogenic	criteria provided, single submitter
2839772	NM_005097.4(LGI1):c.416del (p.Lys139fs)	LGI1	Pathogenic	criteria provided, single submitter
3244840	NC_000010.10:g.(?95517902)(95518608_?)del	LGI1	Pathogenic	criteria provided, single submitter
408590	NM_005097.4(LGI1):c.1128G>A (p.Trp376Ter)	LGI1	Pathogenic	criteria provided, single submitter
408592	NM_005097.4(LGI1):c.688C>T (p.Gln230Ter)	LGI1	Pathogenic	criteria provided, single submitter
464744	NM_005097.4(LGI1):c.1256T>G (p.Leu419Ter)	LGI1	Pathogenic	criteria provided, single submitter
464746	NM_005097.4(LGI1):c.1439_1442del (p.Gln480fs)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4733625	NM_005097.4(LGI1):c.942del (p.Phe314fs)	LGI1	Pathogenic	criteria provided, single submitter
4733798	NM_005097.4(LGI1):c.808_809del (p.Lys270fs)	LGI1	Pathogenic	criteria provided, single submitter
4735529	NM_005097.4(LGI1):c.1035C>G (p.Tyr345Ter)	LGI1	Pathogenic	criteria provided, single submitter
533337	NM_005097.4(LGI1):c.1158_1168dup (p.Thr390delinsLysTer)	LGI1	Pathogenic	criteria provided, single submitter
5433	NM_005097.4(LGI1):c.136T>C (p.Cys46Arg)	LGI1	Pathogenic	criteria provided, single submitter
5438	NM_005097.4(LGI1):c.406C>T (p.Arg136Trp)	LGI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
583153	NM_005097.4(LGI1):c.386C>G (p.Ser129Ter)	LGI1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 8 · 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
DEPDC5	Definitive	Autosomal dominant	epilepsy, familial focal, with variable foci 1	11
LGI1	Definitive	Autosomal dominant	autosomal dominant epilepsy with auditory features	4
RELN	Strong	Autosomal dominant	familial temporal lobe epilepsy 7	11
MICAL1	Moderate	Autosomal dominant	autosomal dominant epilepsy with auditory features	2

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LGI1	HGNC:6572	ENSG00000108231	O95970	Leucine-rich glioma-inactivated protein 1	gencc,clinvar
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	gencc
MICAL1	HGNC:20619	ENSG00000135596	Q8TDZ2	[F-actin]-monooxygenase MICAL1	gencc
RELN	HGNC:9957	ENSG00000189056	P78509	Reelin	gencc
CEP55	HGNC:1161	ENSG00000138180	Q53EZ4	Centrosomal protein of 55 kDa	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.
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.
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.
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.
CEP55	Centrosomal protein of 55 kDa	Plays a role in mitotic exit and cytokinesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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	1	1.6×	0.476
Other/Unknown	4	1.4×	0.476

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
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
MICAL1	Transcription factor	no	1.14.13.225	CH_dom, Znf_LIM, FAD-bd
RELN	Other/Unknown	no		EGF, Reeler_dom, EGF_extracell
CEP55	Other/Unknown	no		EABR, CEP55

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
pons	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
granulocyte	1
left coronary artery	1
right coronary artery	1
cerebellar vermis	1
cerebellum	1
olfactory bulb	1
primordial germ cell in gonad	1
secondary oocyte	1
ventricular zone	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
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
MICAL1	234	ubiquitous	marker	right coronary artery, granulocyte, left coronary artery
RELN	254	broad	marker	olfactory bulb, cerebellar vermis, cerebellum
CEP55	189	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CEP55	2,662
RELN	2,305
DEPDC5	1,273
MICAL1	1,045
LGI1	1,038

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DEPDC5	O75140	11
MICAL1	Q8TDZ2	11
LGI1	O95970	9
CEP55	Q53EZ4	4
RELN	P78509	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 5 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
Reelin signalling pathway	1	475.8×	0.013	RELN
LGI-ADAM interactions	1	203.9×	0.015	LGI1
Amino acids regulate mTORC1	1	50.1×	0.040	DEPDC5
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.088	MICAL1
Hemostasis	1	9.0×	0.128	MICAL1
Developmental Biology	1	3.6×	0.249	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 5 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	3370.4×	0.010	RELN
positive regulation of lateral motor column neuron migration	1	3370.4×	0.010	RELN
sulfur oxidation	1	1685.2×	0.010	MICAL1
regulation of regulated secretory pathway	1	1685.2×	0.010	MICAL1
lateral motor column neuron migration	1	1123.5×	0.010	RELN
cerebral cortex tangential migration	1	842.6×	0.010	RELN
regulation of synaptic activity	1	842.6×	0.010	RELN
axon guidance	2	36.2×	0.010	LGI1, RELN
NMDA glutamate receptor clustering	1	674.1×	0.011	RELN
postsynaptic density protein 95 clustering	1	561.7×	0.012	RELN
positive regulation of small GTPase mediated signal transduction	1	421.3×	0.012	RELN
receptor localization to synapse	1	421.3×	0.012	RELN
ventral spinal cord development	1	374.5×	0.012	RELN
positive regulation of synapse maturation	1	374.5×	0.012	RELN
postsynaptic density assembly	1	374.5×	0.012	RELN
radial glial cell differentiation	1	306.4×	0.012	RELN
interneuron migration	1	306.4×	0.012	RELN
regulation of behavior	1	280.9×	0.013	RELN
actin filament depolymerization	1	259.3×	0.013	MICAL1
reelin-mediated signaling pathway	1	240.7×	0.013	RELN
layer formation in cerebral cortex	1	224.7×	0.013	RELN
positive regulation of synaptic transmission	1	224.7×	0.013	LGI1
cranial skeletal system development	1	187.2×	0.014	CEP55
glial cell differentiation	1	177.4×	0.014	RELN
response to pain	1	177.4×	0.014	RELN
positive regulation of dendritic spine morphogenesis	1	177.4×	0.014	RELN
neurotransmitter receptor localization to postsynaptic specialization membrane	1	160.5×	0.015	LGI1
protein localization to synapse	1	153.2×	0.015	RELN
regulation of neuron differentiation	1	146.5×	0.015	RELN
midbody abscission	1	146.5×	0.015	CEP55

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LGI1	0	0
DEPDC5	0	0
MICAL1	0	0
RELN	0	0
CEP55	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MICAL1	1.14.13.225	F-actin monooxygenase

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	LGI1, DEPDC5, MICAL1, RELN, CEP55

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)
LGI1	0	—
DEPDC5	0	—
MICAL1	0	—
RELN	0	—
CEP55	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.