Autosomal dominant nocturnal frontal lobe epilepsy 1

Summary

Autosomal dominant nocturnal frontal lobe epilepsy 1 (MONDO:0010899) is a disease caused by CHRNA4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: CHRNA4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 85

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nocturnal frontal lobe epilepsy 1
Mondo ID	MONDO:0010899
MeSH	C563930
OMIM	600513
DOID	DOID:0060682
UMLS	C1838049
MedGen	324932
GARD	0015319
Is cancer (heuristic)	no

Also known as: autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in CHRNA4 · autosomal dominant nocturnal frontal lobe epilepsy type 1 · CHRNA4 autosomal dominant nocturnal frontal lobe epilepsy · ENFL1 · epilepsy, nocturnal frontal lobe, 1 · epilepsy, nocturnal frontal lobe, type 1

Data availability: 85 ClinVar variants · 2 GenCC gene-disease records.

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 › familial sleep-related hypermotor epilepsy › autosomal dominant nocturnal frontal lobe epilepsy 1

Related subtypes (4): autosomal dominant nocturnal frontal lobe epilepsy 2, autosomal dominant nocturnal frontal lobe epilepsy 3, autosomal dominant nocturnal frontal lobe epilepsy 4, autosomal dominant nocturnal frontal lobe epilepsy 5

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

85 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 27 conflicting classifications of pathogenicity, 12 benign, 5 benign/likely benign, 4 pathogenic, 3 likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17498	NM_000744.7(CHRNA4):c.839C>T (p.Ser280Phe)	CHRNA4	Pathogenic	criteria provided, multiple submitters, no conflicts
17500	NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)	CHRNA4	Pathogenic	criteria provided, multiple submitters, no conflicts
41030	NM_000744.7(CHRNA4):c.867GCT[3] (p.Leu291dup)	CHRNA4	Pathogenic	no assertion criteria provided
17496	NM_000748.3(CHRNB2):c.859G>A (p.Val287Met)	CHRNB2	Pathogenic	criteria provided, multiple submitters, no conflicts
575241	NM_020822.3(KCNT1):c.2896G>A (p.Ala966Thr)	KCNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802235	NM_000744.7(CHRNA4):c.1113_1114insTATG (p.Ile372fs)	CHRNA4	Likely pathogenic	criteria provided, single submitter
3391126	NM_000744.7(CHRNA4):c.481T>C (p.Cys161Arg)	CHRNA4	Likely pathogenic	criteria provided, single submitter
1033118	NM_000744.7(CHRNA4):c.1741G>A (p.Glu581Lys)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1083771	NM_000744.7(CHRNA4):c.1759-4G>A	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303856	NM_000744.7(CHRNA4):c.1742A>G (p.Glu581Gly)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1776494	NM_000744.7(CHRNA4):c.1616C>T (p.Ser539Leu)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205019	NM_000744.7(CHRNA4):c.919G>A (p.Gly307Ser)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205020	NM_000744.7(CHRNA4):c.1006C>T (p.Arg336Cys)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205026	NM_000744.7(CHRNA4):c.1316A>C (p.Lys439Thr)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205030	NM_000744.7(CHRNA4):c.1430C>T (p.Ala477Val)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205031	NM_000744.7(CHRNA4):c.1448G>A (p.Arg483Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205041	NM_000744.7(CHRNA4):c.1861C>A (p.Pro621Thr)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205043	NM_000744.7(CHRNA4):c.274G>C (p.Glu92Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205046	NM_000744.7(CHRNA4):c.358C>T (p.Arg120Trp)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2169905	NM_000744.7(CHRNA4):c.1271C>T (p.Ser424Leu)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287521	NM_000744.7(CHRNA4):c.1495G>A (p.Ala499Thr)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419347	NM_000744.7(CHRNA4):c.1106G>A (p.Arg369Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420173	NM_000744.7(CHRNA4):c.38_49dup (p.Pro13_Leu16dup)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
422514	NM_000744.7(CHRNA4):c.1682C>T (p.Ser561Leu)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452325	NM_000744.7(CHRNA4):c.1667C>G (p.Pro556Arg)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477005	NM_000744.7(CHRNA4):c.1697G>A (p.Arg566Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
506637	NM_000744.7(CHRNA4):c.1538G>A (p.Arg513His)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510852	NM_000744.7(CHRNA4):c.138C>T (p.Ser46=)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
578560	NM_000744.7(CHRNA4):c.640G>A (p.Ala214Thr)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
854387	NM_000744.7(CHRNA4):c.13G>A (p.Gly5Ser)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
CHRNA4	Definitive	Autosomal dominant	familial sleep-related hypermotor epilepsy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy
KCNT1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNT1	Orphanet:98784	Sleep-related hypermotor epilepsy
CHRNB2	Orphanet:98784	Sleep-related hypermotor epilepsy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	gencc,clinvar
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	clinvar
CHRNB2	HGNC:1962	ENSG00000160716	P17787	Neuronal acetylcholine receptor subunit beta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
CHRNB2	Neuronal acetylcholine receptor subunit beta-2	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…

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)
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
CHRNB2	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
cingulate cortex	1
cortical plate	1
right lobe of liver	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cervix squamous epithelium	1
tongue squamous epithelium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex
KCNT1	153	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CHRNB2	208	broad	yes	tongue squamous epithelium, cervix squamous epithelium, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNA4	1,989
KCNT1	1,562
CHRNB2	1,547

Intra-cohort edges

A	B	Sources
CHRNA4	CHRNB2	biogrid_interaction, intact, string_interaction
CHRNA4	KCNT1	string_interaction
CHRNB2	KCNT1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNB2	P17787	15
CHRNA4	P43681	12
KCNT1	Q5JUK3	6

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
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	2	1631.4×	2e-06	CHRNA4, CHRNB2
Highly calcium permeable nicotinic acetylcholine receptors	2	1268.9×	2e-06	CHRNA4, CHRNB2
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	2	1038.2×	2e-06	CHRNA4, CHRNB2
Presynaptic nicotinic acetylcholine receptors	2	951.7×	2e-06	CHRNA4, CHRNB2
Acetylcholine binding and downstream events	2	815.7×	2e-06	CHRNA4, CHRNB2
Postsynaptic nicotinic acetylcholine receptors	2	815.7×	2e-06	CHRNA4, CHRNB2
Neurotransmitter receptors and postsynaptic signal transmission	2	100.2×	1e-04	CHRNA4, CHRNB2
Transmission across Chemical Synapses	2	76.1×	2e-04	CHRNA4, CHRNB2
Neuronal System	2	44.3×	5e-04	CHRNA4, CHRNB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
behavioral response to nicotine	2	1248.3×	3e-05	CHRNA4, CHRNB2
regulation of dopamine secretion	2	802.5×	3e-05	CHRNA4, CHRNB2
nervous system process	2	802.5×	3e-05	CHRNA4, CHRNB2
synaptic transmission, cholinergic	2	535.0×	6e-05	CHRNA4, CHRNB2
acetylcholine receptor signaling pathway	2	416.1×	7e-05	CHRNA4, CHRNB2
membrane depolarization	2	340.4×	9e-05	CHRNA4, CHRNB2
B cell activation	2	303.6×	1e-04	CHRNA4, CHRNB2
response to nicotine	2	280.9×	1e-04	CHRNA4, CHRNB2
sensory perception of pain	2	249.7×	1e-04	CHRNA4, CHRNB2
cognition	2	190.4×	2e-04	CHRNA4, CHRNB2
monoatomic ion transmembrane transport	2	138.7×	3e-04	CHRNA4, CHRNB2
calcium ion transport	2	120.8×	4e-04	CHRNA4, CHRNB2
monoatomic ion transport	2	104.0×	5e-04	CHRNA4, CHRNB2
lateral geniculate nucleus development	1	5617.3×	6e-04	CHRNB2
response to hypoxia	2	63.8×	0.001	CHRNA4, CHRNB2
regulation of circadian sleep/wake cycle, REM sleep	1	2808.7×	0.001	CHRNB2
chemical synaptic transmission	2	51.5×	0.001	CHRNA4, CHRNB2
vestibulocochlear nerve development	1	1872.4×	0.001	CHRNB2
regulation of synaptic transmission, dopaminergic	1	1404.3×	0.002	CHRNB2
negative regulation of action potential	1	1404.3×	0.002	CHRNB2
synaptic transmission involved in micturition	1	1404.3×	0.002	CHRNB2
optic nerve morphogenesis	1	1123.5×	0.002	CHRNB2
response to acetylcholine	1	702.2×	0.003	CHRNB2
central nervous system projection neuron axonogenesis	1	624.1×	0.003	CHRNB2
positive regulation of dopamine secretion	1	561.7×	0.003	CHRNB2
regulation of dopamine metabolic process	1	561.7×	0.003	CHRNB2
inhibitory postsynaptic potential	1	561.7×	0.003	CHRNA4
smooth muscle contraction	1	267.5×	0.007	CHRNB2
regulation of dendrite morphogenesis	1	244.2×	0.007	CHRNB2
regulation of synapse assembly	1	234.1×	0.007	CHRNB2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
CHRNA4	VARENICLINE
KCNT1	BEPRIDIL
CHRNB2	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA4	64	4
CHRNB2	26	4
KCNT1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARENICLINE	4	CHRNA4, CHRNB2
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4, CHRNB2
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4
AZELASTINE	4	CHRNA4
ACETYLCHOLINE	4	CHRNA4, CHRNB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNB2	696	Binding:567, Functional:127, Toxicity:1, ADMET:1
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
KCNT1	24	Binding:24

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHRNA4	624
CHRNB2	696

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
VARENICLINE	4	CHRNA4, CHRNB2
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4, CHRNB2
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4
AZELASTINE	4	CHRNA4
ACETYLCHOLINE	4	CHRNA4, CHRNB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CHRNA4, KCNT1, CHRNB2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.