Benign neonatal seizures

Summary

Benign neonatal seizures (MONDO:0016027) is a disease with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 963
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		272	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0002266	Focal clonic seizure	Very frequent (80-99%)
HP:0007359	Focal-onset seizure	Very frequent (80-99%)
HP:0011167	Focal tonic seizure	Very frequent (80-99%)
HP:0011188	Focal EEG discharges with secondary generalization	Very frequent (80-99%)
HP:0032807	Neonatal seizure	Very frequent (80-99%)
HP:0002104	Apnea	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0010818	Generalized tonic seizure	Frequent (30-79%)
HP:0011154	Focal autonomic seizure	Frequent (30-79%)
HP:0032556	Circumoral cyanosis	Frequent (30-79%)
HP:0045084	Limb myoclonus	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0011171	Simple febrile seizures	Occasional (5-29%)
HP:0011468	Facial tics	Occasional (5-29%)
HP:0002133	Status epilepticus	Very rare (<1-4%)
HP:0031535	Increased theta frequency activity in EEG	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	benign neonatal seizures
Mondo ID	MONDO:0016027
OMIM	121200
Orphanet	1949
DOID	DOID:14264, DOID:14777
NCIT	C117307
SNOMED CT	279953009, 38281008
UMLS	C0220669
MedGen	65082
GARD	0001519
MedDRA	10067866
Is cancer (heuristic)	no

Also known as: benign familal neonatal seizures · benign familial convulsion · benign familial convulsions · benign familial neonatal convulsions · benign familial neonatal epilepsy · benign familial neonatal seizures · BFNS · seizures, benign familial neonatal

Data availability: 963 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › neonatal epilepsy syndrome › benign neonatal seizures

Related subtypes (5): severe neonatal-onset encephalopathy with microcephaly, developmental and epileptic encephalopathy, 39, malignant migrating partial seizures of infancy, undetermined early-onset epileptic encephalopathy, benign idiopathic neonatal seizures

Subtypes (4): seizures, benign familial neonatal, 1, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, autosomal recessive, seizures, benign familial neonatal, 3

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

600 retrieved; paginated sample, class counts are floors:

301 uncertain significance, 214 likely benign, 35 conflicting classifications of pathogenicity, 20 benign/likely benign, 11 pathogenic, 11 benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071385	NC_000008.10:g.(?133141509)(133492779_?)del	KCNQ3	Pathogenic	criteria provided, single submitter
1334436	NM_004519.4(KCNQ3):c.989G>T (p.Arg330Leu)	KCNQ3	Pathogenic	criteria provided, single submitter
1355934	NM_004519.4(KCNQ3):c.802G>C (p.Gly268Arg)	KCNQ3	Pathogenic	criteria provided, single submitter
1451762	NM_004519.4(KCNQ3):c.1423del (p.Ala475fs)	KCNQ3	Pathogenic	criteria provided, single submitter
1453259	NM_004519.4(KCNQ3):c.1599del (p.Lys533fs)	KCNQ3	Pathogenic	criteria provided, single submitter
2009234	NM_004519.4(KCNQ3):c.893del (p.Glu298fs)	KCNQ3	Pathogenic	criteria provided, single submitter
205963	NM_004519.4(KCNQ3):c.688C>T (p.Arg230Cys)	KCNQ3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205966	NM_004519.4(KCNQ3):c.917C>T (p.Ala306Val)	KCNQ3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2134180	NM_004519.4(KCNQ3):c.710T>A (p.Met237Lys)	KCNQ3	Pathogenic	criteria provided, single submitter
21417	NM_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)	KCNQ3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2705067	NM_004519.4(KCNQ3):c.299_302del (p.Asn100fs)	KCNQ3	Pathogenic	criteria provided, single submitter
2713298	NM_004519.4(KCNQ3):c.115G>T (p.Glu39Ter)	KCNQ3	Pathogenic	criteria provided, single submitter
2724292	NM_004519.4(KCNQ3):c.1576C>T (p.Gln526Ter)	KCNQ3	Pathogenic	criteria provided, single submitter
1071384	NC_000008.10:g.(?133141509)(134296554_?)del	TG	Pathogenic	criteria provided, single submitter
1067197	NM_004519.4(KCNQ3):c.929G>A (p.Gly310Asp)	KCNQ3	Likely pathogenic	criteria provided, single submitter
1067624	NM_004519.4(KCNQ3):c.1123G>A (p.Ala375Thr)	KCNQ3	Likely pathogenic	criteria provided, single submitter
1466336	NM_004519.4(KCNQ3):c.951T>G (p.Ile317Met)	KCNQ3	Likely pathogenic	criteria provided, single submitter
2757946	NM_004519.4(KCNQ3):c.777+1G>T	KCNQ3	Likely pathogenic	criteria provided, single submitter
2842212	NM_004519.4(KCNQ3):c.1262+1G>T	KCNQ3	Likely pathogenic	criteria provided, single submitter
1036952	NM_004519.4(KCNQ3):c.508G>A (p.Glu170Lys)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1068557	NM_004519.4(KCNQ3):c.1558C>T (p.Arg520Ter)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1072811	NM_004519.4(KCNQ3):c.1206T>A (p.Tyr402Ter)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305361	NM_004519.4(KCNQ3):c.1621del (p.Tyr541fs)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138041	NM_004519.4(KCNQ3):c.954C>A (p.Gly318=)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138047	NM_004519.4(KCNQ3):c.1935A>G (p.Gln645=)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1399817	NM_004519.4(KCNQ3):c.2312C>T (p.Ser771Leu)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1686662	NM_004519.4(KCNQ3):c.977C>T (p.Thr326Met)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1780781	NM_004519.4(KCNQ3):c.1822C>G (p.Pro608Ala)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193878	NM_004519.4(KCNQ3):c.1564G>A (p.Val522Ile)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194513	NM_004519.4(KCNQ3):c.1994C>T (p.Ser665Leu)	KCNQ3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 10 · 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
KCNQ2	Definitive	Autosomal dominant	seizures, benign familial neonatal, 1	12
KCNQ3	Strong	Autosomal dominant	seizures, benign familial neonatal, 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy
KCNQ3	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ3	Orphanet:306	Self-limited infantile epilepsy
KCNQ3	Orphanet:307	Juvenile myoclonic epilepsy
TG	Orphanet:95716	Familial thyroid dyshormonogenesis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	gencc,clinvar
KCNQ3	HGNC:6297	ENSG00000184156	O43525	Potassium voltage-gated channel subfamily KQT member 3	gencc,clinvar
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	clinvar
CCN4	HGNC:12769	ENSG00000104415	O95388	CCN family member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
KCNQ3	Potassium voltage-gated channel subfamily KQT member 3	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
CCN4	CCN family member 4	Downstream regulator in the Wnt/Frizzled-signaling pathway.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	2	55.8×	9e-04
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom
KCNQ3	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ3, Ion_trans_dom
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
CCN4	Other/Unknown	no		IGFBP-like, TSP1_rpt, VWF_dom

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 23	1
ganglionic eminence	1
lateral nuclear group of thalamus	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
cartilage tissue	1
mucosa of paranasal sinus	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
KCNQ3	180	broad	marker	ganglionic eminence, lateral nuclear group of thalamus, Brodmann (1909) area 23
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
CCN4	177	broad	yes	cartilage tissue, tibia, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ2	3,388
KCNQ3	2,665
TG	1,493
CCN4	1,195

Intra-cohort edges

A	B	Sources
KCNQ2	KCNQ3	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ2	O43526	39
KCNQ3	O43525	16
TG	P01266	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCN4	O95388	77.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 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
Interaction between L1 and Ankyrins	2	368.4×	6e-05	KCNQ2, KCNQ3
Voltage gated Potassium channels	2	243.0×	7e-05	KCNQ2, KCNQ3
Potassium Channels	2	134.3×	1e-04	KCNQ2, KCNQ3
L1CAM interactions	2	120.2×	1e-04	KCNQ2, KCNQ3
Axon guidance	2	45.1×	6e-04	KCNQ2, KCNQ3
Neuronal System	2	44.3×	6e-04	KCNQ2, KCNQ3
Nervous system development	2	42.9×	6e-04	KCNQ2, KCNQ3
Developmental Biology	2	14.5×	0.005	KCNQ2, KCNQ3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
apoptosome assembly	1	4213.0×	0.005	KCNQ3
regulation of action potential firing threshold	1	4213.0×	0.005	KCNQ3
potassium ion transmembrane transport	2	68.0×	0.005	KCNQ2, KCNQ3
substantia propria of cornea development	1	2106.5×	0.006	KCNQ3
inhibitory chemical synaptic transmission	1	1404.3×	0.006	KCNQ3
action potential initiation	1	1404.3×	0.006	KCNQ3
chemical synaptic transmission	2	38.6×	0.007	KCNQ2, KCNQ3
psychomotor behavior	1	842.6×	0.007	KCNQ3
iodide transport	1	601.9×	0.008	TG
mitochondrial depolarization	1	601.9×	0.008	KCNQ3
membrane hyperpolarization	1	468.1×	0.010	KCNQ3
hormone biosynthetic process	1	351.1×	0.012	TG
excitatory chemical synaptic transmission	1	324.1×	0.012	KCNQ3
neuron remodeling	1	300.9×	0.012	KCNQ3
thyroid hormone generation	1	247.8×	0.013	TG
positive regulation of smooth muscle cell migration	1	247.8×	0.013	CCN4
nerve development	1	234.1×	0.013	KCNQ3
regulation of myelination	1	221.7×	0.013	TG
response to auditory stimulus	1	183.2×	0.014	KCNQ3
negative regulation of chondrocyte differentiation	1	168.5×	0.015	CCN4
thyroid gland development	1	135.9×	0.017	TG
positive regulation of wound healing	1	131.7×	0.017	CCN4
neuronal action potential	1	120.4×	0.018	KCNQ3
positive regulation of Wnt signaling pathway	1	95.8×	0.021	CCN4
protein targeting	1	91.6×	0.021	KCNQ3
action potential	1	89.6×	0.021	KCNQ2
osteoclast differentiation	1	86.0×	0.021	CCN4
positive regulation of smooth muscle cell proliferation	1	82.6×	0.022	CCN4
negative regulation of fat cell differentiation	1	78.0×	0.022	CCN4
bone development	1	69.1×	0.024	CCN4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
KCNQ2	FLUPIRTINE
KCNQ3	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ2	4	4
KCNQ3	3	4
TG	0	0
CCN4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLUPIRTINE	4	KCNQ2, KCNQ3
EZOGABINE	4	KCNQ2, KCNQ3
FLINDOKALNER	3	KCNQ2, KCNQ3
AZETUKALNER	3	KCNQ2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
KCNQ3	97	Binding:91, Functional:4, ADMET:1, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
FLUPIRTINE	4	KCNQ2, KCNQ3
EZOGABINE	4	KCNQ2, KCNQ3
FLINDOKALNER	3	KCNQ2, KCNQ3
AZETUKALNER	3	KCNQ2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNQ2, KCNQ3
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	TG, CCN4

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)
TG	0	—
CCN4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.