Developmental and epileptic encephalopathy, 24

Summary

Developmental and epileptic encephalopathy, 24 (MONDO:0014377) is a disease caused by HCN1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: HCN1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 24
Mondo ID	MONDO:0014377
OMIM	615871
DOID	DOID:0080429
UMLS	C4014531
MedGen	862968
GARD	0016024
Is cancer (heuristic)	no

Also known as: DEE24 · developmental and epileptic encephalopathy 24 · early infantile epileptic encephalopathy caused by mutation in HCN1 · EIEE24 · epileptic encephalopathy, early infantile, 24 · epileptic encephalopathy, early infantile, type 24 · HCN1 early infantile epileptic encephalopathy

Data availability: 49 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 › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy › developmental and epileptic encephalopathy, 24

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 45, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

49 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 11 conflicting classifications of pathogenicity, 8 likely pathogenic, 5 pathogenic, 3 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
139572	NM_021072.4(HCN1):c.299C>T (p.Ser100Phe)	HCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139573	NM_021072.4(HCN1):c.814T>C (p.Ser272Pro)	HCN1	Pathogenic	criteria provided, multiple submitters, no conflicts
139574	NM_021072.4(HCN1):c.890G>C (p.Arg297Thr)	HCN1	Pathogenic	criteria provided, single submitter
139575	NM_021072.4(HCN1):c.835C>T (p.His279Tyr)	HCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3358955	NM_021072.4(HCN1):c.1171G>T (p.Gly391Cys)	HCN1	Pathogenic	criteria provided, single submitter
635189	NM_021072.4(HCN1):c.1171G>A (p.Gly391Ser)	HCN1	Pathogenic	criteria provided, multiple submitters, no conflicts
976076	NM_021072.4(HCN1):c.1562G>T (p.Gly521Val)	HCN1	Pathogenic	criteria provided, single submitter
1803035	NM_021072.4(HCN1):c.794T>A (p.Leu265His)	HCN1	Likely pathogenic	criteria provided, single submitter
1803037	NM_021072.4(HCN1):c.535A>T (p.Asn179Tyr)	HCN1	Likely pathogenic	criteria provided, single submitter
2627061	NM_021072.4(HCN1):c.1096C>A (p.Pro366Thr)	HCN1	Likely pathogenic	no assertion criteria provided
3382566	NM_021072.4(HCN1):c.499T>C (p.Phe167Leu)	HCN1	Likely pathogenic	criteria provided, single submitter
375529	NM_021072.4(HCN1):c.1172G>A (p.Gly391Asp)	HCN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
375530	NM_021072.4(HCN1):c.459G>C (p.Met153Ile)	HCN1	Likely pathogenic	criteria provided, single submitter
384546	NM_021072.4(HCN1):c.913A>T (p.Met305Leu)	HCN1	Likely pathogenic	criteria provided, single submitter
496679	NM_021072.4(HCN1):c.414del (p.Pro137_Tyr138insTer)	HCN1	Likely pathogenic	criteria provided, single submitter
1028215	NM_021072.4(HCN1):c.1948A>C (p.Thr650Pro)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033971	NM_021072.4(HCN1):c.282G>A (p.Met94Ile)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033972	NM_021072.4(HCN1):c.74C>A (p.Ala25Glu)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2724937	NM_021072.4(HCN1):c.159C>A (p.His53Gln)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2963474	NM_021072.4(HCN1):c.2246A>C (p.Gln749Pro)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3366984	NM_021072.4(HCN1):c.701A>G (p.Tyr234Cys)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
573431	NM_021072.4(HCN1):c.192_206dup (p.Gly70_Gly74dup)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576892	NM_021072.4(HCN1):c.2390T>G (p.Val797Gly)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581499	NM_021072.4(HCN1):c.203GCG[6] (p.Gly74del)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
848402	NM_021072.4(HCN1):c.1183G>A (p.Ala395Thr)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857604	NM_021072.4(HCN1):c.1777C>G (p.Arg593Gly)	HCN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325609	NM_021072.4(HCN1):c.2165C>T (p.Pro722Leu)	HCN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342851	NM_021072.4(HCN1):c.928C>T (p.His310Tyr)	HCN1	Uncertain significance	criteria provided, single submitter
139571	NM_021072.4(HCN1):c.1201G>C (p.Asp401His)	HCN1	Uncertain significance	criteria provided, single submitter
1679655	NM_021072.4(HCN1):c.1377+19834C>T	HCN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
HCN1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 24	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCN1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
HCN1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HCN1	HGNC:4845	ENSG00000164588	O60741	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HCN1	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCN1	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCN1	147	broad	marker	endothelial cell, Brodmann (1909) area 23, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCN1	726

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HCN1	O60741	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HCN channels	1	2855.0×	4e-04	HCN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 membrane hyperpolarization	1	16852.0×	0.001	HCN1
negative regulation of action potential	1	4213.0×	0.002	HCN1
general adaptation syndrome, behavioral process	1	3370.4×	0.002	HCN1
regulation of SA node cell action potential	1	2808.7×	0.002	HCN1
regulation of membrane depolarization	1	1872.4×	0.002	HCN1
negative regulation of synaptic transmission, glutamatergic	1	1685.2×	0.002	HCN1
response to L-glutamate	1	1685.2×	0.002	HCN1
retinal cone cell development	1	1404.3×	0.002	HCN1
maternal behavior	1	1123.5×	0.002	HCN1
apical protein localization	1	991.3×	0.002	HCN1
sodium ion import across plasma membrane	1	624.1×	0.003	HCN1
cellular response to interferon-beta	1	526.6×	0.003	HCN1
neuronal action potential	1	481.5×	0.003	HCN1
regulation of heart rate by cardiac conduction	1	374.5×	0.004	HCN1
potassium ion import across plasma membrane	1	366.4×	0.004	HCN1
response to calcium ion	1	318.0×	0.004	HCN1
cellular response to cAMP	1	290.6×	0.004	HCN1
protein homotetramerization	1	237.3×	0.005	HCN1
regulation of membrane potential	1	230.8×	0.005	HCN1
sodium ion transmembrane transport	1	203.0×	0.005	HCN1
potassium ion transmembrane transport	1	135.9×	0.007	HCN1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HCN1	21	Binding:12, Functional:8, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	HCN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HCN1	21	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.