Developmental and epileptic encephalopathy, 26

Summary

Developmental and epileptic encephalopathy, 26 (MONDO:0014477) is a disease caused by KCNB1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: KCNB1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 708

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 26
Mondo ID	MONDO:0014477
OMIM	616056
DOID	DOID:0080461
UMLS	C4015119
MedGen	863556
GARD	0012391
Is cancer (heuristic)	no

Also known as: DEE26 · developmental and epileptic encephalopathy 26 · early infantile epileptic encephalopathy 26 · early infantile epileptic encephalopathy caused by mutation in KCNB1 · EIEE26 · epileptic encephalopathy, early infantile, 26 · epileptic encephalopathy, early infantile, type 26 · KCNB1 early infantile epileptic encephalopathy

Data availability: 708 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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, 26

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, 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

600 retrieved; paginated sample, class counts are floors:

242 likely benign, 190 uncertain significance, 56 benign, 37 conflicting classifications of pathogenicity, 26 likely pathogenic, 21 benign/likely benign, 19 pathogenic, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031489	NM_004975.4(KCNB1):c.1136G>T (p.Gly379Val)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1052355	NM_004975.4(KCNB1):c.1249T>C (p.Ser417Pro)	KCNB1	Pathogenic	criteria provided, single submitter
1068345	NM_004975.4(KCNB1):c.961G>A (p.Gly321Ser)	KCNB1	Pathogenic	criteria provided, single submitter
1199933	NM_004975.4(KCNB1):c.1136G>A (p.Gly379Glu)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334708	NM_004975.4(KCNB1):c.1503dup (p.Lys502Ter)	KCNB1	Pathogenic	criteria provided, single submitter
1427157	NM_004975.4(KCNB1):c.1107G>A (p.Trp369Ter)	KCNB1	Pathogenic	criteria provided, single submitter
1428239	NM_004975.4(KCNB1):c.1229C>T (p.Pro410Leu)	KCNB1	Pathogenic	criteria provided, single submitter
1446788	NM_004975.4(KCNB1):c.959T>C (p.Leu320Pro)	KCNB1	Pathogenic	criteria provided, single submitter
1452081	NM_004975.4(KCNB1):c.1169G>A (p.Gly390Glu)	KCNB1	Pathogenic	criteria provided, single submitter
1457665	NM_004975.4(KCNB1):c.629C>A (p.Thr210Lys)	KCNB1	Pathogenic	criteria provided, single submitter
156533	NM_004975.4(KCNB1):c.1041C>A (p.Ser347Arg)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
156534	NM_004975.4(KCNB1):c.1121C>T (p.Thr374Ile)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
156535	NM_004975.4(KCNB1):c.1135G>A (p.Gly379Arg)	KCNB1	Pathogenic	no assertion criteria provided
1803045	NM_004975.4(KCNB1):c.1106G>T (p.Trp369Leu)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575245	NM_004975.4(KCNB1):c.1141G>A (p.Gly381Arg)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
265207	NM_004975.4(KCNB1):c.934C>T (p.Arg312Cys)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2709811	NM_004975.4(KCNB1):c.1051T>G (p.Phe351Val)	KCNB1	Pathogenic	criteria provided, single submitter
2811308	NM_004975.4(KCNB1):c.988G>C (p.Glu330Gln)	KCNB1	Pathogenic	criteria provided, single submitter
3062072	NM_004975.4(KCNB1):c.682C>T (p.Gln228Ter)	KCNB1	Pathogenic	criteria provided, single submitter
420881	NM_004975.4(KCNB1):c.1297C>T (p.Arg433Ter)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449693	NM_004975.4(KCNB1):c.916C>T (p.Arg306Cys)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
452347	NM_004975.4(KCNB1):c.1190G>A (p.Cys397Tyr)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
475255	NM_004975.4(KCNB1):c.1041C>G (p.Ser347Arg)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813524	NM_004975.4(KCNB1):c.975GAG[1] (p.Arg326del)	KCNB1	Pathogenic	criteria provided, single submitter
523478	NM_004975.4(KCNB1):c.935G>A (p.Arg312His)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542057	NM_004975.4(KCNB1):c.629C>T (p.Thr210Met)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633622	NM_004975.4(KCNB1):c.968C>T (p.Thr323Ile)	KCNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330181	GRCh37/hg19 20q13.12-13.13(chr20:42985044-48599046)x1	RBPJL	Pathogenic	criteria provided, single submitter
1057900	NM_004975.4(KCNB1):c.919A>G (p.Ile307Val)	KCNB1	Likely pathogenic	criteria provided, single submitter
1067365	NM_004975.4(KCNB1):c.956C>A (p.Ser319Tyr)	KCNB1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
KCNB1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 26	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNB1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ARFGEF2	Orphanet:98892	Periventricular nodular heterotopia

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
KCNB1	HGNC:6231	ENSG00000158445	Q14721	Potassium voltage-gated channel subfamily B member 1	gencc,clinvar
RBPJL	HGNC:13761	ENSG00000124232	Q9UBG7	Recombining binding protein suppressor of hairless-like protein	clinvar
DDX27	HGNC:15837	ENSG00000124228	Q96GQ7	Probable ATP-dependent RNA helicase DDX27	clinvar
ARFGEF2	HGNC:15853	ENSG00000124198	Q9Y6D5	Brefeldin A-inhibited guanine nucleotide-exchange protein 2	clinvar
IRF3	HGNC:6118	ENSG00000126456	Q14653	Interferon regulatory factor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNB1	Potassium voltage-gated channel subfamily B member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system.
RBPJL	Recombining binding protein suppressor of hairless-like protein	Putative transcription factor, which cooperates with EBNA2 to activate transcription.
DDX27	Probable ATP-dependent RNA helicase DDX27	Probable ATP-dependent RNA helicase.
ARFGEF2	Brefeldin A-inhibited guanine nucleotide-exchange protein 2	Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6.
IRF3	Interferon regulatory factor 3	Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	22.3×	0.132
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNB1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
RBPJL	Transcription factor	no		p53-like_TF_DNA-bd_sf, Ig-like_fold, Ig_E-set
DDX27	Other/Unknown	no		RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom
ARFGEF2	Other/Unknown	no		Sec7_dom, ARM-like, Mon2/Sec7/BIG1-like_HDS
IRF3	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf

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
parietal lobe	1
postcentral gyrus	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
cervix squamous epithelium	1
pancreatic ductal cell	1
tendon of biceps brachii	1
cartilage tissue	1
jejunal mucosa	1
parotid gland	1
granulocyte	1
lower esophagus mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNB1	236	broad	marker	Brodmann (1909) area 23, parietal lobe, postcentral gyrus
RBPJL	122	tissue_specific	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
DDX27	291	ubiquitous	marker	tendon of biceps brachii, pancreatic ductal cell, cervix squamous epithelium
ARFGEF2	289	ubiquitous	marker	cartilage tissue, jejunal mucosa, parotid gland
IRF3	266	ubiquitous	marker	granulocyte, right uterine tube, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRF3	4,434
DDX27	4,202
KCNB1	2,877
ARFGEF2	2,022
RBPJL	1,319

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IRF3	Q14653	18
KCNB1	Q14721	6
ARFGEF2	Q9Y6D5	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RBPJL	Q9UBG7	80.58
DDX27	Q96GQ7	72.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	761.3×	0.025	IRF3
IRF3 mediated activation of type 1 IFN	1	634.4×	0.025	IRF3
ZBP1(DAI) mediated induction of type I IFNs	1	346.1×	0.025	IRF3
STING mediated induction of host immune responses	1	346.1×	0.025	IRF3
IRF3-mediated induction of type I IFN	1	271.9×	0.025	IRF3
TICAM1-dependent activation of IRF3/IRF7	1	271.9×	0.025	IRF3
Regulation of innate immune responses to cytosolic DNA	1	253.8×	0.025	IRF3
TRAF3-dependent IRF activation pathway	1	253.8×	0.025	IRF3
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	200.3×	0.028	IRF3
TRAF6 mediated IRF7 activation	1	126.9×	0.030	IRF3
Negative regulators of DDX58/IFIH1 signaling	1	108.8×	0.030	IRF3
Evasion by RSV of host interferon responses	1	108.8×	0.030	IRF3
Chaperonin-mediated protein folding	1	100.2×	0.030	ARFGEF2
Association of TriC/CCT with target proteins during biosynthesis	1	97.6×	0.030	ARFGEF2
Cytosolic sensors of pathogen-associated DNA	1	95.2×	0.030	IRF3
SARS-CoV-1 activates/modulates innate immune responses	1	90.6×	0.030	IRF3
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	88.5×	0.030	KCNB1
Protein folding	1	86.5×	0.030	ARFGEF2
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	84.6×	0.030	IRF3
Voltage gated Potassium channels	1	81.0×	0.030	KCNB1
Regulation of insulin secretion	1	73.2×	0.030	KCNB1
Antimicrobial mechanism of IFN-stimulated genes	1	65.6×	0.030	IRF3
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.030	IRF3
Toll Like Receptor 3 (TLR3) Cascade	1	64.5×	0.030	IRF3
TRIF (TICAM1)-mediated TLR4 signaling	1	63.4×	0.030	IRF3
MyD88-independent TLR4 cascade	1	61.4×	0.030	IRF3
Integration of energy metabolism	1	58.6×	0.030	KCNB1
SARS-CoV-1-host interactions	1	58.6×	0.030	IRF3
RSV-host interactions	1	52.1×	0.032	IRF3
Interferon alpha/beta signaling	1	50.8×	0.032	IRF3

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
endomembrane system organization	1	1685.2×	0.009	ARFGEF2
regulation of motor neuron apoptotic process	1	1685.2×	0.009	KCNB1
positive regulation of norepinephrine secretion	1	1123.5×	0.009	KCNB1
positive regulation of catecholamine secretion	1	1123.5×	0.009	KCNB1
macrophage apoptotic process	1	1123.5×	0.009	IRF3
regulation of action potential	1	1123.5×	0.009	KCNB1
MDA-5 signaling pathway	1	842.6×	0.009	IRF3
clustering of voltage-gated potassium channels	1	842.6×	0.009	KCNB1
mRNA transcription	1	674.1×	0.009	IRF3
cGAS/STING signaling pathway	1	674.1×	0.009	IRF3
programmed necrotic cell death	1	421.3×	0.013	IRF3
positive regulation of long-term synaptic depression	1	374.5×	0.014	KCNB1
response to L-glutamate	1	337.0×	0.014	KCNB1
TRIF-dependent toll-like receptor signaling pathway	1	306.4×	0.014	IRF3
receptor recycling	1	259.3×	0.015	ARFGEF2
positive regulation of calcium ion-dependent exocytosis	1	259.3×	0.015	KCNB1
cellular response to exogenous dsRNA	1	210.7×	0.016	IRF3
potassium ion export across plasma membrane	1	210.7×	0.016	KCNB1
glutamate receptor signaling pathway	1	187.2×	0.016	KCNB1
cytoplasmic pattern recognition receptor signaling pathway	1	177.4×	0.016	IRF3
regulation of ARF protein signal transduction	1	177.4×	0.016	ARFGEF2
positive regulation of type I interferon-mediated signaling pathway	1	168.5×	0.016	IRF3
obsolete vesicle docking involved in exocytosis	1	134.8×	0.020	KCNB1
positive regulation of interferon-alpha production	1	129.6×	0.020	IRF3
Golgi to plasma membrane transport	1	112.3×	0.020	ARFGEF2
positive regulation of protein targeting to membrane	1	112.3×	0.020	KCNB1
positive regulation of cytokine production involved in inflammatory response	1	108.7×	0.020	IRF3
lipopolysaccharide-mediated signaling pathway	1	105.3×	0.020	IRF3
toll-like receptor 4 signaling pathway	1	105.3×	0.020	IRF3
response to axon injury	1	102.1×	0.020	KCNB1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNB1	0	0
RBPJL	0	0
DDX27	0	0
ARFGEF2	0	0
IRF3	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
KCNB1	28	Binding:27, Toxicity:1
IRF3	7	Binding:7
ARFGEF2	1	Binding:1

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	1	KCNB1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RBPJL, DDX27, ARFGEF2, IRF3

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)
KCNB1	28	—
RBPJL	0	—
DDX27	0	—
ARFGEF2	1	—
IRF3	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.