Developmental and epileptic encephalopathy, 32

Summary

Developmental and epileptic encephalopathy, 32 (MONDO:0014607) is a disease caused by KCNA2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: KCNA2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 444

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 32
Mondo ID	MONDO:0014607
OMIM	616366
DOID	DOID:0080416
UMLS	C4225350
MedGen	909501
GARD	0016096
Is cancer (heuristic)	no

Also known as: DEE32 · developmental and epileptic encephalopathy 32 · early infantile epileptic encephalopathy caused by mutation in KCNA2 · EIEE32 · epileptic encephalopathy, early infantile, 32 · epileptic encephalopathy, early infantile, type 32 · KCNA2 early infantile epileptic encephalopathy

Data availability: 444 ClinVar variants · 3 GenCC gene-disease records · 7 cell lines.

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, 32

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, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, 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

444 retrieved; paginated sample, class counts are floors:

234 uncertain significance, 133 likely benign, 21 pathogenic, 18 conflicting classifications of pathogenicity, 15 likely pathogenic, 12 pathogenic/likely pathogenic, 9 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1459387	NC_000001.10:g.(?110603355)(111147404_?)del	ALX3	Pathogenic	criteria provided, single submitter
1060438	NM_004974.4(KCNA2):c.1175C>T (p.Ser392Phe)	KCNA2	Pathogenic	criteria provided, single submitter
1067683	NM_004974.4(KCNA2):c.1220C>G (p.Pro407Arg)	KCNA2	Pathogenic	criteria provided, single submitter
1070041	NM_004974.4(KCNA2):c.765_773del (p.Met255_Ile257del)	KCNA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1721403	NM_004974.4(KCNA2):c.773T>A (p.Ile258Asn)	KCNA2	Pathogenic	criteria provided, single submitter
1803043	NM_004974.4(KCNA2):c.785C>T (p.Ala262Val)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803044	NM_004974.4(KCNA2):c.1130A>G (p.Tyr377Cys)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190325	NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190326	NM_004974.4(KCNA2):c.788T>C (p.Ile263Thr)	KCNA2	Pathogenic	criteria provided, single submitter
190327	NM_004974.4(KCNA2):c.894G>T (p.Leu298Phe)	KCNA2	Pathogenic	criteria provided, single submitter
190328	NM_004974.4(KCNA2):c.890G>A (p.Arg297Gln)	KCNA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2015540	NM_004974.4(KCNA2):c.181del (p.Asp61fs)	KCNA2	Pathogenic	criteria provided, single submitter
2091004	NM_004974.4(KCNA2):c.730T>C (p.Cys244Arg)	KCNA2	Pathogenic	criteria provided, single submitter
2118816	NM_004974.4(KCNA2):c.900A>C (p.Arg300Ser)	KCNA2	Pathogenic	criteria provided, single submitter
2151893	NM_004974.4(KCNA2):c.637C>T (p.Gln213Ter)	KCNA2	Pathogenic	criteria provided, single submitter
2431063	NM_004974.4(KCNA2):c.1220C>T (p.Pro407Leu)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2757952	NM_004974.4(KCNA2):c.1193G>A (p.Gly398Asp)	KCNA2	Pathogenic	criteria provided, single submitter
2760866	NM_004974.4(KCNA2):c.494T>A (p.Ile165Lys)	KCNA2	Pathogenic	criteria provided, single submitter
280584	NM_004974.4(KCNA2):c.881G>A (p.Arg294His)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2822519	NM_004974.4(KCNA2):c.1015G>T (p.Val339Phe)	KCNA2	Pathogenic	criteria provided, single submitter
2825567	NM_004974.4(KCNA2):c.919T>G (p.Leu307Val)	KCNA2	Pathogenic	criteria provided, single submitter
3061873	NM_004974.4(KCNA2):c.636C>G (p.Tyr212Ter)	KCNA2	Pathogenic	criteria provided, single submitter
420845	NM_004974.4(KCNA2):c.1195G>A (p.Val399Met)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423204	NM_004974.4(KCNA2):c.1265_1266del (p.Glu422fs)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452594	NM_004974.4(KCNA2):c.1118C>T (p.Thr373Ile)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542660	NM_004974.4(KCNA2):c.1013G>A (p.Gly338Glu)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542666	NM_004974.4(KCNA2):c.1216G>T (p.Val406Phe)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559647	NM_004974.4(KCNA2):c.1120A>G (p.Thr374Ala)	KCNA2	Pathogenic	criteria provided, multiple submitters, no conflicts
623699	NM_004974.4(KCNA2):c.1219C>G (p.Pro407Ala)	KCNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666316	NM_004974.4(KCNA2):c.1223T>C (p.Val408Ala)	KCNA2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
KCNA2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 32	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNA2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ALX3	Orphanet:391474	Frontorhiny

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNA2	HGNC:6220	ENSG00000177301	P16389	Potassium voltage-gated channel subfamily A member 2	gencc,clinvar
ALX3	HGNC:449	ENSG00000156150	O95076	Homeobox protein aristaless-like 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNA2	Potassium voltage-gated channel subfamily A member 2	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system.
ALX3	Homeobox protein aristaless-like 3	Transcriptional regulator with a possible role in patterning of mesoderm during development.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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	1	55.8×	0.036
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNA2	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
ALX3	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNA2	179	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, lateral nuclear group of thalamus
ALX3	68	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNA2	2,817
ALX3	1,262

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA2	P16389	78.01
ALX3	O95076	62.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Voltage gated Potassium channels	1	121.5×	0.026	KCNA2
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.026	ALX3
Potassium Channels	1	67.2×	0.026	KCNA2
MITF-M-regulated melanocyte development	1	57.1×	0.026	ALX3
Neuronal System	1	22.1×	0.054	KCNA2
Developmental Biology	1	7.2×	0.134	ALX3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
optic nerve structural organization	1	4213.0×	0.003	KCNA2
regulation of circadian sleep/wake cycle, non-REM sleep	1	2808.7×	0.003	KCNA2
regulation of dopamine secretion	1	601.9×	0.009	KCNA2
potassium ion export across plasma membrane	1	526.6×	0.009	KCNA2
corpus callosum development	1	421.3×	0.009	KCNA2
embryonic hindlimb morphogenesis	1	290.6×	0.009	ALX3
embryonic forelimb morphogenesis	1	247.8×	0.009	ALX3
neuronal action potential	1	240.7×	0.009	KCNA2
pattern specification process	1	234.1×	0.009	ALX3
embryonic skeletal system morphogenesis	1	195.9×	0.009	ALX3
sensory perception of pain	1	187.2×	0.009	KCNA2
action potential	1	179.3×	0.009	KCNA2
neuron development	1	127.7×	0.011	ALX3
cerebral cortex development	1	102.8×	0.013	KCNA2
potassium ion transport	1	95.8×	0.013	KCNA2
potassium ion transmembrane transport	1	68.0×	0.017	KCNA2
protein homooligomerization	1	61.1×	0.018	KCNA2
regulation of apoptotic process	1	41.7×	0.025	ALX3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ALX3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNA2	1	3
ALX3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERGAPTEN	3	KCNA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNA2	36	Binding:31, Functional:3, ADMET:1, Toxicity:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
BERGAPTEN	3	KCNA2

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	1	KCNA2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ALX3

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)
ALX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.