Developmental and epileptic encephalopathy, 69

disease

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Also known as DEE69developmental and epileptic encephalopathy 69EIEE69EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 69

Summary

Developmental and epileptic encephalopathy, 69 (MONDO:0032657) is a disease caused by CACNA1E (GenCC Definitive), with 1 cohort gene.

At a glance

Causal gene: CACNA1E (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 258

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 69
Mondo ID	MONDO:0032657
OMIM	618285
DOID	DOID:0112205
UMLS	C4748988
MedGen	1648381
GARD	0025714
Is cancer (heuristic)	no

Also known as: DEE69 · developmental and epileptic encephalopathy 69 · EIEE69 · EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 69 · epileptic encephalopathy, early infantile, 69

Data availability: 258 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 69

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

258 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 62 benign/likely benign, 39 benign, 35 likely benign, 28 conflicting classifications of pathogenicity, 7 likely pathogenic, 6 pathogenic/likely pathogenic, 4 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1320140	NM_001205293.3(CACNA1E):c.1042G>C (p.Gly348Arg)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685598	NM_001205293.3(CACNA1E):c.3940A>C (p.Lys1314Gln)	CACNA1E	Pathogenic	criteria provided, single submitter
1703708	NM_001205293.3(CACNA1E):c.2104G>T (p.Ala702Ser)	CACNA1E	Pathogenic	no assertion criteria provided
2574666	NM_001205293.3(CACNA1E):c.6658C>T (p.Gln2220Ter)	CACNA1E	Pathogenic	no assertion criteria provided
265066	NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
390468	NM_001205293.3(CACNA1E):c.1807A>C (p.Ile603Leu)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452392	NM_001205293.3(CACNA1E):c.683T>C (p.Leu228Pro)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521483	NM_001205293.3(CACNA1E):c.2104G>A (p.Ala702Thr)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617451	NM_001205293.3(CACNA1E):c.2101A>G (p.Ile701Val)	CACNA1E	Pathogenic	criteria provided, single submitter
870847	NM_001205293.3(CACNA1E):c.2094C>A (p.Phe698Leu)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224995	NM_001205293.3(CACNA1E):c.2093T>C (p.Phe698Ser)	CACNA1E	Likely pathogenic	criteria provided, single submitter
2505203	NM_001205293.3(CACNA1E):c.1090C>T (p.Arg364Ter)	CACNA1E	Likely pathogenic	criteria provided, single submitter
3254659	NM_001205293.3(CACNA1E):c.3697G>A (p.Ala1233Thr)	CACNA1E	Likely pathogenic	criteria provided, single submitter
4072024	NM_001205293.3(CACNA1E):c.901_904del (p.Thr301fs)	CACNA1E	Likely pathogenic	criteria provided, single submitter
4277654	NM_001205293.3(CACNA1E):c.1055G>A (p.Gly352Glu)	CACNA1E	Likely pathogenic	criteria provided, single submitter
4687986	NM_001205293.3(CACNA1E):c.4736G>C (p.Arg1579Pro)	CACNA1E	Likely pathogenic	criteria provided, single submitter
989253	NM_001205293.3(CACNA1E):c.4004A>T (p.Asp1335Val)	CACNA1E	Likely pathogenic	criteria provided, single submitter
1213760	NM_001205293.3(CACNA1E):c.6664G>A (p.Ala2222Thr)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1251961	NM_001205293.3(CACNA1E):c.3544C>T (p.Arg1182Cys)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1321639	NM_001205293.3(CACNA1E):c.2405C>T (p.Ala802Val)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1352660	NM_001205293.3(CACNA1E):c.3054C>A (p.His1018Gln)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1383761	NM_001205293.3(CACNA1E):c.3235C>T (p.Pro1079Ser)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1406622	NM_001205293.3(CACNA1E):c.3262A>G (p.Ile1088Val)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1449699	NM_001205293.3(CACNA1E):c.6083G>A (p.Arg2028His)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1466152	NM_001205293.3(CACNA1E):c.3253G>A (p.Val1085Met)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1470204	NM_001205293.3(CACNA1E):c.3032C>T (p.Pro1011Leu)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1482994	NM_001205293.3(CACNA1E):c.176G>A (p.Arg59Gln)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1496889	NM_001205293.3(CACNA1E):c.241T>C (p.Tyr81His)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1555255	NM_001205293.3(CACNA1E):c.6500G>A (p.Arg2167Gln)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1573285	NM_001205293.3(CACNA1E):c.2555G>A (p.Arg852His)	CACNA1E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
CACNA1E	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 69	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1E	Orphanet:1934	Early infantile developmental and 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
CACNA1E	HGNC:1392	ENSG00000198216	Q15878	Voltage-dependent R-type calcium channel subunit alpha-1E	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1E	Voltage-dependent R-type calcium channel subunit alpha-1E	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.

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)
CACNA1E	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_R_a1su

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
cortical plate	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1E	144	broad	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1E	2,008

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1E	Q15878	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Presynaptic depolarization and calcium channel opening	1	951.7×	0.006	CACNA1E
Regulation of insulin secretion	1	219.6×	0.011	CACNA1E
Integration of energy metabolism	1	175.7×	0.011	CACNA1E
Transmission across Chemical Synapses	1	76.1×	0.020	CACNA1E
Neuronal System	1	44.3×	0.027	CACNA1E
Metabolism	1	11.6×	0.086	CACNA1E

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion import across plasma membrane	1	543.6×	0.004	CACNA1E
chemical synaptic transmission	1	77.3×	0.013	CACNA1E

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
CACNA1E	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1E	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1E
TACRINE	4	CACNA1E

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1E	14	Binding:14

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

2 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)
NIMODIPINE	4	CACNA1E
TACRINE	4	CACNA1E

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1E
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.

Cohort genes: CACNA1E