Developmental and epileptic encephalopathy, 42

Summary

Developmental and epileptic encephalopathy, 42 (MONDO:0014917) is a disease caused by CACNA1A (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: CACNA1A (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 3,123

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 42
Mondo ID	MONDO:0014917
OMIM	617106
DOID	DOID:0080454
UMLS	C4310716
MedGen	934683
GARD	0016191
Is cancer (heuristic)	no

Also known as: CACNA1A early infantile epileptic encephalopathy · DEE42 · developmental and epileptic encephalopathy 42 · early infantile epileptic encephalopathy caused by mutation in CACNA1A · EIEE42 · epileptic encephalopathy, early infantile, 42 · epileptic encephalopathy, early infantile, 42; EIEE42 · epileptic encephalopathy, early infantile, type 42

Data availability: 3,123 ClinVar variants · 3 GenCC gene-disease records · 10 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, 42

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, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, 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:

253 uncertain significance, 196 likely benign, 56 conflicting classifications of pathogenicity, 40 pathogenic, 28 benign, 14 likely pathogenic, 8 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1011068	NM_001127222.2(CACNA1A):c.4324T>G (p.Tyr1442Asp)	CACNA1A	Pathogenic	criteria provided, single submitter
1027687	NM_001127222.2(CACNA1A):c.826G>T (p.Glu276Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1051890	NM_001127222.2(CACNA1A):c.1882G>A (p.Ala628Thr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068487	NM_001127222.2(CACNA1A):c.4514T>C (p.Phe1505Ser)	CACNA1A	Pathogenic	criteria provided, single submitter
1070324	NM_001127222.2(CACNA1A):c.3563del (p.Asn1188fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1070484	NC_000019.9:g.(?13338225)(13342694_?)del	CACNA1A	Pathogenic	criteria provided, single submitter
1072305	NM_001127222.2(CACNA1A):c.6397_6403del (p.Arg2133fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1074371	NM_001127222.2(CACNA1A):c.4085del (p.Leu1362fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1074784	NM_001127222.2(CACNA1A):c.2401G>T (p.Glu801Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1075147	NM_001127222.2(CACNA1A):c.6371C>A (p.Ser2124Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1075289	NM_001127222.2(CACNA1A):c.4795del (p.Val1599fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1075959	NM_001127222.2(CACNA1A):c.3006_3007delinsCT (p.Arg1002_Arg1003delinsSerTer)	CACNA1A	Pathogenic	criteria provided, single submitter
1076899	NM_001127221.2(CACNA1A):c.5588_5589del (p.Leu1863fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1204133	NM_001127222.2(CACNA1A):c.4403C>T (p.Ser1468Leu)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1303894	NM_001127222.2(CACNA1A):c.2026G>A (p.Gly676Arg)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334375	NM_001127222.2(CACNA1A):c.526del (p.Val176fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1342943	NM_001127222.2(CACNA1A):c.2752G>T (p.Gly918Cys)	CACNA1A	Pathogenic	no assertion criteria provided
1366064	NC_000019.9:g.(?13427906)(13617038_?)del	CACNA1A	Pathogenic	criteria provided, single submitter
1373236	NM_001127222.2(CACNA1A):c.2840del (p.Pro947fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1374639	NM_001127222.2(CACNA1A):c.507G>A (p.Trp169Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1376008	NM_001127222.2(CACNA1A):c.876dup (p.Gly293fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1377252	NM_001127222.2(CACNA1A):c.5477dup (p.His1826fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1382040	NM_001127222.2(CACNA1A):c.3838_3841del (p.Asp1280fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1387896	NM_001127222.2(CACNA1A):c.3277_3283del (p.Ser1093fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1395073	NM_001127222.2(CACNA1A):c.110_125dup (p.Gly43fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1398258	NM_001127222.2(CACNA1A):c.841del (p.Cys281fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1401261	NM_001127222.2(CACNA1A):c.4366del (p.Ser1456fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1416873	NM_001127222.2(CACNA1A):c.4599C>A (p.Cys1533Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1418651	NC_000019.9:g.(?13445172)(13446743_?)del	CACNA1A	Pathogenic	criteria provided, single submitter
1421109	NM_001127222.2(CACNA1A):c.5422G>A (p.Val1808Ile)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 14 · 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
CACNA1A	Definitive	Autosomal dominant	undetermined early-onset epileptic encephalopathy	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
ACP5	Orphanet:1855	Spondyloenchondrodysplasia
CACNA1C	Orphanet:101016	Romano-Ward syndrome
CACNA1C	Orphanet:130	Brugada syndrome
CACNA1C	Orphanet:528084	Non-specific syndromic intellectual disability
CACNA1C	Orphanet:595098	Timothy syndrome type 1
CACNA1C	Orphanet:595105	Timothy syndrome type 2
CACNA1C	Orphanet:595109	Atypical Timothy syndrome

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
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar
ACP5	HGNC:124	ENSG00000102575	P13686	Tartrate-resistant acid phosphatase type 5	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
BEST2	HGNC:17107	ENSG00000039987	Q8NFU1	Bestrophin-2a	clinvar
WDR83OS	HGNC:30203	ENSG00000105583	Q9Y284	PAT complex subunit Asterix	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
ACP5	Tartrate-resistant acid phosphatase type 5	Involved in osteopontin/bone sialoprotein dephosphorylation.
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
BEST2	Bestrophin-2a	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
WDR83OS	PAT complex subunit Asterix	Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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	44.6×	0.002
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
ACP5	Enzyme (other)	yes	3.1.3.2	Calcineurin-like_PHP, Acid_PPase, Metallo-depent_PP-like
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
BEST2	Other/Unknown	no		Bestrophin, Bestrophin-like
WDR83OS	Other/Unknown	no		ASTER

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
periodontal ligament	1
right lung	1
upper lobe of left lung	1
apex of heart	1
muscle layer of sigmoid colon	1
right coronary artery	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1
transverse colon	1
fallopian tube	1
pituitary gland	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
ACP5	233	broad	marker	periodontal ligament, upper lobe of left lung, right lung
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
BEST2	153	tissue_specific	marker	mucosa of transverse colon, transverse colon, mucosa of sigmoid colon
WDR83OS	134	ubiquitous	marker	right adrenal gland, pituitary gland, fallopian tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1C	3,145
ACP5	2,983
WDR83OS	979
BEST2	584
CACNA1A	346

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1C	Q13936	33
BEST2	Q8NFU1	10
CACNA1A	O00555	4
ACP5	P13686	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDR83OS	Q9Y284	62.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of insulin secretion	2	109.8×	0.002	CACNA1A, CACNA1C
Integration of energy metabolism	2	87.8×	0.002	CACNA1A, CACNA1C
Vitamin B2 (riboflavin) metabolism	1	407.9×	0.016	ACP5
Presynaptic depolarization and calcium channel opening	1	237.9×	0.021	CACNA1A
Phase 2 - plateau phase	1	190.3×	0.021	CACNA1C
Adrenaline,noradrenaline inhibits insulin secretion	1	98.5×	0.033	CACNA1C
Phase 0 - rapid depolarisation	1	86.5×	0.033	CACNA1C
NCAM signaling for neurite out-growth	1	68.0×	0.036	CACNA1C
NCAM1 interactions	1	62.1×	0.036	CACNA1C
Stimuli-sensing channels	1	34.0×	0.058	BEST2
Cardiac conduction	1	27.2×	0.063	CACNA1C
Ion channel transport	1	24.0×	0.063	BEST2
Metabolism	2	5.8×	0.063	CACNA1A, CACNA1C
Muscle contraction	1	19.3×	0.069	CACNA1C
Transmission across Chemical Synapses	1	19.0×	0.069	CACNA1A
Axon guidance	1	11.3×	0.100	CACNA1C
Neuronal System	1	11.1×	0.100	CACNA1A
Nervous system development	1	10.7×	0.100	CACNA1C
Transport of small molecules	1	6.3×	0.158	BEST2
Developmental Biology	1	3.6×	0.249	CACNA1C

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
calcium ion import across plasma membrane	2	217.4×	0.001	CACNA1A, CACNA1C
calcium ion transmembrane transport	2	84.3×	0.005	CACNA1A, CACNA1C
negative regulation of superoxide anion generation	1	1685.2×	0.006	ACP5
calcium ion transmembrane transport via high voltage-gated calcium channel	1	1123.5×	0.006	CACNA1C
membrane depolarization during atrial cardiac muscle cell action potential	1	1123.5×	0.006	CACNA1C
positive regulation of cytosolic calcium ion concentration	2	46.8×	0.006	CACNA1A, CACNA1C
immune system development	1	842.6×	0.007	CACNA1C
positive regulation of adenylate cyclase activity	1	674.1×	0.007	CACNA1C
membrane depolarization during AV node cell action potential	1	674.1×	0.007	CACNA1C
positive regulation of muscle contraction	1	481.5×	0.009	CACNA1C
multi-pass transmembrane protein insertion into ER membrane	1	374.5×	0.010	WDR83OS
cardiac conduction	1	337.0×	0.010	CACNA1C
protein insertion into ER membrane	1	306.4×	0.010	WDR83OS
membrane depolarization during cardiac muscle cell action potential	1	280.9×	0.010	CACNA1C
cell communication by electrical coupling involved in cardiac conduction	1	280.9×	0.010	CACNA1C
regulation of ventricular cardiac muscle cell action potential	1	280.9×	0.010	CACNA1C
negative regulation of macrophage cytokine production	1	240.7×	0.010	ACP5
calcium ion transport into cytosol	1	240.7×	0.010	CACNA1C
negative regulation of interleukin-12 production	1	210.7×	0.010	ACP5
negative regulation of nitric oxide biosynthetic process	1	198.3×	0.010	ACP5
response to amyloid-beta	1	198.3×	0.010	CACNA1A
nitric oxide biosynthetic process	1	140.4×	0.013	ACP5
cardiac muscle cell action potential involved in contraction	1	140.4×	0.013	CACNA1C
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	134.8×	0.013	CACNA1C
superoxide anion generation	1	134.8×	0.013	ACP5
bone morphogenesis	1	120.4×	0.014	ACP5
bone resorption	1	116.2×	0.014	ACP5
negative regulation of interleukin-1 beta production	1	102.1×	0.014	ACP5
membrane depolarization	1	102.1×	0.014	BEST2
embryonic forelimb morphogenesis	1	99.1×	0.014	CACNA1C

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
CACNA1A	NIMODIPINE
CACNA1C	REMIFENTANIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1C	85	4
CACNA1A	2	4
ACP5	0	0
BEST2	0	0
WDR83OS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A, CACNA1C
TACRINE	4	CACNA1A, CACNA1C
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
CACNA1A	19	Binding:18, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACP5	3.1.3.2	acid phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1C	575

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

30 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	CACNA1A, CACNA1C
TACRINE	4	CACNA1A, CACNA1C
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CACNA1A, CACNA1C
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACP5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BEST2, WDR83OS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACP5	0	—
BEST2	0	—
WDR83OS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.