Developmental and epileptic encephalopathy 94

Summary

Developmental and epileptic encephalopathy 94 (MONDO:0014150) is a disease caused by CHD2 (GenCC Definitive), with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include memantine.

At a glance

• Causal gene: CHD2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,995
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy 94
Mondo ID	MONDO:0014150
OMIM	615369
DOID	DOID:0081325
UMLS	C3809278
MedGen	815608
GARD	0013197
Is cancer (heuristic)	no

Also known as: CHCHD10-related disorders · CHD2 myoclonic encephalopathy · childhood onset epileptic encephalopathy · childhood-onset epileptic encephalopathy · DEE94 · developmental and epileptic encephalopathy 94 · EEOC · epileptic encephalopathy, childhood-onset

Data availability: 1,995 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Lennox-Gastaut syndrome › developmental and epileptic encephalopathy 94

Related subtypes (2): developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 43

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:

265 likely benign, 228 uncertain significance, 51 pathogenic, 24 likely pathogenic, 21 conflicting classifications of pathogenicity, 6 benign, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012379	NM_001271.4(CHD2):c.1934C>T (p.Thr645Met)	CHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048635	NM_001271.4(CHD2):c.1387C>T (p.Gln463Ter)	CHD2	Pathogenic	criteria provided, single submitter
1057862	NM_001271.4(CHD2):c.2698C>G (p.Arg900Gly)	CHD2	Pathogenic	criteria provided, single submitter
1067558	NM_001271.4(CHD2):c.1052+2T>C	CHD2	Pathogenic	criteria provided, single submitter
1068680	NM_001271.4(CHD2):c.2888_2889insAT (p.Phe963fs)	CHD2	Pathogenic	criteria provided, single submitter
1069342	NC_000015.9:g.(?93514985)(93518190_?)del	CHD2	Pathogenic	criteria provided, single submitter
1069402	NM_001271.4(CHD2):c.4184_4187del (p.Lys1395fs)	CHD2	Pathogenic	criteria provided, single submitter
1069910	NM_001271.4(CHD2):c.2587_2591del (p.Phe863fs)	CHD2	Pathogenic	criteria provided, single submitter
1071676	NM_001271.4(CHD2):c.2536C>T (p.Arg846Ter)	CHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1071922	NM_001271.4(CHD2):c.3638_3644delinsAAAATGCACAGAAATGTCATCAAGAGGTTAANNNNNNNNNNATGCATTTCCCCAGTAGATGGGTCCTTGTACACCAAGACTTTTTGTTCGTCTTTGTACCAGAGTTTAGCCAAAG (p.Ser1213_Val1215delinsTer)	CHD2	Pathogenic	criteria provided, single submitter
1073543	NM_001271.4(CHD2):c.3355_3356del (p.Arg1119fs)	CHD2	Pathogenic	criteria provided, single submitter
1074629	NM_001271.4(CHD2):c.2826_2827insTGGC (p.Met943fs)	CHD2	Pathogenic	criteria provided, single submitter
1076209	NM_001271.4(CHD2):c.938_948del (p.Gly313fs)	CHD2	Pathogenic	criteria provided, single submitter
1076494	NM_001271.4(CHD2):c.1880_1883del (p.Ser627fs)	CHD2	Pathogenic	criteria provided, single submitter
1076495	NM_001271.4(CHD2):c.4949dup (p.Gly1651fs)	CHD2	Pathogenic	criteria provided, single submitter
1076544	NM_001271.4(CHD2):c.3323_3324del (p.Asp1107_Ser1108insTer)	CHD2	Pathogenic	criteria provided, single submitter
1188134	NM_001271.4(CHD2):c.4935del (p.Lys1645fs)	CHD2	Pathogenic	criteria provided, single submitter
1219194	NM_001271.4(CHD2):c.4176_4177del (p.Lys1393fs)	CHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1351835	NM_001271.4(CHD2):c.3100G>T (p.Glu1034Ter)	CHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1352740	NM_001271.4(CHD2):c.1787_1788del (p.Thr595_Tyr596insTer)	CHD2	Pathogenic	criteria provided, single submitter
1353592	NC_000015.9:g.(?93444468)(93583743_?)del	CHD2	Pathogenic	criteria provided, single submitter
1359923	NM_001271.4(CHD2):c.3412del (p.Arg1138fs)	CHD2	Pathogenic	criteria provided, single submitter
1365520	NM_001271.4(CHD2):c.4304del (p.Ser1434_Ser1435insTer)	CHD2	Pathogenic	criteria provided, single submitter
1370206	NM_001271.4(CHD2):c.294+3A>G	CHD2	Pathogenic	criteria provided, single submitter
1370712	NM_001271.4(CHD2):c.1833G>A (p.Trp611Ter)	CHD2	Pathogenic	criteria provided, single submitter
1379909	NM_001271.4(CHD2):c.5153+1G>T	CHD2	Pathogenic	criteria provided, single submitter
1381751	NM_001271.4(CHD2):c.654dup (p.Lys219fs)	CHD2	Pathogenic	criteria provided, single submitter
1402168	NM_001271.4(CHD2):c.1032dup (p.Glu345fs)	CHD2	Pathogenic	criteria provided, single submitter
1408227	NM_001271.4(CHD2):c.2686C>G (p.Gln896Glu)	CHD2	Pathogenic	criteria provided, single submitter
1408540	NM_001271.4(CHD2):c.975del (p.Glu325fs)	CHD2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
CHD2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy 94	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHD2	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
CHD2	Orphanet:2382	Lennox-Gastaut syndrome
SLC6A1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SLC6A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHD2	HGNC:1917	ENSG00000173575	O14647	ATP-dependent chromatin remodeler CHD2	gencc,clinvar
SLC6A1	HGNC:11042	ENSG00000157103	P30531	Sodium- and chloride-dependent GABA transporter 1	clinvar
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHD2	ATP-dependent chromatin remodeler CHD2	ATP-dependent chromatin-remodeling factor that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3.
SLC6A1	Sodium- and chloride-dependent GABA transporter 1	Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse.
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHD2	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
SLC6A1	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_GABA_GAT1, SNS_sf
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
cerebellar vermis	1
lateral globus pallidus	1
lateral nuclear group of thalamus	1
cingulate cortex	1
cortical plate	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHD2	268	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
SLC6A1	207	broad	marker	lateral nuclear group of thalamus, lateral globus pallidus, cerebellar vermis
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC6A1	2,841
CHD2	2,392
CHRNA4	1,989

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA4	P43681	12
SLC6A1	P30531	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHD2	O14647	60.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 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
Reuptake of GABA	1	951.7×	0.007	SLC6A1
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	543.8×	0.007	CHRNA4
Highly calcium permeable nicotinic acetylcholine receptors	1	423.0×	0.007	CHRNA4
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	346.1×	0.007	CHRNA4
Presynaptic nicotinic acetylcholine receptors	1	317.2×	0.007	CHRNA4
Acetylcholine binding and downstream events	1	271.9×	0.007	CHRNA4
Postsynaptic nicotinic acetylcholine receptors	1	271.9×	0.007	CHRNA4
Transmission across Chemical Synapses	2	50.8×	0.007	SLC6A1, CHRNA4
Neuronal System	2	29.5×	0.007	SLC6A1, CHRNA4
GABA synthesis, release, reuptake and degradation	1	211.5×	0.008	SLC6A1
Neurotransmitter release cycle	1	146.4×	0.010	SLC6A1
SLC-mediated transport of neurotransmitters	1	135.9×	0.010	SLC6A1
R-HSA-425366	1	60.4×	0.022	SLC6A1
CHD1 and CHD2 subfamily	1	36.2×	0.033	CHD2
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.034	CHRNA4
SLC-mediated transmembrane transport	1	19.7×	0.053	SLC6A1
Transport of small molecules	1	8.4×	0.115	SLC6A1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inorganic anion import across plasma membrane	1	2808.7×	0.008	SLC6A1
gamma-aminobutyric acid reuptake	1	1404.3×	0.008	SLC6A1
nucleosome organization	1	936.2×	0.008	CHD2
gamma-aminobutyric acid import	1	936.2×	0.008	SLC6A1
chemical synaptic transmission	2	51.5×	0.008	SLC6A1, CHRNA4
behavioral response to nicotine	1	624.1×	0.010	CHRNA4
inhibitory postsynaptic potential	1	561.7×	0.010	CHRNA4
regulation of dopamine secretion	1	401.2×	0.011	CHRNA4
nervous system process	1	401.2×	0.011	CHRNA4
synaptic transmission, cholinergic	1	267.5×	0.014	CHRNA4
hematopoietic stem cell differentiation	1	255.3×	0.014	CHD2
acetylcholine receptor signaling pathway	1	208.1×	0.014	CHRNA4
sodium ion import across plasma membrane	1	208.1×	0.014	SLC6A1
neuromuscular synaptic transmission	1	200.6×	0.014	CHRNA4
membrane depolarization	1	170.2×	0.014	CHRNA4
associative learning	1	160.5×	0.014	SLC6A1
B cell activation	1	151.8×	0.014	CHRNA4
presynaptic modulation of chemical synaptic transmission	1	151.8×	0.014	CHRNA4
response to nicotine	1	140.4×	0.015	CHRNA4
sensory perception of pain	1	124.8×	0.015	CHRNA4
action potential	1	119.5×	0.015	CHRNA4
amino acid transport	1	104.0×	0.017	SLC6A1
cognition	1	95.2×	0.017	CHRNA4
synapse organization	1	93.6×	0.017	SLC6A1
chloride transmembrane transport	1	79.1×	0.019	SLC6A1
regulation of membrane potential	1	77.0×	0.019	CHRNA4
monoatomic ion transmembrane transport	1	69.3×	0.020	CHRNA4
sodium ion transmembrane transport	1	67.7×	0.020	SLC6A1
memory	1	61.1×	0.021	SLC6A1
calcium ion transport	1	60.4×	0.021	CHRNA4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
SLC6A1	TIAGABINE
CHRNA4	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA4	64	4
SLC6A1	3	4
CHD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TIAGABINE	4	SLC6A1
TIAGABINE HYDROCHLORIDE	4	SLC6A1
VARENICLINE	4	CHRNA4
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
SLC6A1	56	Binding:55, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHRNA4	624

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
TIAGABINE	4	SLC6A1
TIAGABINE HYDROCHLORIDE	4	SLC6A1
VARENICLINE	4	CHRNA4
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC6A1, CHRNA4
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	1	CHD2

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)
CHD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03779672	PHASE4	COMPLETED	Memantine for Epileptic Encephalopathy
NCT06500260	Not specified	RECRUITING	CNKSR2 Natural History Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MEMANTINE	4	1