Developmental and epileptic encephalopathy, 33

Summary

Developmental and epileptic encephalopathy, 33 (MONDO:0014625) is a disease caused by EEF1A2 (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: EEF1A2 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 476

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 33
Mondo ID	MONDO:0014625
OMIM	616409
DOID	DOID:0080463
UMLS	C4225337
MedGen	897930
GARD	0016106
NORD	111336
Is cancer (heuristic)	no

Also known as: DEE33 · developmental and epileptic encephalopathy 33 · early infantile epileptic encephalopathy caused by mutation in EEF1A2 · EEF1A2 early infantile epileptic encephalopathy · EEF1A2-Related Neurodevelopmental Disorder · EEF1A2-related neurodevelopmental disorder · EIEE33 · epileptic encephalopathy, early infantile, 33 · epileptic encephalopathy, early infantile, type 33

Data availability: 476 ClinVar variants · 3 GenCC gene-disease records.

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, 33

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, 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

476 retrieved; paginated sample, class counts are floors:

253 likely benign, 137 uncertain significance, 26 conflicting classifications of pathogenicity, 21 benign, 17 benign/likely benign, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
476031	NC_000020.10:g.(?61977556)(62159505_?)del	CHRNA4	Pathogenic	criteria provided, single submitter
100782	NM_001958.5(EEF1A2):c.208G>A (p.Gly70Ser)	EEF1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1018904	NM_001958.5(EEF1A2):c.274G>A (p.Ala92Thr)	EEF1A2	Pathogenic	criteria provided, single submitter
1459521	NM_001958.5(EEF1A2):c.1304T>C (p.Val435Ala)	EEF1A2	Pathogenic	criteria provided, single submitter
1470873	NM_001958.5(EEF1A2):c.289G>A (p.Asp97Asn)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
192252	NM_001958.5(EEF1A2):c.364G>A (p.Glu122Lys)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265111	NM_001958.5(EEF1A2):c.1267C>T (p.Arg423Cys)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279803	NM_001958.5(EEF1A2):c.271G>A (p.Asp91Asn)	EEF1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
280924	NM_001958.5(EEF1A2):c.370G>A (p.Glu124Lys)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449242	NM_001958.5(EEF1A2):c.796C>T (p.Arg266Trp)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542650	NM_001958.5(EEF1A2):c.1150G>C (p.Gly384Arg)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542651	NM_001958.5(EEF1A2):c.205C>T (p.Arg69Cys)	EEF1A2	Pathogenic	criteria provided, single submitter
830077	NM_001958.5(EEF1A2):c.1295C>T (p.Thr432Met)	EEF1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1474102	NM_001958.5(EEF1A2):c.50_51delinsGA (p.Asp17Gly)	EEF1A2	Likely pathogenic	criteria provided, single submitter
1803024	NM_001958.5(EEF1A2):c.43C>A (p.His15Asn)	EEF1A2	Likely pathogenic	criteria provided, single submitter
2499558	NM_001958.5(EEF1A2):c.1259C>G (p.Pro420Arg)	EEF1A2	Likely pathogenic	criteria provided, single submitter
383531	NM_001958.5(EEF1A2):c.1309G>T (p.Val437Phe)	EEF1A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
567537	NM_001958.5(EEF1A2):c.863A>G (p.Glu288Gly)	EEF1A2	Likely pathogenic	criteria provided, single submitter
620070	NM_001958.5(EEF1A2):c.821C>T (p.Pro274Leu)	EEF1A2	Likely pathogenic	criteria provided, single submitter
870132	NM_001958.5(EEF1A2):c.46G>C (p.Val16Leu)	EEF1A2	Likely pathogenic	no assertion criteria provided
975543	NM_001958.5(EEF1A2):c.1138G>C (p.Asp380His)	EEF1A2	Likely pathogenic	no assertion criteria provided
4278451	NM_020851.3(ISLR2):c.968G>A (p.Trp323Ter)	ISLR2	Likely pathogenic	criteria provided, single submitter
1059380	NM_001958.5(EEF1A2):c.1029+3G>C	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064103	NC_000020.10:g.(?62103511)(62120515_?)del	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1514727	NM_001958.5(EEF1A2):c.725C>T (p.Thr242Met)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1595477	NM_001958.5(EEF1A2):c.667G>A (p.Ala223Thr)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1661415	NM_001958.5(EEF1A2):c.332G>A (p.Cys111Tyr)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192251	NM_001958.5(EEF1A2):c.754G>C (p.Asp252His)	EEF1A2	Conflicting classifications of pathogenicity	no assertion criteria provided
2074793	NM_001958.5(EEF1A2):c.391G>A (p.Gly131Arg)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441178	NM_001958.5(EEF1A2):c.270C>T (p.Ile90=)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
EEF1A2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 33	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EEF1A2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
EEF1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	gencc,clinvar
MRGBP	HGNC:15866	ENSG00000101189	Q9NV56	MRG/MORF4L-binding protein	clinvar
ABHD16B	HGNC:16128	ENSG00000183260	Q9H3Z7	ABHD16B	clinvar
PPDPF	HGNC:16142	ENSG00000125534	Q9H3Y8	Pancreatic progenitor cell differentiation and proliferation factor	clinvar
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar
ISLR2	HGNC:29286	ENSG00000167178	Q6UXK2	Immunoglobulin superfamily containing leucine-rich repeat protein 2	clinvar
HAR1A	HGNC:33117	ENSG00000225978		highly accelerated region 1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
MRGBP	MRG/MORF4L-binding protein	Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A.
ABHD16B	ABHD16B	Hydrolyzes the sn-1 position of glycerophospholipids with high specificity towards phosphatidylserine (PS), PS-PLA1 enzyme.
PPDPF	Pancreatic progenitor cell differentiation and proliferation factor	Probable regulator of exocrine pancreas development.
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…
ISLR2	Immunoglobulin superfamily containing leucine-rich repeat protein 2	Required for axon extension during neural development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.14

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
Antibody/Immunoglobulin	1	4.2×	0.217
Other/Unknown	6	1.5×	0.217

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
MRGBP	Other/Unknown	no		Eaf7/MRGBP
ABHD16B	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
PPDPF	Other/Unknown	no		PPDPF
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
ISLR2	Antibody/Immunoglobulin	yes		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
HAR1A	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
right testis	2
cortical plate	2
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1
sperm	1
testis	1
lower esophagus mucosa	1
mucosa of transverse colon	1
right coronary artery	1
cingulate cortex	1
right lobe of liver	1
ganglionic eminence	1
ventricular zone	1
Brodmann (1909) area 9	1
male germ line stem cell (sensu Vertebrata) in testis	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle
MRGBP	249	ubiquitous	yes	sperm, left testis, right testis
ABHD16B	106		yes	right testis, left testis, testis
PPDPF	262	ubiquitous	marker	lower esophagus mucosa, right coronary artery, mucosa of transverse colon
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex
ISLR2	154	broad	marker	cortical plate, ganglionic eminence, ventricular zone
HAR1A	166		yes	male germ line stem cell (sensu Vertebrata) in testis, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNA4	1,989
MRGBP	1,573
ISLR2	1,152
EEF1A2	745
PPDPF	439
ABHD16B	427
HAR1A	0

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA4	P43681	12
EEF1A2	Q05639	2
MRGBP	Q9NV56	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD16B	Q9H3Z7	86.64
ISLR2	Q6UXK2	67.24
PPDPF	Q9H3Y8	60.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 7 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
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	543.8×	0.008	CHRNA4
Highly calcium permeable nicotinic acetylcholine receptors	1	423.0×	0.008	CHRNA4
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	346.1×	0.008	CHRNA4
Presynaptic nicotinic acetylcholine receptors	1	317.2×	0.008	CHRNA4
Acetylcholine binding and downstream events	1	271.9×	0.008	CHRNA4
Postsynaptic nicotinic acetylcholine receptors	1	271.9×	0.008	CHRNA4
Eukaryotic Translation Elongation	1	92.8×	0.020	EEF1A2
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.044	CHRNA4
Chromatin organization	1	27.2×	0.044	MRGBP
HATs acetylate histones	1	26.4×	0.044	MRGBP
Transmission across Chemical Synapses	1	25.4×	0.044	CHRNA4
Chromatin modifying enzymes	1	24.1×	0.044	MRGBP
Neuronal System	1	14.8×	0.066	CHRNA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of lipid kinase activity	1	2808.7×	0.015	EEF1A2
phosphatidylserine catabolic process	1	702.2×	0.023	ABHD16B
regulation of chaperone-mediated autophagy	1	561.7×	0.023	EEF1A2
monoacylglycerol catabolic process	1	401.2×	0.023	ABHD16B
behavioral response to nicotine	1	312.1×	0.023	CHRNA4
inhibitory postsynaptic potential	1	280.9×	0.023	CHRNA4
translational elongation	1	200.6×	0.023	EEF1A2
regulation of dopamine secretion	1	200.6×	0.023	CHRNA4
nervous system process	1	200.6×	0.023	CHRNA4
synaptic transmission, cholinergic	1	133.8×	0.028	CHRNA4
TORC1 signaling	1	133.8×	0.028	PPDPF
acetylcholine receptor signaling pathway	1	104.0×	0.031	CHRNA4
neuromuscular synaptic transmission	1	100.3×	0.031	CHRNA4
regulation of double-strand break repair	1	96.8×	0.031	MRGBP
positive regulation of axon extension	1	85.1×	0.031	ISLR2
membrane depolarization	1	85.1×	0.031	CHRNA4
B cell activation	1	75.9×	0.031	CHRNA4
presynaptic modulation of chemical synaptic transmission	1	75.9×	0.031	CHRNA4
response to nicotine	1	70.2×	0.031	CHRNA4
positive regulation of double-strand break repair via homologous recombination	1	63.8×	0.032	MRGBP
sensory perception of pain	1	62.4×	0.032	CHRNA4
action potential	1	59.8×	0.032	CHRNA4
cognition	1	47.6×	0.038	CHRNA4
regulation of membrane potential	1	38.5×	0.045	CHRNA4
liver development	1	37.0×	0.045	PPDPF
monoatomic ion transmembrane transport	1	34.7×	0.046	CHRNA4
calcium ion transport	1	30.2×	0.051	CHRNA4
monoatomic ion transport	1	26.0×	0.057	CHRNA4
response to oxidative stress	1	21.8×	0.065	CHRNA4
translation	1	17.1×	0.080	EEF1A2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 2 of 7 evidence-associated genes (29%) 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
CHRNA4	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA4	64	4
EEF1A2	0	0
MRGBP	0	0
ABHD16B	0	0
PPDPF	0	0
ISLR2	0	0
HAR1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
AZELASTINE	4	CHRNA4
ACETYLCHOLINE	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
EEF1A2	8	Binding:8

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: 7; 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)
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
AZELASTINE	4	CHRNA4
ACETYLCHOLINE	4	CHRNA4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNA4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ISLR2
E	Difficult family or no structure, no drug	5	EEF1A2, MRGBP, ABHD16B, PPDPF, HAR1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EEF1A2	8	—
MRGBP	0	—
ABHD16B	0	—
PPDPF	0	—
ISLR2	0	—
HAR1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.