early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation

Summary

early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation (MONDO:0017325) is a disease caused by GRIN2A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GRIN2A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 29

Clinical features

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010844	EEG with multifocal slow activity	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012736	Profound global developmental delay	Frequent (30-79%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005484	Secondary microcephaly	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0010818	Generalized tonic seizure	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)
HP:0011451	Congenital microcephaly	Occasional (5-29%)
HP:0012171	Stereotypical hand wringing	Occasional (5-29%)
HP:0012447	Abnormal myelination	Occasional (5-29%)
HP:0012547	Abnormal involuntary eye movements	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Mondo ID	MONDO:0017325
OMIM	245570, 613971
Orphanet	289266
ICD-11	1655554340
UMLS	C4749281
MedGen	1663334
GARD	0021134
Is cancer (heuristic)	no

Also known as: early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation · epilepsy, focal, with speech disorder and with or without impaired intellectual development

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

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › childhood-onset epilepsy syndrome › early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation

Related subtypes (15): self-limited childhood occipital epilepsy, Landau-Kleffner syndrome, rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome, perioral myoclonia with absences, cryptogenic late-onset epileptic spasms, rolandic epilepsy-speech dyspraxia syndrome, familial partial epilepsy, acute encephalopathy with biphasic seizures and late reduced diffusion, new-onset refractory status epilepticus, atypical childhood epilepsy with centrotemporal spikes, Sunflower syndrome, childhood-onset genetic generalized epilepsy syndrome, childhood-onset idiopathic generalized epilepsy syndrome, childhood-onset epilepsy syndrome with developmental and/or epileptic encephalopathy, childhood-onset self-limited focal epilepsy syndrome

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
224108	NM_001134407.3(GRIN2A):c.4375A>G (p.Ser1459Gly)	GRIN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
860497	NM_001134407.3(GRIN2A):c.1497+5G>C	GRIN2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
GRIN2A	Strong	Autosomal dominant	early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIN2A	Orphanet:163721	Rolandic epilepsy-speech dyspraxia syndrome
GRIN2A	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GRIN2A	Orphanet:289266	Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
GRIN2A	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
GRIN2A	Orphanet:98818	Landau-Kleffner syndrome

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
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

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
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIN2A	3,146

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2A	Q12879	37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
MECP2 regulates neuronal receptors and channels	1	601.0×	0.003	GRIN2A
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.003	GRIN2A
Synaptic adhesion-like molecules	1	543.8×	0.003	GRIN2A
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.003	GRIN2A
Long-term potentiation	1	475.8×	0.003	GRIN2A
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.005	GRIN2A
Neurexins and neuroligins	1	196.9×	0.005	GRIN2A

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
directional locomotion	1	5617.3×	0.003	GRIN2A
protein localization to postsynaptic membrane	1	5617.3×	0.003	GRIN2A
sleep	1	2407.4×	0.003	GRIN2A
regulation of monoatomic cation transmembrane transport	1	2106.5×	0.003	GRIN2A
serotonin metabolic process	1	1685.2×	0.003	GRIN2A
calcium ion transmembrane import into cytosol	1	1532.0×	0.003	GRIN2A
ionotropic glutamate receptor signaling pathway	1	1296.3×	0.003	GRIN2A
excitatory chemical synaptic transmission	1	1296.3×	0.003	GRIN2A
startle response	1	1123.5×	0.003	GRIN2A
dopamine metabolic process	1	991.3×	0.003	GRIN2A
glutamate receptor signaling pathway	1	936.2×	0.003	GRIN2A
regulation of neuronal synaptic plasticity	1	674.1×	0.004	GRIN2A
positive regulation of synaptic transmission, glutamatergic	1	624.1×	0.004	GRIN2A
monoatomic cation transmembrane transport	1	624.1×	0.004	GRIN2A
positive regulation of excitatory postsynaptic potential	1	526.6×	0.004	GRIN2A
response to amphetamine	1	495.6×	0.004	GRIN2A
excitatory postsynaptic potential	1	443.5×	0.005	GRIN2A
sensory perception of pain	1	374.5×	0.005	GRIN2A
negative regulation of protein catabolic process	1	366.4×	0.005	GRIN2A
synaptic transmission, glutamatergic	1	358.6×	0.005	GRIN2A
visual learning	1	306.4×	0.005	GRIN2A
long-term synaptic potentiation	1	280.9×	0.006	GRIN2A
regulation of synaptic plasticity	1	259.3×	0.006	GRIN2A
learning or memory	1	240.7×	0.006	GRIN2A
protein catabolic process	1	237.3×	0.006	GRIN2A
response to wounding	1	221.7×	0.006	GRIN2A
calcium ion transmembrane transport	1	210.7×	0.006	GRIN2A
neurogenesis	1	208.1×	0.006	GRIN2A
sodium ion transmembrane transport	1	203.0×	0.006	GRIN2A
memory	1	183.2×	0.006	GRIN2A

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
GRIN2A	MEMANTINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIN2A	37	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEMANTINE HYDROCHLORIDE	4	GRIN2A
ESKETAMINE	4	GRIN2A
DEXTROMETHORPHAN	4	GRIN2A
PENTAMIDINE	4	GRIN2A
AMANTADINE	4	GRIN2A
KETAMINE	4	GRIN2A
CYCLOSERINE	4	GRIN2A
MEMANTINE	4	GRIN2A
TACRINE	4	GRIN2A
LEVORPHANOL	4	GRIN2A
CHLORPROMAZINE	4	GRIN2A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
ESMETHADONE	3	GRIN2A
DALZANEMDOR	3	GRIN2A
LATREPIRDINE	3	GRIN2A
GLUTAMIC ACID	3	GRIN2A
DEXOXADROL	2	GRIN2A
DEXTRORPHAN	2	GRIN2A
LEVOMETHADONE	2	GRIN2A
ALPHAMETHADOL	2	GRIN2A
BETAMETHADOL	2	GRIN2A
DIMEMORFAN	2	GRIN2A
PHENCYCLIDINE	2	GRIN2A
DIZOCILPINE	2	GRIN2A
ETOXADROL	2	GRIN2A
IFENPRODIL	2	GRIN2A
TEZAMPANEL ANHYDROUS	2	GRIN2A
TRAXOPRODIL	2	GRIN2A
RADIPRODIL	2	GRIN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRIN2A	324

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

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)
MEMANTINE HYDROCHLORIDE	4	GRIN2A
ESKETAMINE	4	GRIN2A
DEXTROMETHORPHAN	4	GRIN2A
PENTAMIDINE	4	GRIN2A
AMANTADINE	4	GRIN2A
KETAMINE	4	GRIN2A
CYCLOSERINE	4	GRIN2A
MEMANTINE	4	GRIN2A
TACRINE	4	GRIN2A
LEVORPHANOL	4	GRIN2A
CHLORPROMAZINE	4	GRIN2A
PROCYCLIDINE	4	GRIN2A
ORPHENADRINE	4	GRIN2A
ESMETHADONE	3	GRIN2A
DALZANEMDOR	3	GRIN2A
LATREPIRDINE	3	GRIN2A
GLUTAMIC ACID	3	GRIN2A
DEXOXADROL	2	GRIN2A
DEXTRORPHAN	2	GRIN2A
LEVOMETHADONE	2	GRIN2A
ALPHAMETHADOL	2	GRIN2A
BETAMETHADOL	2	GRIN2A
DIMEMORFAN	2	GRIN2A
PHENCYCLIDINE	2	GRIN2A
DIZOCILPINE	2	GRIN2A
ETOXADROL	2	GRIN2A
IFENPRODIL	2	GRIN2A
TEZAMPANEL ANHYDROUS	2	GRIN2A
TRAXOPRODIL	2	GRIN2A
RADIPRODIL	2	GRIN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIN2A
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.