Developmental and epileptic encephalopathy, 46

Summary

Developmental and epileptic encephalopathy, 46 (MONDO:0014947) is a disease caused by GRIN2D (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GRIN2D (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 95

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 46
Mondo ID	MONDO:0014947
OMIM	617162
DOID	DOID:0080456
UMLS	C4310687
MedGen	934654
GARD	0016205
Is cancer (heuristic)	no

Also known as: DEE46 · developmental and epileptic encephalopathy 46 · early infantile epileptic encephalopathy caused by mutation in GRIN2D · EIEE46 · epileptic encephalopathy, early infantile, 46 · epileptic encephalopathy, early infantile, 46; EIEE46 · epileptic encephalopathy, early infantile, type 46 · GRIN2D early infantile epileptic encephalopathy · GRIN2D-related complex neurodevelopmental disorder · GRIN2D-related DEE · GRIN2D-related developmental and epileptic encephalopathy

Data availability: 95 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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, 46

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, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 45, 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

95 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 14 conflicting classifications of pathogenicity, 5 likely pathogenic, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 benign, 2 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1013174	NM_000836.4(GRIN2D):c.2041A>G (p.Met681Val)	GRIN2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325736	NM_000836.4(GRIN2D):c.1718C>T (p.Ser573Phe)	GRIN2D	Pathogenic	criteria provided, single submitter
1685871	NM_000836.4(GRIN2D):c.1997C>T (p.Ala666Val)	GRIN2D	Pathogenic	criteria provided, single submitter
267211	NM_000836.4(GRIN2D):c.1999G>A (p.Val667Ile)	GRIN2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
599388	NM_000836.4(GRIN2D):c.2043G>C (p.Met681Ile)	GRIN2D	Pathogenic	no assertion criteria provided
599389	NM_000836.4(GRIN2D):c.2080A>C (p.Ser694Arg)	GRIN2D	Pathogenic	no assertion criteria provided
1325737	NM_000836.4(GRIN2D):c.2033C>A (p.Ala678Asp)	GRIN2D	Likely pathogenic	criteria provided, single submitter
1333739	NM_000836.4(GRIN2D):c.2029C>G (p.Leu677Val)	GRIN2D	Likely pathogenic	criteria provided, single submitter
1803034	NM_000836.4(GRIN2D):c.2330C>T (p.Thr777Ile)	GRIN2D	Likely pathogenic	criteria provided, single submitter
3901882	NM_000836.4(GRIN2D):c.2530A>C (p.Asn844His)	GRIN2D	Likely pathogenic	criteria provided, single submitter
599390	NM_000836.4(GRIN2D):c.1345G>A (p.Asp449Asn)	GRIN2D	Likely pathogenic	criteria provided, single submitter
1325738	NM_000836.4(GRIN2D):c.3812C>T (p.Ser1271Leu)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325740	NM_000836.4(GRIN2D):c.2533A>G (p.Met845Val)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1377325	NM_000836.4(GRIN2D):c.3706_3723del (p.Pro1236_Arg1241del)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1435324	NM_000836.4(GRIN2D):c.3947G>T (p.Arg1316Leu)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878541	NM_000836.4(GRIN2D):c.3340G>A (p.Asp1114Asn)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2607223	NM_000836.4(GRIN2D):c.2858G>C (p.Gly953Ala)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2621893	NM_000836.4(GRIN2D):c.1282G>A (p.Asp428Asn)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2671705	NM_000836.4(GRIN2D):c.1033G>A (p.Gly345Ser)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2672780	NM_000836.4(GRIN2D):c.3235G>T (p.Ala1079Ser)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2852562	NM_000836.4(GRIN2D):c.2791C>G (p.Pro931Ala)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808609	NM_000836.4(GRIN2D):c.2024C>T (p.Ala675Val)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
813811	NM_000836.4(GRIN2D):c.2008C>T (p.Leu670Phe)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
974877	NM_000836.4(GRIN2D):c.1724C>T (p.Ser575Leu)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985175	NM_000836.4(GRIN2D):c.2023G>A (p.Ala675Thr)	GRIN2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029953	NM_000836.4(GRIN2D):c.2356A>G (p.Thr786Ala)	GRIN2D	Uncertain significance	criteria provided, single submitter
1029954	NM_000836.4(GRIN2D):c.3076G>A (p.Gly1026Ser)	GRIN2D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029955	NM_000836.4(GRIN2D):c.3888G>C (p.Arg1296Ser)	GRIN2D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029956	NM_000836.4(GRIN2D):c.3929C>T (p.Ala1310Val)	GRIN2D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031669	NM_000836.4(GRIN2D):c.1085+13G>A	GRIN2D	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GRIN2D	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 46	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIN2D	Orphanet:442835	Non-specific early-onset 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
GRIN2D	HGNC:4588	ENSG00000105464	O15399	Glutamate receptor ionotropic, NMDA 2D	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIN2D	Glutamate receptor ionotropic, NMDA 2D	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)
GRIN2D	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

Expression context

Cohort genes with no expression data: 0.

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
anterior cingulate cortex	1
cingulate cortex	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIN2D	144	broad	yes	cingulate cortex, anterior cingulate cortex, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIN2D	1,230

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2D	O15399	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.003	GRIN2D
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.003	GRIN2D
Synaptic adhesion-like molecules	1	543.8×	0.003	GRIN2D
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.003	GRIN2D
Long-term potentiation	1	475.8×	0.003	GRIN2D
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.005	GRIN2D
Neurexins and neuroligins	1	196.9×	0.006	GRIN2D
RAF/MAP kinase cascade	1	61.1×	0.016	GRIN2D

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
regulation of monoatomic cation transmembrane transport	1	2106.5×	0.002	GRIN2D
cellular response to L-glutamate	1	1685.2×	0.002	GRIN2D
calcium ion transmembrane import into cytosol	1	1532.0×	0.002	GRIN2D
ionotropic glutamate receptor signaling pathway	1	1296.3×	0.002	GRIN2D
excitatory chemical synaptic transmission	1	1296.3×	0.002	GRIN2D
startle response	1	1123.5×	0.002	GRIN2D
regulation of sensory perception of pain	1	991.3×	0.002	GRIN2D
regulation of neuronal synaptic plasticity	1	674.1×	0.003	GRIN2D
positive regulation of synaptic transmission, glutamatergic	1	624.1×	0.003	GRIN2D
monoatomic cation transmembrane transport	1	624.1×	0.003	GRIN2D
positive regulation of excitatory postsynaptic potential	1	526.6×	0.003	GRIN2D
excitatory postsynaptic potential	1	443.5×	0.003	GRIN2D
synaptic transmission, glutamatergic	1	358.6×	0.004	GRIN2D
adult locomotory behavior	1	300.9×	0.004	GRIN2D
long-term synaptic potentiation	1	280.9×	0.004	GRIN2D
regulation of synaptic plasticity	1	259.3×	0.004	GRIN2D
brain development	1	79.5×	0.013	GRIN2D

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
GRIN2D	DEXTROMETHORPHAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIN2D	29	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DEXTROMETHORPHAN	4	GRIN2D
LEVORPHANOL	4	GRIN2D
AMANTADINE	4	GRIN2D
CHLORPROMAZINE	4	GRIN2D
KETAMINE	4	GRIN2D
MEMANTINE	4	GRIN2D
PROCYCLIDINE	4	GRIN2D
ORPHENADRINE	4	GRIN2D
CYCLOSERINE	4	GRIN2D
GLUTAMIC ACID	3	GRIN2D
DALZANEMDOR	3	GRIN2D
ESMETHADONE	3	GRIN2D
DEXTRORPHAN	2	GRIN2D
TEZAMPANEL ANHYDROUS	2	GRIN2D
TRAXOPRODIL	2	GRIN2D
RADIPRODIL	2	GRIN2D
RACEMETHORPHAN	2	GRIN2D
PHENCYCLIDINE	2	GRIN2D
DIZOCILPINE	2	GRIN2D
LICOSTINEL	2	GRIN2D
BUDIPINE	2	GRIN2D
SELFOTEL	2	GRIN2D
PERZINFOTEL	2	GRIN2D
LANICEMINE	2	GRIN2D
IFENPRODIL	2	GRIN2D
LEVOMETHADONE	2	GRIN2D
ALPHAMETHADOL	2	GRIN2D
BETAMETHADOL	2	GRIN2D
TRANSTORINE	1	GRIN2D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIN2D	227	Binding:214, Functional:8, 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
GRIN2D	227

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

29 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)
DEXTROMETHORPHAN	4	GRIN2D
LEVORPHANOL	4	GRIN2D
AMANTADINE	4	GRIN2D
CHLORPROMAZINE	4	GRIN2D
KETAMINE	4	GRIN2D
MEMANTINE	4	GRIN2D
PROCYCLIDINE	4	GRIN2D
ORPHENADRINE	4	GRIN2D
CYCLOSERINE	4	GRIN2D
GLUTAMIC ACID	3	GRIN2D
DALZANEMDOR	3	GRIN2D
ESMETHADONE	3	GRIN2D
DEXTRORPHAN	2	GRIN2D
TEZAMPANEL ANHYDROUS	2	GRIN2D
TRAXOPRODIL	2	GRIN2D
RADIPRODIL	2	GRIN2D
RACEMETHORPHAN	2	GRIN2D
PHENCYCLIDINE	2	GRIN2D
DIZOCILPINE	2	GRIN2D
LICOSTINEL	2	GRIN2D
BUDIPINE	2	GRIN2D
SELFOTEL	2	GRIN2D
PERZINFOTEL	2	GRIN2D
LANICEMINE	2	GRIN2D
IFENPRODIL	2	GRIN2D
LEVOMETHADONE	2	GRIN2D
ALPHAMETHADOL	2	GRIN2D
BETAMETHADOL	2	GRIN2D
TRANSTORINE	1	GRIN2D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIN2D
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.