GRIN2B-Related Developmental and Epileptic Encephalopathy — Research Report

1. Disease Information

What it is. GRIN2B-related neurodevelopmental disorder is a single-gene, autosomal-dominant condition caused by heterozygous de novo variants in GRIN2B, which encodes the GluN2B (NR2B) subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor. Every affected person has developmental delay/intellectual disability (DD/ID); on top of that, a big chunk have epilepsy, autism/behavioral issues, muscle-tone problems, and movement disorders. The "developmental and epileptic encephalopathy" (DEE) framing captures the more severe end — early-onset drug-resistant seizures layered on top of (and worsening) the developmental impairment — but the disorder is really one continuous spectrum from mild ID-without-seizures all the way to catastrophic epileptic encephalopathy.

Key identifiers. - Gene: GRIN2B — OMIM *138252; HGNC:4586 (hgnc:4586); chromosome 12p13.1; NCBI Gene 2904. - Disease (severe/epileptic end): Developmental and Epileptic Encephalopathy 27 (DEE27) — OMIM #616139; MONDO:0014505. - Disease (milder end): Autosomal Dominant Intellectual Developmental Disorder 6 (MRD6, formerly "mental retardation, autosomal dominant 6") — OMIM #613970; MONDO:0013655. - Orphanet: GRIN2B is the gene for several ORPHA entries; the broad umbrella "non-specific/syndromic intellectual disability" and "GRIN2B-related" concepts apply. (Worth pulling the exact ORPHA leaf via just structured-rebuild-orphanet during curation.) - ICD-11: most naturally 8A61-region DEE / 6A00 disorders of intellectual development, coded by phenotype; there's no GRIN2B-specific ICD code. - MeSH: no gene-specific descriptor; indexed under "Epileptic Syndromes," "Intellectual Disability," "Receptors, N-Methyl-D-Aspartate."

Data provenance. Information is a mix of disease-level aggregated resources (GeneReviews, OMIM, Orphanet) built from individual patient case series — the field's backbone is aggregated cohorts of de novo variant carriers (Endele 2010, Lemke 2014, Platzer 2017) plus functional studies. Fewer than a couple hundred individuals are described in detail; a lot of the frequency numbers come from the 61-person clinically-characterized subset in GeneReviews and the 91-person Platzer cohort.

Synonyms / alternative names: GRIN2B encephalopathy; GRIN2B-related neurodevelopmental disorder; NMDA-receptor GluN2B/NR2B-related disorder; intellectual disability, autosomal dominant 6; DEE27; part of the broader "GRIN disorders" / "GRIN-related disorders" family (with GRIN1, GRIN2A, GRIN2D).

2. Etiology

Primary cause — genetic, monogenic. Heterozygous pathogenic variants in GRIN2B, essentially always de novo (arising fresh in the affected child, not inherited). GeneReviews reports that all probands with parental testing had de novo variants; there is no known environmental or infectious cause. This is a dominant, high-penetrance Mendelian disorder — the variant is the disease.

Genetic risk factors. - The causal lesion itself: a pathogenic GRIN2B variant (see §4). - GRIN2B is one of the most mutation-intolerant genes in the genome, which is why de novo hits there are so consequential: pLI = 1.00, LOEUF = 0.06 (extreme loss-of-function intolerance), missense Z-score = 5.42 in gnomAD (gnomAD constraint). Essentially no loss-of-function variants are seen in the healthy population, so any real LoF hit is high-impact. - Advanced paternal age is the generic risk factor for de novo mutations broadly, but it has not been specifically quantified for GRIN2B.

Protective factors. None established. There are no known protective alleles or modifier variants that rescue the phenotype, and no lifestyle/dietary protective factors (this isn't a multifactorial disease). L-serine and NMDA antagonists are treatments, not prevention (see §12).

Gene–environment interactions. Not a meaningful axis for this disorder — it's driven by the germline (or post-zygotic mosaic) variant. The one "environmental" modulator worth noting mechanistically is activity-dependent regulation of the GluN2B→GluN2A developmental switch: synaptic activity normally times the swap of GluN2B for GluN2A during the third postnatal week (rodent), so the developmental window itself is a biological context that shapes when/how the variant bites (Frontiers review, PMC9873235).

3. Phenotypes

Frequencies below are from the GeneReviews clinically-characterized cohort (n≈61 unless noted; Platzer & Myers, GeneReviews, PMID:29851452). Onset is infantile-to-early-childhood for essentially all features.

Speech and motor milestones. Delayed speech and motor development is near-universal; some individuals never develop speech or independent walking. Suggest HP:0000750 (Delayed speech and language development), HP:0002540 (Inability to walk).

Epilepsy sub-phenotyping (within the 31 with epilepsy): - Generalized seizures: 58% (18/31) — HP:0002197 (Generalized-onset seizure) - Focal seizures: 48% (15/31) — HP:0007359 (Focal-onset seizure) - Epileptic (infantile) spasms: 35% (11/31), most meeting West syndrome criteria — HP:0012469 (Infantile spasms) - Onset: birth to age 9 years; ~50% drug-resistant — HP:0011171 (Refractory epilepsy)

Additional/associated features reported: strabismus, cortical visual impairment, feeding difficulties, hyperkinesis/ADHD-like features, stereotypies, and occasionally hyperphagia/obesity in some series.

Quality-of-life impact. No GRIN2B-specific EQ-5D/SF-36 data. Impact is dominated by the severe-profound ID majority (61%): most affected individuals need lifelong assistance with daily living, communication supports, and — where epilepsy is refractory — carry the additional QoL burden of drug-resistant seizures and their treatment side effects. Non-verbal, non-ambulatory individuals at the profound end represent the highest care-dependency group.

4. Genetic / Molecular Information

Causal gene. GRIN2B (OMIM *138252; HGNC:4586; 12p13.1). Encodes GluN2B/NR2B, a regulatory subunit of the heterotetrameric NMDA receptor (two obligate GluN1 + two GluN2/GluN3 subunits).

Variant landscape. - Missense is the dominant class (~65% of disease-associated GRIN variants overall), typically clustering in functionally critical domains and associated with the more severe end. Platzer 2017 found missense variants significantly enriched for severe ID (p = 0.0079, Fisher's exact; PMID:28377535). - Protein-truncating variants (nonsense, frameshift, splice-site) and whole/partial-gene deletions — "null alleles" — trend toward milder-to-moderate ID and are less often associated with severe epilepsy. - Structural: the original Endele 2010 report found GRIN2B disrupted by chromosomal translocation breakpoints in ID/epilepsy patients (PMID:20890276). - Detection: GeneReviews — sequence analysis picks up ~95% (82/86), deletion/dup or CMA the remaining ~5% (4/86).

Landmark variant examples: - N615I and V618G — de novo missense in the M2 re-entrant pore loop; increase Ca²⁺ permeability and reduce Mg²⁺ block → gain of function; West syndrome/severe DD (Lemke 2014, PMID:24272827). - E413G, C461F (ligand-binding domain) — reduced surface expression / trafficking defects → loss of function. - G689C, G689S — ~1,000–2,000-fold lower glutamate EC50 (bizarrely, a loss-type consequence via non-functional NMDARs at synapses despite altered agonist potency). - C456Y — modeled as a knock-in mouse (see §15).

Variant classification. Under ACMG/AMP, established recurrent de novo missense in constrained domains are typically Pathogenic/Likely Pathogenic (PS2 de novo, PM1 mutational hotspot, PM2 absent from gnomAD, PP3 in silico). Given GRIN2B's extreme constraint, novel LoF variants readily reach LP/P; missense VUS require functional data to resolve. Curate against ClinVar and ClinGen (CGGV: gene-disease validity and CGDS: dosage) records during entry-building.

Allele frequency. Pathogenic variants are absent from population databases (gnomAD) — consistent with de novo origin and pLI 1.00 / LOEUF 0.06 constraint.

Somatic vs germline. Germline de novo is the rule; post-zygotic/parental mosaicism is documented and underlies the ~1% empiric recurrence risk quoted to families.

Functional consequence — the key duality. Variants split into gain-of-function (GoF) (↑Ca²⁺ flux, ↓Mg²⁺ block, ↑agonist potency, slowed deactivation) versus loss-of-function (LoF) (trafficking failure, non-functional channels, haploinsufficiency). Some truncating/translocation variants act dominant-negative by co-assembling mutant with wild-type subunits into hybrid receptors (Freunscht et al.; Frontiers review PMC9873235). This GoF/LoF distinction is the single most therapeutically important fact about the disorder (see §12).

Modifier genes / epigenetics / chromosomal abnormalities. No established modifier genes. An open hypothesis is compensatory GluN2A upregulation modulating severity. No disorder-specific epigenetic signature is established (unlike some ID genes, GRIN2B lacks a validated DNA-methylation "episignature" to date). Large 12p13.1 deletions/translocations disrupting GRIN2B are the relevant chromosomal lesions.

5. Environmental Information

Not applicable / minimal. This is a de novo monogenic disorder with no established environmental, lifestyle, toxic, or infectious contributors. There are no dietary, occupational, or exposure risk factors. (The only "environmental" levers are therapeutic — dietary L-serine supplementation and NMDA-antagonist drugs — covered under Treatment.) Curate §5 as not applicable for causation.

6. Mechanism / Pathophysiology

Normal biology. GluN2B is the developmentally dominant GluN2 subunit: in rodent cortex/hippocampus, most NMDARs contain GluN2B early postnatally (peaking ~3rd postnatal week), then a "2A/2B switch" gradually replaces it with GluN2A as circuits mature. GluN2B-containing NMDARs mediate the slow, high-Ca²⁺ component of glutamatergic transmission critical for neuronal differentiation, dendritogenesis, synaptogenesis, circuit refinement, and synaptic plasticity (LTP/LTD). Domains: extracellular amino-terminal domain (ATD), ligand-binding domain (LBD, S1/S2) binding glutamate, four membrane segments M1–M4 (M2 = re-entrant pore loop lining the Ca²⁺-conducting channel), and a long intracellular C-terminal domain for trafficking/signaling scaffolds (PSD-95, CaMKII).

Causal chain — two convergent arms:

Arm A — Gain of function (pore/linker variants, e.g., N615I, V618G): 1. Missense in M2 re-entrant loop / M2–M3 linker → ↓ Mg²⁺ block + ↑ Ca²⁺ permeability, and/or slowed channel deactivation. 2. → excess Ca²⁺ influx and NMDAR-mediated excitation at rest/subthreshold. 3. → neuronal hyperexcitability, excitotoxic stress, disrupted excitation/inhibition balance. 4. → early-onset seizures / West syndrome + severe DD (upstream = channel biophysics; downstream = network hyperexcitability and developmental encephalopathy). - GO: GO:0004972 (NMDA glutamate receptor activity), GO:0005262/GO:0070588 (calcium ion transmembrane transport), GO:0051966 (regulation of synaptic transmission, glutamatergic), GO:0060079 (excitatory postsynaptic potential).

Arm B — Loss of function / haploinsufficiency (trafficking & LBD variants, truncations): 1. Variant → impaired surface trafficking / non-functional channels / reduced dendritic targeting (e.g., E413G, C461F, S2-loop truncations not reaching the membrane). 2. → reduced NMDAR-mediated Ca²⁺ signaling during the critical developmental window. 3. → suppressed neural-progenitor→neuron differentiation (iPSC data), impaired dendrite length/branching (724t truncation — reduced elongation, increased pruning), fewer functional synaptic NMDARs. 4. → cortical malformation (in ~13%), impaired circuit formation, DD/ID (often with less severe or no epilepsy). - GO: GO:0021954/GO:0022008 (CNS neuron differentiation/neurogenesis), GO:0016358 (dendrite development), GO:0050808 (synapse organization), GO:0060291 (long-term synaptic potentiation), GO:0016311/plasticity terms.

Convergent downstream: both arms funnel into abnormal synaptic plasticity (impaired LTP/LTD — the C456Y knock-in mouse shows selectively impaired NMDAR-dependent LTD with intact synapse density) and disrupted cortical circuit assembly, producing the shared DD/ID core.

Protein dysfunction. Misassembly/trafficking failure (LoF) vs biophysical channel gain (GoF); dominant-negative poisoning of wild-type receptors via hybrid tetramers for some truncations. UniProt Q13224 (GRIN2B_HUMAN); structural context from cryo-EM NMDAR structures (PDB e.g. 4PE5, 5FXG-class).

Cell types & anatomy involved: glutamatergic (excitatory) cortical pyramidal neurons (CL:0000598 pyramidal neuron / CL:0000679 glutamatergic neuron), hippocampal neurons, and broadly CNS neurons; subcellularly the postsynaptic density / dendritic spine (GO:0014069 postsynaptic density, GO:0043197 dendritic spine, GO:0098794 postsynapse), plasma membrane (GO:0005886), and ER trafficking machinery.

Molecular profiling. iPSC-derived neuron models (single-cell/functional genomics) show the differentiation and dendrite deficits above; no large-scale disease-specific transcriptomic/proteomic/metabolomic signature is established. Immune involvement: none (this is not an autoimmune/inflammatory encephalopathy — important to distinguish from anti-NMDAR autoimmune encephalitis, which is mechanistically unrelated despite the shared receptor).

7. Anatomical Structures Affected

• Primary organ/system: brain / central nervous system — cerebral cortex (UBERON:0000956), hippocampus (UBERON:0002421), basal ganglia (UBERON:0002420, enlarged/dysplastic in some), corpus callosum (UBERON:0002336, hypoplastic in some). Body system: nervous system (UBERON:0001016).
• Secondary/complications: musculoskeletal (tone abnormalities, contractures secondary to spasticity), GI (feeding difficulty/tube dependence), visual pathway (cortical visual impairment — the defect is cortical, not ocular).
• Tissue/cell level: nervous tissue; excitatory glutamatergic neurons — pyramidal neurons (CL:0000598), glutamatergic neurons (CL:0000679); cortical neuron populations. Cortical malformations (polymicrogyria, cortical dysplasia, hippocampal dysplasia) reflect disrupted neuronal migration/organization.
• Subcellular: postsynaptic density and dendritic spines of excitatory synapses (GO:0014069, GO:0043197); plasma membrane channel; dendritic arbor.
• Localization/lateralization: bilateral, generally diffuse CNS involvement; cortical malformations may be diffuse or focal/regional; microcephaly is a whole-brain volumetric sign.

8. Temporal Development

• Onset: congenital-to-infantile. DD is apparent in infancy/early childhood; epilepsy onset ranges birth to ~9 years (many in infancy, esp. West syndrome/spasms). Pattern is typically insidious/chronic-developmental rather than acute — though seizure onset can be abrupt, and DEE27 notes development can be "normal prior to seizure onset, after which cognitive/motor delays become apparent" in the epilepsy-driven subset.
• Progression: predominantly a static (non-degenerative) encephalopathy — the underlying lesion is developmental, and most individuals do not neurodegenerate. Developmental regression is uncommon (~7%), often peri-seizure-onset. Disability is lifelong/chronic.
• Course pattern: stable-with-developmental-plateau for the core ID; epilepsy course varies (some refractory/persistent, some more controlled; ~50% drug-resistant).
• Critical periods: the GluN2B→GluN2A developmental switch window (early postnatal, activity-dependent) is the mechanistically critical window — and, hopefully, the therapeutic window; the C456Y mouse work suggests early correction of the LTD defect improves later behavior, hinting at an early-intervention opportunity.
• Remission: no spontaneous remission of ID; seizure remission is treatment-dependent and variable.

9. Inheritance and Population

• Inheritance pattern: autosomal dominant (HP:0000006), essentially always de novo. Penetrance reported as 100% in GeneReviews. Expressivity is highly variable (mild ID → profound encephalopathy), correlated partly with variant class (null vs missense) and GoF/LoF mechanism.
• Recurrence risk: ~1% empiric (accounting for possible parental germline/somatic mosaicism); documented mosaicism cases exist.
• Genetic anticipation: not applicable (not a repeat-expansion disorder).
• Founder effects / consanguinity / carrier frequency: not applicable — de novo dominant, so no founder alleles, no consanguinity role, and no meaningful carrier frequency (pathogenic alleles absent from gnomAD).
• Epidemiology: exact prevalence unknown; a rare disease. GRIN2B variants account for ~0.2% of neurodevelopmental disorder / childhood-onset epilepsy cohorts; fewer than ~100–200 well-characterized individuals published. For a Prevalence record, this is best coded qualitatively (RARE/ULTRA_RARE, or Orphanet NOT_YET_DOCUMENTED) rather than a fabricated rate.
• Sex ratio: no strong sex bias established (autosomal); roughly equal.
• Geographic/ethnic distribution: worldwide, pan-ethnic; no population clustering (consistent with de novo origin).

10. Diagnostics

• Genetic testing (definitive). Diagnosis rests on identifying a heterozygous pathogenic GRIN2B variant or deletion:
• Exome (WES) or genome (WGS) sequencing — highest yield in undiagnosed DD/ID/epilepsy; the usual route to a GRIN2B diagnosis.
• Multigene epilepsy/ID/DEE panels including GRIN2B (and GRIN1/GRIN2A/GRIN2D).
• Single-gene sequencing if GRIN2B specifically suspected.
• Chromosomal microarray (CMA) / gene-targeted del-dup for the ~5% caught by copy-number/structural lesions (12p13.1 deletions, translocations).
• GeneReviews detection split: sequencing ~95%, del/dup or CMA ~5%.
• Trio testing (parents + proband) is key to establishing de novo status → strengthens ACMG PS2 and pathogenicity call.
• Functional confirmation. For missense VUS, electrophysiology in heterologous systems (measuring Ca²⁺ permeability, Mg²⁺ block, agonist EC50, surface expression) determines GoF vs LoF — increasingly clinically actionable because it steers therapy.
• Supportive/phenotyping studies (not diagnostic on their own):
• EEG — characterize seizures; hypsarrhythmia in West syndrome; interictal epileptiform discharges (LOINC-codeable neurophysiology).
• Brain MRI — screen for malformation of cortical development (polymicrogyria, cortical dysplasia), corpus callosum hypoplasia, basal ganglia/hippocampal dysplasia, cerebral atrophy.
• Developmental/cognitive assessment; ophthalmology for cortical visual impairment.
• No routine biochemical biomarker — there's no blood/CSF metabolite or enzyme assay for GRIN2B disorder (differentiate sharply from anti-NMDAR autoimmune encephalitis, which does have CSF autoantibodies — a critical differential when acute).
• Differential diagnosis: other GRIN disorders (GRIN1/GRIN2A/GRIN2D), other DEE genes (STXBP1, SCN2A, CDKL5, KCNQ2, etc.), Rett/Rett-like, Angelman, other cortical-malformation and ID syndromes. Distinguish by gene, EEG pattern, MRI, and (acutely) from autoimmune NMDAR encephalitis.
• Screening. No population/newborn screening (rare, de novo). Relevant genetic-counseling screening is cascade/recurrence-risk assessment for future pregnancies, given mosaicism risk.

11. Outcome / Prognosis

• Survival/mortality: GRIN2B disorder is not primarily life-limiting; there's no established reduced life expectancy for the disorder as a whole. Mortality risk, where present, tracks the severe end — refractory epilepsy (with attendant SUDEP risk), aspiration/feeding complications, and immobility-related morbidity in profoundly affected, non-ambulatory individuals. No disorder-specific survival statistics are published.
• Morbidity/function: dominated by lifelong intellectual disability (profound in the majority) with communication and mobility impairment; many are non-verbal and/or non-ambulatory. Spasticity, dystonia, feeding difficulty, and cortical visual impairment add functional burden.
• Prognostic factors: variant class and functional mechanism are the strongest — missense (esp. in pore/LBD/M3) → more severe ID (p=0.0079); null/truncating → milder-moderate ID. Refractory epilepsy (~50%) and cortical malformation predict worse developmental outcome. GoF pore variants → severe early epilepsy/West syndrome.
• Recovery potential: the core ID is static, not reversible; realistic goals are developmental gains with therapy and seizure control. The mouse "early-correction" data raise cautious hope that mechanism-matched drugs started early could improve trajectory — unproven in humans.
• QoL measures: no GRIN2B-specific validated instruments; caregiver-burden and non-verbal QoL tools apply.

12. Treatment

The organizing principle: match the drug to the mechanism (GoF vs LoF). There are no FDA-approved GRIN2B-specific therapies yet; care is supportive plus mechanism-guided off-label/trial agents.

Mechanism-matched pharmacotherapy (the big story): - Gain-of-function variants → NMDA-receptor antagonism. - Memantine (uncompetitive NMDAR channel blocker; CHEBI:64312). A 2026 Epilepsia multi-patient study (Karnstedt et al., PMID:41489401) reported improvements in behavior, development, and seizure frequency in individuals with GRIN GoF variants; earlier single-case reports (Pierson et al. 2014, in GRIN2A GoF) documented seizure reduction. MAXO: pharmacotherapy (MAXO:0000058 treatment / NCIT:C15986 Pharmacotherapy for the KB pattern; therapeutic_agent CHEBI memantine). - Radiprodil — a GluN2B-selective negative allosteric modulator; the Phase 1b HONEYCOMB study (industry, GRIN2B/GRIN GoF) reported significant seizure-frequency reduction (NeurologyLive coverage). This is the most GRIN2B-tailored agent in development. - Loss-of-function / null variants → NMDA-receptor potentiation. - L-serine (dietary precursor boosting the co-agonist D-serine; CHEBI:17115). A 2022 case series (Soto et al., PMID:34997442) found improvements in behavior, EEG, and seizure frequency in GRIN-related disorder due to null variants; n-of-1 crossover trial protocols in GRIN2B LoF children are underway (PMC10746402). MAXO: dietary intervention (MAXO:0000088) / supplementation. - Caution: giving the wrong mechanism drug (e.g., an NMDA antagonist to an LoF patient, or L-serine to a GoF patient) is theoretically harmful — hence the push for functional variant classification before treating.

Anti-seizure management (standard): conventional ASMs per seizure type; ~50% are drug-resistant. For infantile spasms/West syndrome, standard first-line (ACTH/corticosteroids, vigabatrin) applies; consider mechanism-matched add-on (memantine for GoF). MAXO: pharmacotherapy (MAXO:0000058).

Supportive / rehabilitative (the backbone of care): - Physical, occupational, and speech/language therapy — MAXO:0000011 (physical therapy), MAXO physiotherapy/OT/speech terms. - Management of spasticity/dystonia (e.g., baclofen, botulinum toxin), feeding support (gastrostomy where needed), visual supports for cortical visual impairment, behavioral/ASD interventions. - Genetic counseling — MAXO:0000079.

Pharmacogenomics. The relevant "PGx" here is unusual: it's the causal variant's own functional class (GoF/LoF) that dictates drug choice — a genotype-directed, precision-medicine model rather than classic drug-metabolism PGx.

13. Prevention

• Primary prevention: none possible for a de novo dominant disorder — you can't prevent a fresh germline mutation. No vaccine, no modifiable risk factor.
• Secondary prevention / early detection: early genetic diagnosis (WES/WGS) in a child with DD/epilepsy → enables mechanism-matched therapy and early developmental intervention (the plausible "critical window" for benefit). Early EEG/MRI to catch and treat West syndrome promptly.
• Tertiary prevention: prevent complications — seizure control (SUDEP/injury reduction), aspiration prevention/feeding management, spasticity/contracture prevention via PT, vision and behavioral supports.
• Reproductive counseling: for families with an affected child, genetic counseling on the ~1% recurrence risk (mosaicism), with options including prenatal testing or preimplantation genetic testing (PGT) in future pregnancies once the familial variant is known — MAXO:0000079 (genetic counseling).
• Immunization / public-health / environmental interventions: not applicable.

14. Other Species / Natural Disease

• Orthologs: Grin2b is deeply conserved across vertebrates — mouse (Grin2b, NCBI Gene 14812; MGI:95822), rat (Grin2b), zebrafish (grin2b), and the receptor family extends to invertebrates (C. elegans nmr-1/nmr-2, Drosophila Nmdar2). Alliance of Genome Resources / HomoloGene document the orthology.
• Taxonomy: most relevant experimental species — Mus musculus (NCBITaxon:10090), Rattus norvegicus (NCBITaxon:10116), Danio rerio (NCBITaxon:7955).
• Natural disease in other species: no well-characterized spontaneous naturally-occurring GRIN2B disorder documented in companion animals (OMIA has no flagship GRIN2B entry comparable to the human disease); the disease knowledge is essentially all human + engineered models.
• Comparative biology: the NMDAR GluN2B subunit and the developmental 2B→2A switch are evolutionarily conserved mechanisms, which is exactly why rodent models recapitulate core features — strong evolutionary conservation of the disease-relevant biology.
• Zoonosis: not applicable (genetic, non-transmissible).

15. Model Organisms

• Mouse — constitutive knockout (Grin2b−/−): perinatally lethal — pups fail to suckle (impaired trigeminal/brainstem pattern formation) and die within days; can be kept alive short-term by hand-feeding. Demonstrates GluN2B is essential for neonatal survival and shows suppressed LTD and impaired whisker-barrel patterning. Heterozygous Grin2b+/− mice are viable → useful for studying haploinsufficiency (one WT copy suffices for survival). (Reviewed in PMC9873235.)
• Mouse — knock-in disease variants:
• GluN2B-C456Y knock-in: impaired NMDAR-dependent LTD with preserved synapse density/postsynaptic structure; anxiety-like behavior — and notably, early pharmacological correction of the LTD defect improved adult behavior (PLOS Biology, C456Y model). A worked model of "selective plasticity defect → behavior."
• Additional Grin2b-mutant mice show anterior cingulate functional hyperconnectivity underlying sensory hypersensitivity (Mol Psychiatry 2024), relevant to the ASD phenotype.
• Rat model: a GRIN2B rat model shows absence seizures and sleep–wake abnormalities (PMC12779324) — recapitulating the epilepsy dimension.
• Cellular / iPSC models: patient iPSC-derived neurons and heterologous expression (HEK/Xenopus oocyte electrophysiology) are the workhorses for GoF/LoF classification — showing suppressed neural-progenitor differentiation, impaired dendrite growth (724t truncation), and altered channel biophysics (N615I/V618G GoF; G689C/S agonist-potency shifts).
• Model types available: constitutive KO, heterozygous KO, conditional (floxed) alleles, and knock-in point mutants — resources via MGI/IMPC/KOMP; rat via RGD; zebrafish via ZFIN.
• Phenotype recapitulation & limits: mouse/rat capture LTD/plasticity deficits, learning/memory impairment, seizures, and ASD-like circuit/behavioral features — good face validity. Limitations: rodents can't model the full human intellectual-disability/language phenotype, the human-specific cortical developmental timeline differs, and the constitutive KO's neonatal lethality forces reliance on conditional/knock-in strategies to study postnatal roles. Use evidence_source: MODEL_ORGANISM for all of these; keep them distinct from the human clinical phenotype claims.

Curation notes for the dismech entry

A few things worth flagging as you build this out: - The GoF/LoF axis is the entry's spine. Model it explicitly — two mechanistic arms (Arm A pore/Ca²⁺-hyperexcitation → seizures; Arm B trafficking/haploinsufficiency → impaired neurodevelopment) converging on abnormal synaptic plasticity + DD/ID. The mechanistic_hypotheses + hypothesis_groups machinery fits this two-arm structure nicely, and it directly gates the treatment pattern (memantine/radiprodil target_mechanisms on the GoF node; L-serine on the LoF node). - This could conforms_to epilepsy_excitation_inhibition_imbalance (#Excitation-Inhibition Imbalance) for the seizure arm — a natural module fit. - Verify every PMID before committing per the DR/anti-hallucination SOP. The high-confidence, search-verified ones: 20890276 (Endele 2010, Nat Genet), 24272827 (Lemke 2014, Ann Neurol — N615I/V618G GoF/West), 28377535 (Platzer 2017, J Med Genet — the cohort + frequencies), 29851452 (GeneReviews), 34997442 (L-serine null variants), 41489401 (memantine GoF, Epilepsia 2026). Run just fetch-reference on each and confirm exact-quote snippets against the cached abstract before use — I've paraphrased throughout, so none of the above are quote-ready yet. - NEC check: GRIN2B sits near GRIN2A/GRIN2D/GRIN1 (a numbered/related-gene series → moderate NEC risk). Confirm the MONDO you anchor on (MONDO:0014505 DEE27 vs MONDO:0013655 MRD6) matches the intended severity framing, and that report content is about 2B, not 2A. - Prevalence: code qualitatively (RARE/ULTRA_RARE), don't invent a rate — the literature only gives "~0.2% of NDD/epilepsy cohorts, <100–200 described."

Sources: - GRIN2B-Related Neurodevelopmental Disorder — GeneReviews (PMID:29851452) - Frontiers/PMC9873235 — pathophysiological mechanisms review - OMIM #616139 DEE27 · OMIM *138252 GRIN2B - Endele 2010, Nat Genet, PMID:20890276 · Lemke 2014, Ann Neurol, PMID:24272827 · Platzer 2017, J Med Genet, PMID:28377535 - Soto 2022, L-serine null variants, PMID:34997442 · Karnstedt 2026, memantine GoF, PMID:41489401 · Radiprodil HONEYCOMB coverage - C456Y knock-in mouse, PLOS Biology · Grin2b-mutant mouse, Mol Psychiatry 2024 · GRIN2B rat model, PMC12779324 - NORD — GRIN-related disorders · gnomAD constraint / SFARI GRIN2B