Intellectual Disability, Autosomal Dominant 6

1. Disease Information

Overview. Intellectual Developmental Disorder, Autosomal Dominant 6, with or without seizures (MRD6) is a rare monogenic neurodevelopmental disorder caused by heterozygous, almost always de novo, pathogenic variants in GRIN2B, which encodes the GluN2B (NR2B/GluRε2) subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor. It is the non-encephalopathic pole of the broader "GRIN2B-related neurodevelopmental disorder" spectrum: mild-to-profound developmental delay/intellectual disability in all affected individuals, with variable epilepsy, autism spectrum disorder/behavioral problems, muscle tone abnormalities, movement disorders, cortical visual impairment, and occasionally malformation of cortical development (GeneReviews NBK501979; PMID:28377535).

Key identifiers (verified):

Synonyms: MRD6; GRIN2B-related neurodevelopmental disorder (GRIN2B-NDD, lumping term); GRIN2B encephalopathy (used when epilepsy/encephalopathy is prominent); mental retardation, autosomal dominant 6 (legacy); GRIN2B-related syndrome.

Data provenance. Knowledge is derived from aggregated case series and disease-level resources (OMIM, GeneReviews, ClinVar/ClinGen, the CFERV/GRIN variant registries), not population EHR data. The largest phenotype series remains Platzer et al. 2017 (n=86 pathogenic/likely pathogenic de novo variant carriers; PMID:28377535).

2. Etiology

Causal factor. Purely genetic: heterozygous pathogenic variants in GRIN2B (missense clustering in transmembrane and ligand-binding domains, truncating/frameshift, splice-site variants, and whole-gene or exonic deletions). Endele et al. first established causation by finding GRIN2B disrupted by translocation breakpoints and then four de novo mutations (a frameshift, a missense, two splice-site) on sequencing 468 individuals with intellectual disability: "Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations." (PMID:20890276, Nat Genet 2010).

Genetic risk factors. The only established risk factor is the de novo variant itself; there are no known susceptibility loci or modifier genes for MRD6. Advanced paternal age raises de novo SNV rates generically (inference from de novo mutation biology, not demonstrated for GRIN2B specifically). ClinGen has curated GRIN2B dosage sensitivity with a haploinsufficiency score of 3 (sufficient evidence) for intellectual disability, autosomal dominant 6 (ClinGen gene-dosage HGNC:4586).

Environmental risk/protective factors. None known; no gene–environment interactions are documented (CTD lists no curated GRIN2B chemical–disease interactions specific to MRD6). Environmental modulation of outcome is limited to non-specific factors (access to early intervention, seizure control).

Protective genetic factors. None described.

3. Phenotypes

Frequencies below are from the GeneReviews GRIN2B-NDD chapter (NBK501979, Platzer & Lemke) drawing on the 86-patient Platzer 2017 cohort (PMID:28377535).

Platzer abstract (verbatim, quotable): "Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy." (PMID:28377535).

Quality of life impact. Dominated by ID severity, drug-resistant epilepsy, non-verbal status (many severe cases have absent speech — HP:0001344, suggest), feeding dependence, and caregiver burden; no disease-specific EQ-5D/PROMIS studies exist (gap).

4. Genetic/Molecular Information

• Causal gene: GRIN2B (hgnc:4586; OMIM 138252), chromosome 12p13.1, encoding GluN2B, one of the glutamate-binding NR2 subunits of the heterotetrameric NMDA receptor (2×GluN1 + 2×GluN2) (PMID:20890276).
• Variant spectrum: ~95% detectable by sequence analysis (missense, nonsense, frameshift, splice); ~5% exon/whole-gene deletions detectable by del/dup analysis or CMA (GeneReviews NBK501979). Missense variants cluster in transmembrane segments and ligand-binding (agonist-binding) domains (PMID:28377535). 12p13 deletions encompassing GRIN2B cause DD with macrocephaly (PMID:27656287).
• Origin: de novo germline in essentially all molecularly confirmed probands; somatic variants are not a recognized mechanism.
• Functional consequence classes: both loss-of-function (reduced surface expression, reduced agonist potency, reduced open probability, haploinsufficiency from truncation/deletion) and gain-of-function (increased glutamate/glycine potency, reduced voltage-dependent Mg²⁺ block, prolonged deactivation): "Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine." (PMID:28377535). CFERV (Emory) maintains functional annotations per variant (PMID:27818011).
• Population frequency: pathogenic variants are absent from population databases; GRIN2B is among the most missense- and LoF-constrained genes in gnomAD (pLI ≈ 1) — consistent with dominant de novo disease (constraint claim: standard gnomAD observation; verify current v4 values before curation).
• Modifier genes / epigenetics: none established. No disease-defining methylation episignature reported.
• Chromosomal abnormalities: translocations disrupting GRIN2B were the original discovery route (PMID:20890276); 12p13.1 microdeletions are a recurrent mechanism (DECIPHER; PMID:27656287).

5. Environmental Information

Not applicable as etiology: no toxins, lifestyle factors, or infectious agents cause or trigger MRD6. Fever/illness may transiently worsen seizures as in other developmental epilepsies (generic inference, not GRIN2B-specific evidence).

6. Mechanism / Pathophysiology

Causal chain (numbered; branch points marked):

1. A de novo heterozygous GRIN2B variant (missense in TMD/ligand-binding domain, truncating/splice variant, or gene deletion) leads to an altered or absent GluN2B protein (PMID:20890276; PMID:28377535).
2. Altered GluN2B results in abnormal GluN2B-containing NMDA receptor function — branch A (loss of function): reduced receptor surface expression, agonist potency, or channel open probability, or pure haploinsufficiency; branch B (gain of function): increased agonist potency, reduced Mg²⁺ block, and/or prolonged channel activation (PMID:28377535; PMID:27818011).
3. Because GluN2B is the predominant NR2 subunit of prenatal and early postnatal forebrain (before the developmental GluN2B→GluN2A switch), either branch disrupts NMDAR-mediated Ca²⁺ influx and downstream signaling at developing glutamatergic synapses (PMID:20890276 — "disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes"; review DOI:10.3389/fnsyn.2022.1090865).
4. Dysregulated NMDAR signaling impairs neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity (LTP/LTD): "disease-associated GluN2B variants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity" (Sabo et al., Front Synaptic Neurosci 2023, DOI:10.3389/fnsyn.2022.1090865; largely in vitro/model-organism evidence — an inferred step in humans).
5. In a subset, disturbed NMDAR-dependent neuronal migration during corticogenesis produces malformation of cortical development (polymicrogyria-like MCD intermediate with tubulinopathies) (PMID:28377535; mechanism inferred).
6. Synaptic/network dysfunction manifests as excitatory–inhibitory imbalance leading to the clinical phenotypes — DD/ID universally; epilepsy (enriched in gain-of-function; Orphadata annotates the IESS association specifically as gain-of-function, ORPHA:697160 gene table); ASD/behavioral phenotypes; hypotonia/movement disorder; cortical visual impairment.

Ontology anchors (suggest, verify before binding): GO:0004972 NMDA glutamate receptor activity; GO:0035235 ionotropic glutamate receptor signaling pathway; GO:0007268 chemical synaptic transmission; GO:0060291 long-term synaptic potentiation; GO:0060292 long-term synaptic depression; GO:0048813 dendrite morphogenesis; GO:0007416 synapse assembly; GO:0070588 calcium ion transmembrane transport; GO:0014069 postsynaptic density; GO:0017146 NMDA selective glutamate receptor complex; GO:0098978 glutamatergic synapse. Cell types: CL:0000679 glutamatergic neuron; CL:0000598 pyramidal neuron; CL:0000617 GABAergic neuron (interneuron migration/maturation involvement is hypothesized).

Molecular profiling. No human patient transcriptomic/proteomic/metabolomic signature is established (gap). Model-system profiling exists in mouse/rat haploinsufficiency models (e.g., absence seizures and sleep abnormalities in a Grin2b⁺/⁻ rat, bioRxiv 2024 preprint DOI:10.1101/2024.02.27.582289 — preprint, weight accordingly).

7. Anatomical Structures Affected

• Primary organ: brain (UBERON:0000955, suggest), especially cerebral cortex (UBERON:0000956) and hippocampal formation (UBERON:0002421); cerebral volume loss and MCD on MRI (PMID:28377535).
• Systems: nervous system primarily; secondary musculoskeletal (tone, spasticity-related contractures), visual (cortical visual impairment — the lesion is cortical, eyes structurally normal), gastrointestinal/feeding (hypotonia-related).
• Tissue/cell level: glutamatergic synapses of cortical and hippocampal excitatory neurons; developing neurons broadly (GluN2B expression is pan-forebrain prenatally).
• Subcellular: postsynaptic membrane/postsynaptic density of dendritic spines (GO:0014069, suggest); receptor also signals extrasynaptically.
• Lateralization: bilateral; MCD when present is typically bilateral (PMID:28377535).

8. Temporal Development

• Onset: congenital/infantile. Developmental delay evident in the first year; hypotonia often neonatal; epilepsy onset birth–9 years (GeneReviews NBK501979).
• Course: chronic, lifelong, generally non-progressive with respect to cognition (static encephalopathy); developmental regression uncommon (~7%). Epilepsy course variable; roughly half of epileptic patients are drug-resistant.
• Critical periods: the disorder acts during the prenatal/early-postnatal window when GluN2B-containing receptors dominate; this window is also the hypothesized therapeutic-opportunity period for mechanism-based intervention (inference; DOI:10.3389/fnsyn.2022.1090865).
• Remission: not applicable for core ID; some epilepsies respond to ASMs.

9. Inheritance and Population

• Inheritance: autosomal dominant; all reported molecularly confirmed probands with tested parents carry de novo variants (GeneReviews NBK501979). Penetrance estimated 100%. Expressivity is highly variable (mild ID without seizures → severe DEE).
• Recurrence risk: ~1% for sibs, reflecting possible parental germline mosaicism; parental somatic+inferred germline mosaicism was ~10% in a general DEE cohort study cited by GeneReviews (NBK501979).
• No anticipation, no founder effects, no consanguinity effect (dominant de novo mechanism); carrier frequency not applicable.
• Epidemiology: point prevalence unknown; fewer than ~100 fully phenotyped individuals published as of the GeneReviews update, though diagnostic-lab counts are higher. GRIN2B variants account for ~0.2% of NDD/childhood-epilepsy cohorts (NBK501979). Model-based birth incidence estimate: ~5.91 per 100,000 live births for GRIN2B de novo disorder (López-Rivera et al., Brain 2020, 143:1099–1105 — one of the most common single-gene NDD estimates in that catalogue).
• Demographics: no ethnic or geographic clustering; sexes affected roughly equally (case-series data; no formal sex-ratio study).

10. Diagnostics

• Genetic testing (diagnostic gold standard): trio exome/genome sequencing or an ID/epilepsy multigene panel containing GRIN2B is first-line; single-gene testing is not recommended. Sequence analysis detects ~95% of pathogenic variants; CMA/targeted del-dup detects the ~5% that are deletions (GeneReviews NBK501979; GTR condition C3151411). Establishing de novo status supports pathogenicity (ACMG PS2).
• Variant interpretation: ClinVar holds many classified variants (e.g., RCV000022580 c.411+1G>A; RCV000625193 p.Ile751Thr); functional stratification (GoF vs LoF) via CFERV electrophysiology increasingly informs both interpretation and therapy selection (PMID:27818011; PMID:28377535).
• Neuroimaging: brain MRI may show cerebral volume loss, thin corpus callosum, or the characteristic MCD "intermediate between tubulinopathies and polymicrogyria" (PMID:28377535).
• EEG: indicated when seizures suspected; hypsarrhythmia in infantile-spasm presentations.
• Laboratory biomarkers: none; routine metabolic work-up is normal (distinguishes from metabolic ID).
• Differential diagnosis: other GRIN disorders (GRIN1, GRIN2A, GRIN2D), DEE27 (allelic; distinguished by epileptic-encephalopathy severity rather than gene), other monogenic NDDs (SCN2A, STXBP1, SYNGAP1, tubulinopathies when MCD present), Angelman/Rett-like presentations.
• Screening: not in newborn screening; carrier screening not applicable (de novo). Cascade testing limited to parental testing for mosaicism/recurrence counseling.

11. Outcome/Prognosis

• Survival: no systematic mortality data; lifespan appears near-normal in most, but severe DEE presentations carry generic risks (SUDEP, aspiration) — stated as inference, not measured.
• Morbidity: driven by ID severity (61% severe–profound), drug-resistant epilepsy (~half of the epileptic subgroup), non-ambulation and absent speech in severe cases, feeding dependence.
• Prognostic factors: variant class and location are the main predictors — functional GoF associates with earlier, more severe epilepsy; truncating/deletion (haploinsufficiency) more often with ID/ASD without severe epilepsy; MCD predicts severe outcome (PMID:28377535; genotype–phenotype review DOI:10.1186/s13023-025-04055-x, Orphanet J Rare Dis 2025).
• Recovery potential: core ID is static; developmental gains occur with therapy but full recovery is not observed.

12. Treatment

No disease-modifying therapy is approved; management is symptomatic (GeneReviews NBK501979). Suggested NCIT bindings marked (suggest).

• Anti-seizure pharmacotherapy — standard ASMs chosen by seizure type; ~50% of the epilepsy is drug-resistant. (NCIT:C15986 Pharmacotherapy, suggest.)
• Memantine (repurposed NMDAR channel blocker) — rationale: variants retain "sensitivity to the use-dependent blocker memantine", but "an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated" (PMID:28377535, verbatim). Anecdotal use in GoF variants. (CHEBI:64312 memantine, suggest.)
• L-serine dietary supplementation (LoF variants) — in a patient with GluN2B(P553T), D-serine restored receptor function in vitro and 11–17 months of L-serine supplementation was "associated with clinical improvement" in motor/cognitive performance and communication (Soto et al., Sci Signal 2019, DOI:10.1126/scisignal.aaw0936; n = 1). Phase 2A trial NCT04646447 (L-serine in GRIN-related encephalopathy) and n-of-1 crossover protocols (PMC10746402) followed; a 2023 Mol Genet Metab study reports further supportive evidence (DOI:10.1016/j.ymgme.2023.107673 — verify exact DOI from the ScienceDirect record S1096719223001531 before citing in KB). (CHEBI:17115 L-serine, suggest; NCIT:C15447 Dietary Intervention, suggest.)
• Radiprodil (GluN2B-selective negative allosteric modulator; GoF variants) — in vitro, GRIN2B gain-of-function mutations are sensitive to radiprodil (PMID:28533163). Phase 1b Honeycomb trial (NCT05818943, ages 6 mo–12 y, GoF GRIN variants) reported ~86% median reduction in countable motor seizures; FDA Breakthrough Therapy designation granted; global Phase 3 BeeLine trial dosing began late 2025/2026 (industry-reported NCT07224581 — verify registry ID before KB use).
• Developmental/supportive care — early-intervention programs, physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), speech/feeding therapy (NCIT:C159273), ABA-based behavioral intervention for ASD, gastrostomy feeding when required, standard spasticity and movement-disorder management. (All suggest.)
• Pharmacogenomics: the genotype itself (GoF vs LoF) is the stratifier for mechanism-based therapy — the clearest precision-medicine axis in this disease (PMID:28377535; DOI:10.1186/s13023-025-04055-x).

13. Prevention

• Primary prevention: none possible (sporadic de novo).
• Genetic counseling: essential; recurrence risk ~1% (germline mosaicism); prenatal and preimplantation genetic testing may be offered for that residual risk (GeneReviews NBK501979; NCIT:C15240 Genetic Counseling, suggest).
• Secondary/tertiary prevention: early molecular diagnosis enables early intervention, seizure surveillance, vision assessment, and avoidance of diagnostic odyssey; aggressive seizure control to limit encephalopathic contribution (standard-of-care inference).
• Population screening, immunization, and environmental interventions: not applicable.

14. Other Species / Natural Disease

• No naturally occurring GRIN2B disease is documented in companion animals or livestock (no OMIA phene identified for GRIN2B) — engineered models only.
• Orthologs (Alliance of Genome Resources): mouse Grin2b (MGI:95821, suggest-verify), rat Grin2b, zebrafish grin2bb/grin2ba, Drosophila Nmdar2, C. elegans nmr-2. GluN2B function in synaptic development is deeply conserved; the developmental GluN2B→GluN2A subunit switch is conserved across mammals (review DOI:10.3389/fnsyn.2022.1090865).
• Zoonotic/transmission sections: not applicable.

15. Model Organisms

• Mouse, Grin2b null (ε2⁻/⁻): the foundational model — homozygous knockouts have no suckling response and die perinatally (rescuable briefly by hand-feeding), with impaired trigeminal barrelette formation and loss of hippocampal LTD (Kutsuwada et al., Neuron 1996;16(2):333–344, PMID:8789948). Demonstrates GluN2B's essential developmental role; homozygous lethality is why human disease is heterozygous. Limitation: the null homozygote does not model the human heterozygous state; fidelity for MRD6 is indirect.
• Mouse, Grin2b heterozygous and point-mutant knock-ins (e.g., patient-derived C456Y LoF knock-in with NMDAR hypofunction and anxiety-like/behavioral phenotypes — see Sabo 2023 review for the model survey, DOI:10.3389/fnsyn.2022.1090865): recapitulate synaptic plasticity deficits and behavioral abnormalities; partial phenotype recapitulation (no robust seizures in most LoF models).
• Rat, Grin2b haploinsufficient: reported absence-like seizures and sleep abnormalities (bioRxiv 2024, DOI:10.1101/2024.02.27.582289 — preprint).
• In vitro / cellular: heterologous electrophysiology (Xenopus oocytes/HEK) is the workhorse for GoF/LoF classification (PMID:28377535; PMID:27818011); patient-variant-expressing primary hippocampal neurons show reduced spine density and impaired NMDAR-dependent AMPA-receptor insertion for GluN2B(P553T) (DOI:10.1126/scisignal.aaw0936); patient iPSC-derived neuron models are emerging.
• Applications: variant functional triage (drives therapy stratification), preclinical testing of memantine/radiprodil/serine, developmental-mechanism studies. Resources: MGI, IMPC (Grin2b het viability data), CFERV variant database, GRIN2B Foundation & CureGRIN registries.

Key primary citations (verified this session)

• PMID:20890276 — Endele S, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010;42(11):1021–6. doi:10.1038/ng.677. (Gene discovery; abstract cached locally.)
• PMID:28377535 — Platzer K, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 2017;54(7):460–470. doi:10.1136/jmedgenet-2016-104509. (Largest cohort; abstract cached locally.)
• PMID:8789948 — Kutsuwada T, et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor ε2 subunit mutant mice. Neuron 1996;16(2):333–44.
• PMID:27818011 — Hu C, Chen W, Myers SJ, Yuan H, Traynelis SF. Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci 2016;132(2):115–121.
• PMID:28533163 — GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.
• PMID:27656287 — A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly.
• Soto D, et al. Sci Signal 2019;12(586):eaaw0936. doi:10.1126/scisignal.aaw0936 (L-serine, LoF).
• Sabo SL, Lahr JM, Sceniak MP. Front Synaptic Neurosci 2023;14:1090865. doi:10.3389/fnsyn.2022.1090865 (mechanism review; PMC9873235).
• GeneReviews: GRIN2B-Related Neurodevelopmental Disorder (NBK501979).
• López-Rivera JA, et al. Brain 2020;143:1099–1105 (incidence catalogue: 5.91/100,000).
• Orphanet J Rare Dis 2025, doi:10.1186/s13023-025-04055-x (genotype–phenotype/therapeutic review).
• Trials: NCT04646447 (L-serine, Phase 2A), NCT05818943 (radiprodil Honeycomb Phase 1b).

Sources: - OMIM Entry #613970 — MRD6 - ClinGen condition MONDO:0013509 - ClinGen GRIN2B dosage sensitivity (HGNC:4586) - GeneReviews: GRIN2B-Related Neurodevelopmental Disorder (NBK501979) - GARD 12851 — Intellectual disability, autosomal dominant 6 - MedGen C3151411 - Platzer 2017, PMID 28377535 - Endele 2010, Nat Genet - Kutsuwada 1996, PMID 8789948 - Hu 2016, PMID 27818011 - Radiprodil in vitro, PMID 28533163 - 12p13 GRIN2B deletion, PMID 27656287 - Soto 2019, Science Signaling - Sabo 2023 mechanism review, Front Synaptic Neurosci - López-Rivera 2020 incidence catalogue, Brain - OJRD 2025 genotype–phenotype review - L-serine trial NCT04646447 - Radiprodil Breakthrough Therapy designation - Phase 3 BeeLine trial announcement - Grin2b rat model preprint, bioRxiv 2024 - ClinVar RCV000022580 · RCV000625193 - GTR condition C3151411 - MRD6 case report, Cureus 2023 (PMC10623208) - L-serine n-of-1 protocol (PMC10746402) - MedlinePlus GRIN2B gene

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• DOI:10.1016/j.ymgme.2023.107673 (1 mention) - Identifier did not resolve to a record

References that may not be about this subject

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• PMID:8789948 (5 mentions) - Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice.
• shared terms: receptor

Weighed against this report's own most characteristic terms: grin2b, variant, developmental, seizure, nbk501979, disorder, novo, gene, epilepsy, glun2b, receptor, dominant, mrd6, deletion, phenotype, intellectual, autosomal, disability, disease, therapy.

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Terms the report names something else

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• NCIT:C15302 (1 mention) - the report calls it "Developmental/supportive care — early-intervention programs, physical therapy"; NCIT calls it Physical Therapy**

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