👪

Inheritance

1

Autosomal dominant HP:0000006

The disorder results from heterozygous GRIN2B variants that are typically de novo; inheritance is autosomal dominant, and most probands represent simplex (single-occurrence) cases.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:29851452 SUPPORT Human Clinical

"All probands reported to date with a GRIN2B-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN2B pathogenic variant or deletion."

GeneReviews genetic-counseling section documents the de novo, autosomal dominant origin.

PMID:20890276 SUPPORT Human Clinical

"Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations."

The founding study identified de novo GRIN2B mutations in affected individuals.

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Discussions and Knowledge Gaps

1

Can GRIN2B missense variants be reliably partitioned into gain-of-function and loss-of-function classes, and does that functional classification predict the clinical phenotype and the response to NMDA-receptor-directed precision therapy (channel blockers such as memantine or dextromethorphan for gain-of-function; receptor-enhancing strategies for loss-of-function)?

KNOWLEDGE GAP OPEN gap_grin2b_gof_vs_lof_precision_therapy

Attached to

pathophysiology#NMDA Receptor Gain-of-Function pathophysiology#NMDA Receptor Loss-of-Function

GRIN2B variants converge on the same downstream disease but through opposite changes in receptor activity, so the gain-of-function versus loss-of-function distinction is potentially the key determinant of both phenotype and rational treatment. However, functional classification requires electrophysiological characterization that is not available for most variants, many variants have mixed or partial effects, and clinical evidence that NMDA-receptor antagonists benefit gain-of-function patients is limited to case reports. Resolving whether functional class predicts phenotype and treatment response is central to precision therapy for this disorder.

Proposed experiments

Systematic functional-class to phenotype and treatment-response mapping

exp_grin2b_variant_functional_treatment_map

Characterize a large panel of patient GRIN2B variants with standardized electrophysiology (agonist potency, open probability, calcium permeability, magnesium block, surface expression) to assign gain- or loss-of-function class, then correlate class with deep clinical phenotyping and with prospectively collected responses to NMDA-receptor-directed therapy.

Show evidence (1 reference)

PMID:28377535 SUPPORT In Vitro

"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."

Variants show diverse gain- and loss-of-function consequences, and gain-of-function receptors retain memantine sensitivity, motivating the precision-therapy question.

⚙

Pathophysiology

6

GRIN2B Variant Altering the GluN2B NMDA Receptor Subunit

De novo heterozygous missense or protein-truncating variants in GRIN2B alter the GluN2B subunit of the NMDA receptor. Because GluN2B-containing NMDA receptors predominate in the developing forebrain, variants perturb the receptor at a developmentally critical window.

glutamatergic neuron CL:0000679

glutamate receptor signaling GO:0007215

Downstream

NMDA Receptor Gain-of-Function A subset of missense variants increases receptor activity.

NMDA Receptor Loss-of-Function Truncating and other missense variants reduce receptor function.

Show evidence (1 reference)

PMID:20890276 SUPPORT Human Clinical

"Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy."

Establishes GRIN2B (GluN2B/NR2B) disruption as a cause of intellectual disability and epilepsy.

NMDA Receptor Gain-of-Function

A subset of GRIN2B missense variants increases NMDA receptor activity by enhancing agonist (glutamate/glycine) potency, increasing channel open probability or calcium permeability, or reducing voltage-dependent magnesium block, producing excessive NMDA-receptor-mediated current and calcium influx.

glutamatergic neuron CL:0000679

calcium ion transmembrane transport GO:0070588 ↑ INCREASED glutamate receptor signaling GO:0007215 ↑ INCREASED

Downstream

Dysregulated NMDA Receptor Signaling Excessive receptor current dysregulates glutamatergic signaling.

Show evidence (1 reference)

PMID:28377535 SUPPORT In Vitro

"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."

Functional characterization identified gain-of-function variant mechanisms.

NMDA Receptor Loss-of-Function

Other GRIN2B variants (protein-truncating variants and missense variants that reduce surface trafficking, agonist potency, or current, sometimes dominant-negatively) decrease NMDA receptor function, reducing NMDA-receptor-mediated signaling.

glutamatergic neuron CL:0000679

glutamate receptor signaling GO:0007215 ↓ DECREASED

Downstream

Dysregulated NMDA Receptor Signaling Reduced receptor function dysregulates glutamatergic signaling.

Show evidence (1 reference)

PMID:28377535 SUPPORT In Vitro

"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."

Functional characterization identified loss-of-function variant mechanisms.

Dysregulated NMDA Receptor Signaling

Whether from excessive or deficient receptor activity, the net consequence is disruption of the tightly regulated NMDA-receptor-mediated glutamatergic signaling and calcium-dependent downstream cascades that developing neurons depend on.

glutamatergic neuron CL:0000679

regulation of glutamatergic synaptic transmission GO:0051966 ↕ DYSREGULATED modulation of chemical synaptic transmission GO:0050804 ↕ DYSREGULATED

Downstream

Impaired Synaptic Development and Plasticity Disrupted NMDAR signaling impairs activity-dependent synapse maturation.

Cortical Excitation-Inhibition Imbalance Disrupted NMDAR signaling shifts network excitation-inhibition balance.

Show evidence (1 reference)

PMID:20890276 SUPPORT Human Clinical

"N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain."

NMDA receptors mediate excitatory neurotransmission, so GRIN2B variants dysregulate this signaling.

Impaired Synaptic Development and Plasticity

NMDA receptors, and GluN2B in particular, drive dendritic and synaptic maturation and activity-dependent plasticity (long-term potentiation and depression). Their dysregulation impairs synapse organization and plasticity, the substrate of the disorder's developmental delay and intellectual disability.

neuron CL:0000540

long-term synaptic potentiation GO:0060291 ⚠ ABNORMAL synapse organization GO:0050808 ⚠ ABNORMAL dendrite development GO:0016358 ⚠ ABNORMAL

Cortical Excitation-Inhibition Imbalance

Dysregulated NMDA-receptor signaling shifts the balance between excitation and inhibition in developing cortical networks, producing neuronal hyperexcitability and hypersynchrony that generate seizures.

neuron CL:0000540

regulation of membrane potential GO:0042391 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."

Epilepsy is a common manifestation, reflecting the cortical excitation-inhibition imbalance produced by disrupted NMDAR signaling.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

13

Digestive 1

Feeding Difficulties Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"occasionally associated with feeding difficulties"

Feeding difficulties occur in association with muscle-tone abnormalities.

Head and Neck 1

Microcephaly Microcephaly HP:0000252

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"Other infantile- or childhood-onset findings include microcephaly"

Microcephaly is among the reported findings.

Musculoskeletal 2

Hypotonia Hypotonia HP:0001252

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties)"

Muscle tone abnormalities including hypotonia are common.

Spasticity Spasticity HP:0001257

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties)"

Spasticity is among the common muscle-tone abnormalities.

Nervous System 4

Seizures FREQUENT Seizure HP:0001250

Show evidence (2 references)

PMID:29851452 SUPPORT Human Clinical

"epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."

Epilepsy is a common feature of the disorder.

PMID:20890276 SUPPORT Human Clinical

"in individuals with mental retardation and/or epilepsy."

GRIN2B disruption is associated with epilepsy.

Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals."

Developmental delay/intellectual disability occurs in all affected individuals.

Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals."

Intellectual disability occurs in all affected individuals.

Autistic Behavior Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"autism spectrum disorder (ASD) / behavioral issues, are common."

Autism spectrum disorder is a common feature.

Other 5

Epileptic Encephalopathy Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."

Epilepsy is a common feature at the epileptic-encephalopathy end of the spectrum.

Infantile Spasms Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:24272827 SUPPORT Human Clinical

"We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay"

De novo GRIN2B mutations were identified in individuals with West syndrome (infantile spasms).

Movement Disorder Hyperkinetic movements HP:0002487

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"dystonic, dyskinetic, or choreiform movement disorder"

A dystonic/dyskinetic/choreiform movement disorder is reported.

Cerebral Visual Impairment Cerebral visual impairment HP:0100704

Show evidence (1 reference)

PMID:28377535 SUPPORT Human Clinical

"GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD"

Cortical visual impairment is a frequently associated feature.

Malformation of Cortical Development Abnormal cortical gyration HP:0002536

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"Brain MRI reveals a malformation of cortical development in a minority of affected individuals."

A malformation of cortical development is seen on MRI in a minority.

🧬

Genetic Associations

1

GRIN2B (Causative)

Gene: GRIN2B hgnc:4586 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:28377535 SUPPORT Human Clinical

"Missense variants cluster in transmembrane segments and ligand-binding sites."

GRIN2B missense variants cluster in functionally critical receptor domains.

PMID:29851452 SUPPORT Human Clinical

"identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing."

Heterozygous GRIN2B variants or deletions establish the diagnosis.

💊

Medical Actions

4

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Seizures are managed with antiseizure medications as per standard practice; response is variable and some individuals have drug-resistant epilepsy.

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice."

Epilepsy is treated symptomatically per standard practice.

NMDA Receptor Antagonist Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: memantine CHEBI:64312

For gain-of-function variants, NMDA-receptor channel blockers such as memantine and dextromethorphan have been used off-label as mechanism-directed therapy in individual cases, aiming to counteract excessive receptor activity.

Mechanism Target:

INHIBITS NMDA Receptor Gain-of-Function — NMDA receptor channel blockade counteracts the excessive receptor activity of gain-of-function variants.

Show evidence (1 reference)

PMID:41489401 SUPPORT Human Clinical

"Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."

A clinical case series reports that memantine improved behavior, development, and seizure frequency in GRIN gain-of-function variants.

L-Serine Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: L-serine CHEBI:17115

For loss-of-function variants, oral L-serine (an NMDA-receptor co-agonist precursor of D-serine and glycine) has been trialed to potentiate hypofunctional NMDA-receptor signaling; a phase 2A trial in GRIN loss-of-function patients reported motor-function improvement.

Mechanism Target:

RESTORES NMDA Receptor Loss-of-Function — L-serine supplies NMDA-receptor co-agonist to potentiate hypofunctional receptors in loss-of-function variants.

Show evidence (1 reference)

PMID:38380699 SUPPORT Human Clinical

"the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function."

L-serine is a mechanism-directed therapy for GRIN loss-of-function variants.

Developmental and Supportive Therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Multidisciplinary developmental support (physical, occupational, and speech therapy) and management of comorbidities address the neurodevelopmental manifestations.

Show evidence (1 reference)

PMID:29851452 SUPPORT Human Clinical

"DD/ID, muscle tone abnormalities (spasticity, hypotonia, and feeding difficulties), epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice."

Developmental manifestations are managed with standard supportive care.

🔬

Clinical Trials

1

NCT07224581 PHASE_III RECRUITING

Beeline (RAD-GRIN-101): a Phase 1b/3 study of radiprodil, a GluN2B-selective NMDA-receptor negative allosteric modulator, in GRIN-related neurodevelopmental disorder with a gain-of-function variant.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

clinicaltrials:NCT07224581 SUPPORT Human Clinical

"evaluate the efficacy and safety of radiprodil in participants with GRIN-related neurodevelopmental disorder (GRIN-NDD) with a gain-of-function (GoF) genetic variant."

A phase 3 trial of the GluN2B-selective modulator radiprodil targeting gain-of-function GRIN variants.

{ }

Source YAML

click to show

name: GRIN2B-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-07-22T00:00:00Z"
category: Mendelian
synonyms:
- DEE27
- EIEE27
- GRIN2B-related developmental and epileptic encephalopathy
- Developmental and epileptic encephalopathy 27
description: >-
  GRIN2B-related developmental and epileptic encephalopathy (DEE27) is a
  neurodevelopmental disorder caused by de novo heterozygous variants in GRIN2B,
  which encodes the GluN2B subunit of the N-methyl-D-aspartate (NMDA) glutamate
  receptor. GluN2B-containing NMDA receptors are the dominant NMDA receptors in
  the developing brain and are central to excitatory synaptic transmission,
  calcium-dependent signaling, and activity-dependent synapse maturation and
  plasticity. Pathogenic GRIN2B variants fall into two broad functional classes:
  gain-of-function variants that increase NMDA receptor activity, and
  loss-of-function variants that reduce receptor function or surface expression.
  Both classes disrupt tightly regulated NMDA-receptor signaling, impairing
  synaptic development and plasticity (producing developmental delay and
  intellectual disability) and altering the cortical excitation-inhibition
  balance (producing seizures). The disorder presents in infancy or early
  childhood with a spectrum from intellectual disability and autism without
  epilepsy to severe early-onset epileptic encephalopathy.
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 27
  term:
    id: MONDO:0014505
    label: developmental and epileptic encephalopathy, 27
parents:
- Neurodevelopmental Disorder
- Genetic Disease
references:
- reference: PMID:29851452
  title: "GRIN2B-Related Neurodevelopmental Disorder."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    The disorder results from heterozygous GRIN2B variants that are typically de
    novo; inheritance is autosomal dominant, and most probands represent simplex
    (single-occurrence) cases.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All probands reported to date with a GRIN2B-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN2B pathogenic variant or deletion."
    explanation: >-
      GeneReviews genetic-counseling section documents the de novo, autosomal
      dominant origin.
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations."
    explanation: >-
      The founding study identified de novo GRIN2B mutations in affected
      individuals.
pathophysiology:
- name: GRIN2B Variant Altering the GluN2B NMDA Receptor Subunit
  description: >-
    De novo heterozygous missense or protein-truncating variants in GRIN2B alter
    the GluN2B subunit of the NMDA receptor. Because GluN2B-containing NMDA
    receptors predominate in the developing forebrain, variants perturb the
    receptor at a developmentally critical window.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  evidence:
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy."
    explanation: >-
      Establishes GRIN2B (GluN2B/NR2B) disruption as a cause of intellectual
      disability and epilepsy.
  downstream:
  - target: NMDA Receptor Gain-of-Function
    causal_link_type: DIRECT
    description: >-
      A subset of missense variants increases receptor activity.
  - target: NMDA Receptor Loss-of-Function
    causal_link_type: DIRECT
    description: >-
      Truncating and other missense variants reduce receptor function.
- name: NMDA Receptor Gain-of-Function
  description: >-
    A subset of GRIN2B missense variants increases NMDA receptor activity by
    enhancing agonist (glutamate/glycine) potency, increasing channel open
    probability or calcium permeability, or reducing voltage-dependent
    magnesium block, producing excessive NMDA-receptor-mediated current and
    calcium influx.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:28377535
    reference_title: "GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >-
      Functional characterization identified gain-of-function variant mechanisms.
  downstream:
  - target: Dysregulated NMDA Receptor Signaling
    causal_link_type: DIRECT
    description: >-
      Excessive receptor current dysregulates glutamatergic signaling.
- name: NMDA Receptor Loss-of-Function
  description: >-
    Other GRIN2B variants (protein-truncating variants and missense variants
    that reduce surface trafficking, agonist potency, or current, sometimes
    dominant-negatively) decrease NMDA receptor function, reducing
    NMDA-receptor-mediated signaling.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:28377535
    reference_title: "GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >-
      Functional characterization identified loss-of-function variant mechanisms.
  downstream:
  - target: Dysregulated NMDA Receptor Signaling
    causal_link_type: DIRECT
    description: >-
      Reduced receptor function dysregulates glutamatergic signaling.
- name: Dysregulated NMDA Receptor Signaling
  description: >-
    Whether from excessive or deficient receptor activity, the net consequence is
    disruption of the tightly regulated NMDA-receptor-mediated glutamatergic
    signaling and calcium-dependent downstream cascades that developing neurons
    depend on.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: regulation of glutamatergic synaptic transmission
    term:
      id: GO:0051966
      label: regulation of synaptic transmission, glutamatergic
    modifier: DYSREGULATED
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain."
    explanation: >-
      NMDA receptors mediate excitatory neurotransmission, so GRIN2B variants
      dysregulate this signaling.
  downstream:
  - target: Impaired Synaptic Development and Plasticity
    causal_link_type: DIRECT
    description: >-
      Disrupted NMDAR signaling impairs activity-dependent synapse maturation.
  - target: Cortical Excitation-Inhibition Imbalance
    causal_link_type: DIRECT
    description: >-
      Disrupted NMDAR signaling shifts network excitation-inhibition balance.
- name: Impaired Synaptic Development and Plasticity
  description: >-
    NMDA receptors, and GluN2B in particular, drive dendritic and synaptic
    maturation and activity-dependent plasticity (long-term potentiation and
    depression). Their dysregulation impairs synapse organization and plasticity,
    the substrate of the disorder's developmental delay and intellectual
    disability.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: ABNORMAL
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: ABNORMAL
  - preferred_term: dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: ABNORMAL
- name: Cortical Excitation-Inhibition Imbalance
  description: >-
    Dysregulated NMDA-receptor signaling shifts the balance between excitation
    and inhibition in developing cortical networks, producing neuronal
    hyperexcitability and hypersynchrony that generate seizures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."
    explanation: >-
      Epilepsy is a common manifestation, reflecting the cortical
      excitation-inhibition imbalance produced by disrupted NMDAR signaling.
phenotypes:
- category: Neurologic
  name: Epileptic Encephalopathy
  description: >-
    Many affected individuals develop early-onset epilepsy in which frequent
    seizures and epileptiform activity themselves contribute to developmental
    impairment, ranging to severe developmental and epileptic encephalopathy.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."
    explanation: >-
      Epilepsy is a common feature at the epileptic-encephalopathy end of the
      spectrum.
- category: Neurologic
  name: Seizures
  description: >-
    Seizures of varied types and onset (including infantile-onset) occur in the
    epilepsy-associated end of the GRIN2B spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common."
    explanation: >-
      Epilepsy is a common feature of the disorder.
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in individuals with mental retardation and/or epilepsy."
    explanation: >-
      GRIN2B disruption is associated with epilepsy.
- category: Neurologic
  name: Infantile Spasms
  description: >-
    Some individuals present with infantile spasms / West syndrome, a severe
    early-onset epilepsy phenotype.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:24272827
    reference_title: "GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay"
    explanation: >-
      De novo GRIN2B mutations were identified in individuals with West syndrome
      (infantile spasms).
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Global developmental delay in infancy is a near-constant feature across the
    GRIN2B phenotypic spectrum.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals."
    explanation: >-
      Developmental delay/intellectual disability occurs in all affected
      individuals.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability, ranging from mild to profound, is characteristic.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals."
    explanation: >-
      Intellectual disability occurs in all affected individuals.
- category: Neurodevelopmental
  name: Autistic Behavior
  description: >-
    Autism spectrum features and autistic behaviors are frequent.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autism spectrum disorder (ASD) / behavioral issues, are common."
    explanation: >-
      Autism spectrum disorder is a common feature.
- category: Neurologic
  name: Hypotonia
  description: >-
    Muscular hypotonia is commonly present, particularly in infancy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties)"
    explanation: >-
      Muscle tone abnormalities including hypotonia are common.
- category: Neurologic
  name: Spasticity
  description: >-
    Spasticity, alone or together with hypotonia, is among the common muscle-tone
    abnormalities.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties)"
    explanation: >-
      Spasticity is among the common muscle-tone abnormalities.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties, sometimes requiring tube feeding, occur in association
    with muscle-tone abnormalities.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occasionally associated with feeding difficulties"
    explanation: >-
      Feeding difficulties occur in association with muscle-tone abnormalities.
- category: Neurologic
  name: Movement Disorder
  description: >-
    A hyperkinetic movement disorder, including dystonic, dyskinetic, or
    choreiform movements, occurs in a subset of individuals.
  phenotype_term:
    preferred_term: Hyperkinetic movement disorder
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dystonic, dyskinetic, or choreiform movement disorder"
    explanation: >-
      A dystonic/dyskinetic/choreiform movement disorder is reported.
- category: Ophthalmologic
  name: Cerebral Visual Impairment
  description: >-
    Cortical/cerebral visual impairment is reported in a subset.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:28377535
    reference_title: "GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD"
    explanation: >-
      Cortical visual impairment is a frequently associated feature.
- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly is among the infantile- or childhood-onset findings in a subset.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other infantile- or childhood-onset findings include microcephaly"
    explanation: >-
      Microcephaly is among the reported findings.
- category: Neurologic
  name: Malformation of Cortical Development
  description: >-
    Brain MRI reveals a malformation of cortical development (e.g., polymicrogyria
    or cortical dysplasia) in a minority of affected individuals.
  phenotype_term:
    preferred_term: Malformation of cortical development
    term:
      id: HP:0002536
      label: Abnormal cortical gyration
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI reveals a malformation of cortical development in a minority of affected individuals."
    explanation: >-
      A malformation of cortical development is seen on MRI in a minority.
biochemical: []
genetic:
- name: GRIN2B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: GRIN2B
    term:
      id: hgnc:4586
      label: GRIN2B
  notes: >-
    De novo heterozygous GRIN2B variants (missense and protein-truncating) cause
    the disorder. Missense variants may confer gain-of-function or
    loss-of-function; truncating variants and deletions act through
    loss-of-function (haploinsufficiency).
  evidence:
  - reference: PMID:28377535
    reference_title: "GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants cluster in transmembrane segments and ligand-binding sites."
    explanation: >-
      GRIN2B missense variants cluster in functionally critical receptor domains.
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing."
    explanation: >-
      Heterozygous GRIN2B variants or deletions establish the diagnosis.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A rare disorder; fewer than 100 individuals had been reported at the time of
    the GeneReviews summary.
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported."
    explanation: >-
      Fewer than 100 reported individuals indicates an ultra-rare disorder.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic GRIN2B
    variant or an exon or whole-gene deletion on molecular genetic testing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing."
    explanation: >-
      Defines the molecular diagnostic criteria.
discussions:
- discussion_id: gap_grin2b_gof_vs_lof_precision_therapy
  prompt: >-
    Can GRIN2B missense variants be reliably partitioned into gain-of-function
    and loss-of-function classes, and does that functional classification predict
    the clinical phenotype and the response to NMDA-receptor-directed precision
    therapy (channel blockers such as memantine or dextromethorphan for
    gain-of-function; receptor-enhancing strategies for loss-of-function)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NMDA Receptor Gain-of-Function
  - pathophysiology#NMDA Receptor Loss-of-Function
  rationale: >-
    GRIN2B variants converge on the same downstream disease but through opposite
    changes in receptor activity, so the gain-of-function versus loss-of-function
    distinction is potentially the key determinant of both phenotype and rational
    treatment. However, functional classification requires electrophysiological
    characterization that is not available for most variants, many variants have
    mixed or partial effects, and clinical evidence that NMDA-receptor
    antagonists benefit gain-of-function patients is limited to case reports.
    Resolving whether functional class predicts phenotype and treatment response
    is central to precision therapy for this disorder.
  proposed_experiments:
  - experiment_id: exp_grin2b_variant_functional_treatment_map
    name: Systematic functional-class to phenotype and treatment-response mapping
    description: >-
      Characterize a large panel of patient GRIN2B variants with standardized
      electrophysiology (agonist potency, open probability, calcium permeability,
      magnesium block, surface expression) to assign gain- or loss-of-function
      class, then correlate class with deep clinical phenotyping and with
      prospectively collected responses to NMDA-receptor-directed therapy.
  evidence:
  - reference: PMID:28377535
    reference_title: "GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >-
      Variants show diverse gain- and loss-of-function consequences, and
      gain-of-function receptors retain memantine sensitivity, motivating the
      precision-therapy question.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures are managed with antiseizure medications as per standard practice;
    response is variable and some individuals have drug-resistant epilepsy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice."
    explanation: >-
      Epilepsy is treated symptomatically per standard practice.
- name: NMDA Receptor Antagonist Therapy
  description: >-
    For gain-of-function variants, NMDA-receptor channel blockers such as
    memantine and dextromethorphan have been used off-label as mechanism-directed
    therapy in individual cases, aiming to counteract excessive receptor
    activity.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: memantine
      term:
        id: CHEBI:64312
        label: memantine
  target_mechanisms:
  - target: NMDA Receptor Gain-of-Function
    treatment_effect: INHIBITS
    description: >-
      NMDA receptor channel blockade counteracts the excessive receptor activity
      of gain-of-function variants.
  evidence:
  - reference: PMID:41489401
    reference_title: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    explanation: >-
      A clinical case series reports that memantine improved behavior,
      development, and seizure frequency in GRIN gain-of-function variants.
- name: L-Serine Supplementation
  description: >-
    For loss-of-function variants, oral L-serine (an NMDA-receptor co-agonist
    precursor of D-serine and glycine) has been trialed to potentiate
    hypofunctional NMDA-receptor signaling; a phase 2A trial in GRIN
    loss-of-function patients reported motor-function improvement.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_mechanisms:
  - target: NMDA Receptor Loss-of-Function
    treatment_effect: RESTORES
    description: >-
      L-serine supplies NMDA-receptor co-agonist to potentiate hypofunctional
      receptors in loss-of-function variants.
  evidence:
  - reference: PMID:38380699
    reference_title: "L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function."
    explanation: >-
      L-serine is a mechanism-directed therapy for GRIN loss-of-function variants.
- name: Developmental and Supportive Therapy
  description: >-
    Multidisciplinary developmental support (physical, occupational, and speech
    therapy) and management of comorbidities address the neurodevelopmental
    manifestations.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29851452
    reference_title: "GRIN2B-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DD/ID, muscle tone abnormalities (spasticity, hypotonia, and feeding difficulties), epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice."
    explanation: >-
      Developmental manifestations are managed with standard supportive care.
clinical_trials:
- name: NCT07224581
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Beeline (RAD-GRIN-101): a Phase 1b/3 study of radiprodil, a GluN2B-selective
    NMDA-receptor negative allosteric modulator, in GRIN-related neurodevelopmental
    disorder with a gain-of-function variant.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: clinicaltrials:NCT07224581
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "evaluate the efficacy and safety of radiprodil in participants with GRIN-related neurodevelopmental disorder (GRIN-NDD) with a gain-of-function (GoF) genetic variant."
    explanation: >-
      A phase 3 trial of the GluN2B-selective modulator radiprodil targeting
      gain-of-function GRIN variants.
datasets: []

📚

References & Deep Research

References

1

PMID:29851452

GRIN2B-Related Neurodevelopmental Disorder.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

GRIN2B-Related Developmental and Epileptic Encephalopathy — Research Report

claude-haiku-4-5-20251001, claude-opus-4-8 17 citations 2026-07-22T12:22:42.140356

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.

Phenotype	Frequency	HPO suggestion	Notes
Developmental delay / intellectual disability	100% (mild 15% / moderate 24% / severe-profound 61%)	HP:0001263 (Global developmental delay) / HP:0001249 (Intellectual disability)	Defining feature; severity variable
Hypotonia	56% (34/61); ~15% need tube feeding	HP:0001252 (Hypotonia); feeding: HP:0011968 (Feeding difficulties)
Epilepsy / seizures	51% (31/61)	HP:0001250 (Seizure)	See breakdown below
Autism spectrum disorder / behavioral issues	26% (16/61)	HP:0000717 (Autism); HP:0000708 (Behavioral abnormality)
Spasticity	23% (14/61)	HP:0001257 (Spasticity)
Microcephaly	18% (11/61)	HP:0000252 (Microcephaly)
Movement disorder (dystonic/dyskinetic/choreiform)	10% (6/61)	HP:0001300 (Parkinsonism)? no — use HP:0001332 (Dystonia), HP:0002072 (Chorea), HP:0100022 (Abnormal movement)
Cortical visual impairment	8% (5/61)	HP:0100704 (Cerebral visual impairment)
Developmental regression	7% (4/61)	HP:0002376 (Developmental regression)
Malformation of cortical development (MRI)	13% (6/47)	HP:0002536 (Abnormal cortical gyration) / HP:0007younger — use HP:0002119 (Ventriculomegaly)? better HP:0032046 (Abnormal cerebral cortex morphology)	Polymicrogyria, cortical dysplasia
Cerebral atrophy (MRI)	9% (4/47)	HP:0002059 (Cerebral atrophy)

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

GRIN2B-Related Developmental and Epileptic Encephalopathy

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GRIN2B-Related Developmental and Epileptic Encephalopathy — Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Curation notes for the dismech entry