Intellectual disability, autosomal dominant 6 (MRD6; OMIM 613970) is a rare neurodevelopmental disorder caused by heterozygous, almost always de novo, variants in GRIN2B, which encodes the GluN2B subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor. MRD6 is the non-encephalopathic arm of the GRIN2B allelic series: developmental delay and intellectual disability of variable severity, characteristically with a hyperactive, inattentive, stereotypy-prone behavioral profile, language impairment and hypotonia, with or without seizures — but without the severe early-onset epileptic encephalopathy that defines the allelic sibling entity GRIN2B-related developmental and epileptic encephalopathy (DEE27, OMIM 616139, MONDO:0014505). The mechanistic center of gravity of MRD6 is NMDA receptor hypofunction: deletions, truncating variants and loss-of-function missense variants reduce the pool of functional GluN2B-containing receptors, lowering NMDA-receptor-mediated calcium entry in the developing forebrain during the window in which GluN2B is the dominant NR2 subunit. The resulting deficits in neuronal differentiation, dendrite morphogenesis and activity-dependent synaptic plasticity are the substrate of the cognitive phenotype. This directional leaning is what separates MRD6 from its epileptogenic sibling, where gain-of-function variants are enriched, and it sets the opposite therapeutic direction — receptor-potentiating strategies rather than receptor blockade.
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Conditions with similar clinical presentations that must be differentiated from Intellectual Disability, Autosomal Dominant 6:
name: Intellectual Disability, Autosomal Dominant 6
creation_date: "2026-09-04T20:55:00Z"
category: Mendelian
synonyms:
- MRD6
- intellectual developmental disorder, autosomal dominant 6, with or without seizures
- mental retardation, autosomal dominant 6
- mental retardation, autosomal dominant 6, with or without seizures
- GRIN2B autosomal dominant non-syndromic intellectual disability
description: >-
Intellectual disability, autosomal dominant 6 (MRD6; OMIM 613970) is a rare
neurodevelopmental disorder caused by heterozygous, almost always de novo,
variants in GRIN2B, which encodes the GluN2B subunit of the
N-methyl-D-aspartate (NMDA) glutamate receptor. MRD6 is the
non-encephalopathic arm of the GRIN2B allelic series: developmental delay and
intellectual disability of variable severity, characteristically with a
hyperactive, inattentive, stereotypy-prone behavioral profile, language
impairment and hypotonia, with or without seizures — but without the severe
early-onset epileptic encephalopathy that defines the allelic sibling entity
GRIN2B-related developmental and epileptic encephalopathy (DEE27, OMIM
616139, MONDO:0014505). The mechanistic center of gravity of MRD6 is NMDA
receptor hypofunction: deletions, truncating variants and loss-of-function
missense variants reduce the pool of functional GluN2B-containing receptors,
lowering NMDA-receptor-mediated calcium entry in the developing forebrain
during the window in which GluN2B is the dominant NR2 subunit. The resulting
deficits in neuronal differentiation, dendrite morphogenesis and
activity-dependent synaptic plasticity are the substrate of the cognitive
phenotype. This directional leaning is what separates MRD6 from its
epileptogenic sibling, where gain-of-function variants are enriched, and it
sets the opposite therapeutic direction — receptor-potentiating strategies
rather than receptor blockade.
disease_term:
preferred_term: intellectual disability, autosomal dominant 6
term:
id: MONDO:0013509
label: intellectual disability, autosomal dominant 6
parents:
- Neurodevelopmental Disorder
- Genetic Disease
notes: >-
Scope and lump/split rationale. Much of the recent literature uses the single
lumping label "GRIN2B-related neurodevelopmental disorder" for the whole
allelic series, and the MRD6/DEE27 boundary is a spectrum rather than a clean
partition — many individuals sit between the poles. This entry is nonetheless
curated as a distinct disease rather than folded into the DEE sibling as a
subtype, because the two arms are separable on four axes that a subtype record
could not carry: distinct MONDO terms (MONDO:0013509 vs MONDO:0014505) and
distinct OMIM phenotype numbers (613970 vs 616139); a distinct clinical
presentation (ID with variable seizures, without epileptic encephalopathy); a
directional mechanistic leaning documented by variant-class comparison, where
gain-of-function variants are more likely to cause epilepsy and microcephaly
than loss-of-function variants; and an opposite mechanism-directed therapeutic
direction (receptor potentiation rather than channel blockade). The
differential_diagnoses block states the boundary explicitly, and the
grin2b_lof_gof_arm_separability discussion records that the separability itself
is a recent and still-open claim rather than settled nosology.
Module conformance is deliberately partial. Four nodes conform to
nmda_receptor_hypofunction, which the module's own notes sanction ("Conformance
may be partial"). The module's BDNF arm ("Reduced BDNF Expression and
Secretion") is not reproduced here: it is evidenced for the toxicant conformers,
and no GRIN2B-specific evidence for that step was verified during this curation,
so the chain runs from the calcium node directly to plasticity rather than
asserting an unsourced intermediate. The trigger node likewise does not declare
conformance: the module's trigger node describes exogenous routes (toxicant
antagonism, autoantibody-mediated receptor internalization), whereas the lesion
here is a germline genetic one, and stretching that node to cover it would
overstate what the module asserts.
Where `frequency` is and is not assigned. Frequencies come from series that
pool both poles of the GRIN2B allelic spectrum, so the question for each
phenotype is whether the pooled figure transfers to this arm. Developmental
delay/intellectual disability is set VERY_FREQUENT on the strength of sources
reporting it in *all* affected individuals, which is pole-independent.
Hypotonia and language impairment take the pooled figures because no source
consulted reports them as differing by variant functional class. Seizures
deliberately carry no `frequency`, because the same comparison that supports
this entry's existence reports epilepsy as *more likely* in gain-of-function
than in loss-of-function variants, so the pooled 53% is known not to transfer.
The rule is "use the pooled figure unless a source shows the feature varies by
functional class", not an inconsistency between phenotypes.
Microcephaly and malformation of cortical development are deliberately not
curated as MRD6 phenotypes. Both are reported in the broader GRIN2B series,
but microcephaly is one of the two features explicitly reported as enriched in
the gain-of-function class, and the cortical malformation is described in the
cohort that defined the encephalopathy end of the spectrum. Asserting either
as a feature of the loss-of-function arm would import the sibling entity's
phenotype on a pooled denominator.
On the "opposite therapeutic direction" axis. The split is real at the level of
which mechanism a drug is aimed at, but it is not a clean partition of drugs
across the two entries: the DEE27 sibling carries both the receptor-blocking
arm and L-serine, because that entry spans both functional classes. What
selects therapy is the variant's functional class, not the MRD6-versus-DEE27
label, and a diagnosis of MRD6 does not by itself establish that class.
Memantine and radiprodil are therefore left to the sibling and to the
differential-diagnosis block rather than curated as MRD6 treatments: blocking
an already-hypofunctional receptor is the wrong direction for the arm this
entry describes.
Several phenotypes are not wired into the pathograph. Hypotonia, spasticity,
movement disorder, cerebral visual impairment, feeding difficulties and facial
dysmorphism carry evidence but no incoming causal edge, because no source
consulted here places them on a specific chain from the receptor lesion. An
unconnected phenotype is honest; a fabricated edge is not.
references:
- reference: PMID:29851452
title: "GRIN2B-Related Neurodevelopmental Disorder."
tags:
- GeneReviews
inheritance:
- name: Autosomal dominant
description: >-
MRD6 is inherited in an autosomal dominant manner, but is in practice a
sporadic disorder: essentially every molecularly confirmed proband whose
parents have been tested carries a de novo GRIN2B variant or deletion, so
affected individuals are typically simplex cases with unaffected parents.
Residual recurrence risk to sibs reflects the possibility of parental
germline mosaicism.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
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: >-
Supports variable expressivity: severity spans mild to profound among
carriers. Penetrance is deliberately left unset — the same sentence shows
the phenotype is present in all affected individuals, which is not the
same claim as complete penetrance among all variant carriers, and no
source consulted quantified penetrance.
- 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: >-
Establishes the de novo, autosomal dominant origin for the GRIN2B series
that MRD6 belongs to.
- 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 the causal variants as de novo in an
intellectual-disability cohort, which is the MRD6 ascertainment setting.
pathophysiology:
- name: GRIN2B Haploinsufficiency and Loss-of-Function Variation
description: >-
The initiating lesion is a heterozygous, typically de novo GRIN2B variant
that reduces the amount or the function of the GluN2B subunit: whole-gene and
exonic 12p13.1 deletions, frameshift, nonsense and splice-site variants
acting through haploinsufficiency, and missense variants in the
ligand-binding and transmembrane domains that reduce surface expression,
agonist potency or channel open probability. Missense variants across the
GRIN2B series cluster in exactly those two regions. The
loss-of-function-leaning end of this allelic spectrum is the one
underrepresented for epilepsy relative to the gain-of-function end; note that the
supporting comparison reports an enrichment rather than a partition, so this
node does not claim that loss-of-function variants are confined to the
ID-without-encephalopathy presentation.
role: trigger
biological_scale: MOLECULAR
genetic_context:
gene:
preferred_term: GRIN2B
term:
id: hgnc:4586
label: GRIN2B
variant_origin: DE_NOVO
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Applies to the deletion, truncating and loss-of-function missense alleles
that dominate the MRD6 presentation. GRIN2B is allelic for a
gain-of-function class as well; those variants are enriched in the
epileptic-encephalopathy sibling entity, so this entry does not claim a
single functional mechanism across the whole GRIN2B allelic spectrum.
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
evidence:
- reference: PMID:29937144
reference_title: "Disruption of GRIN2B Impairs Differentiation in Human Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment."
explanation: >-
States the loss-of-function heterozygous lesion and the two core MRD6
manifestations it causes.
- reference: PMID:23918416
reference_title: "Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B."
explanation: >-
Documents whole- or partial-gene deletion as a route to the lesion, the
purest available form of GRIN2B haploinsufficiency.
- 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: >-
The canonical 86-patient cohort locating missense variants in the two
functional regions this node names.
downstream:
- target: GluN2B-Containing NMDA Receptor Hypofunction
causal_link_type: DIRECT
description: >-
Reduced GluN2B dosage or function lowers the pool of functional
GluN2B-containing NMDA receptors available at developing synapses.
evidence:
- reference: PMID:35741674
reference_title: "Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification"
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "In the absence of both native GluN2A and GluN2B subunits, functional incorporation into synaptic NMDA receptors was attenuated for GoF mutants, or almost eliminated for LoF GluN2B mutants."
explanation: >-
Loss-of-function GluN2B mutants are nearly excluded from synaptic
receptors, which is a route by which the variant depletes the functional
receptor pool. Graded INDIRECT because the measurement was made in a
GluN2A/GluN2B double-null background rather than in the heterozygous
state of the disease; the same study's countervailing result is recorded
as the next evidence item.
- reference: PMID:35741674
reference_title: "Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification"
supports: REFUTE
evidence_source: IN_VITRO
snippet: "Finally, we show that having a single null Grin2b allele has only a modest effect on NMDA-EPSC decay kinetics."
explanation: >-
Cuts against a simple dosage account of this edge: in the heterozygous
single-null state that actually models the disease, the effect on
NMDA-EPSC decay is modest. Recorded rather than omitted because it
constrains how strongly haploinsufficiency alone can be claimed to
deplete synaptic receptor function.
- name: GluN2B-Containing NMDA Receptor Hypofunction
description: >-
Reduced NMDA-receptor channel activity at developing glutamatergic synapses,
the functional state the loss-of-function allelic classes converge on. GluN2B
is the dominant NR2 subunit of the prenatal and early postnatal forebrain, so
the deficit falls in the window before the developmental GluN2B-to-GluN2A
subunit switch, when the receptor pool cannot be compensated by the mature
subunit.
role: amplifier
biological_scale: MOLECULAR
conforms_to: "nmda_receptor_hypofunction#NMDA Receptor Hypofunction"
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
molecular_functions:
- preferred_term: GluN2B-containing NMDA glutamate receptor activity
term:
id: GO:0004972
label: NMDA glutamate receptor activity
modifier: DECREASED
evidence:
- reference: PMID:40024627
reference_title: "Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits"
explanation: >-
A positive allosteric modulator raises NMDAR-mediated current in
loss-of-function receptors and attenuates their synaptic-density deficit.
Note the same treatment potentiated wild-type currents too, so this shows
the hypofunctional receptor remains pharmacologically addressable rather
than being an independent demonstration that it is hypofunctional; the
synaptic-density deficit is the loss-of-function-specific part.
downstream:
- target: Reduced NMDA Receptor-Mediated Calcium Influx
causal_link_type: DIRECT
description: >-
The NMDA receptor is the principal activity-gated calcium-permeable channel
at the excitatory synapse, so reduced channel activity translates into
reduced calcium entry.
evidence:
- reference: PMID:29937144
reference_title: "Disruption of GRIN2B Impairs Differentiation in Human Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state"
explanation: >-
Directly measures reduced calcium influx as the consequence of the
GRIN2B lesion in human cells.
- name: Reduced NMDA Receptor-Mediated Calcium Influx
description: >-
Loss of GluN2B-containing receptor conductance removes the coincidence-detected
calcium transient that couples synaptic and extrasynaptic activity to the
calcium-dependent signalling machinery of the developing neuron. In GRIN2B
disease this calcium deficit is not confined to the mature synapse: NMDA
receptors are present on neural progenitor cells, so the signal is already
degraded in cells that have not yet differentiated.
role: central_effector
biological_scale: CELLULAR
conforms_to: "nmda_receptor_hypofunction#Reduced NMDA Receptor-Mediated 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: DECREASED
locations:
- preferred_term: hippocampal formation
term:
id: UBERON:0002421
label: hippocampal formation
evidence:
- reference: PMID:29937144
reference_title: "Disruption of GRIN2B Impairs Differentiation in Human Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors"
explanation: >-
Establishes the reduced-calcium node in human cells and locates it earlier
in development than the synapse, which is the GRIN2B-specific feature of
this node.
downstream:
- target: Impaired Neuronal Differentiation
causal_link_type: DIRECT
description: >-
NMDA-receptor-dependent calcium signalling in progenitors and immature
neurons drives the transition out of proliferation and into differentiation.
evidence:
- reference: PMID:36704660
reference_title: "GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms."
supports: SUPPORT
evidence_source: OTHER
snippet: "all mutants interfered with calcium influx through NMDARs"
explanation: >-
The review attributes the differentiation deficit to interference with
NMDAR calcium influx shared across the variant panel.
- target: Impaired Activity-Dependent Synaptic Plasticity
causal_link_type: DIRECT
description: >-
The calcium transient is the trigger for the calcium-dependent cascades that
implement activity-dependent changes in synaptic strength. Note this edge
short-cuts the BDNF intermediate that the nmda_receptor_hypofunction module
places between these two nodes; that step is not reproduced here because no
GRIN2B-specific evidence for it was verified.
evidence:
- reference: PMID:36704660
reference_title: "GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms."
supports: SUPPORT
evidence_source: OTHER
snippet: "various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity"
explanation: >-
Places synaptic plasticity among the processes disrupted downstream of
the GluN2B lesion, which is the claim this edge makes.
- name: Impaired Neuronal Differentiation
description: >-
Loss of the NMDA-receptor calcium signal shifts the developmental program of
the neuron: transcriptional profiling of GRIN2B-null and patient-variant human
cells shows genes of cell proliferation up and genes of neuron differentiation
down. This progenitor-stage arm is what distinguishes the MRD6 mechanism from
a purely synaptic account of the disorder.
role: effector
biological_scale: CELLULAR
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
biological_processes:
- preferred_term: neuron differentiation
term:
id: GO:0030182
label: neuron differentiation
modifier: DECREASED
evidence:
- reference: PMID:29937144
reference_title: "Disruption of GRIN2B Impairs Differentiation in Human Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation"
explanation: >-
Direct transcriptomic measurement of the differentiation deficit in human
cells carrying GRIN2B deletion and loss-of-function variants.
downstream:
- target: Impaired Dendrite Morphogenesis and Synaptogenesis
causal_link_type: DIRECT
description: >-
Neurons that differentiate abnormally go on to elaborate abnormal
dendritic arbors and form synapses abnormally.
evidence:
- reference: PMID:36704660
reference_title: "GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms."
supports: SUPPORT
evidence_source: OTHER
snippet: "These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity."
explanation: >-
The review places differentiation, dendrite morphogenesis and
synaptogenesis on one chain of consequences of the same variants.
- name: Impaired Dendrite Morphogenesis and Synaptogenesis
description: >-
Abnormal elaboration of the dendritic arbor and abnormal formation of
synapses onto it — the structural substrate on which activity-dependent
plasticity later operates.
role: effector
biological_scale: CELLULAR
cell_types:
- preferred_term: glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
biological_processes:
- preferred_term: dendrite morphogenesis
term:
id: GO:0048813
label: dendrite morphogenesis
modifier: ABNORMAL
- preferred_term: synapse assembly
term:
id: GO:0007416
label: synapse assembly
modifier: ABNORMAL
evidence:
- reference: PMID:36704660
reference_title: "GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms."
supports: SUPPORT
evidence_source: OTHER
snippet: "various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity"
explanation: >-
A mechanism review synthesizing the dendrite and synaptogenesis arms
across multiple disease-associated GluN2B variants.
downstream:
- target: Impaired Activity-Dependent Synaptic Plasticity
causal_link_type: DIRECT
description: >-
An abnormally built dendritic and synaptic substrate degrades the
activity-dependent plasticity that operates on it.
- name: Impaired Activity-Dependent Synaptic Plasticity
description: >-
Degraded activity-dependent modification of synaptic strength, evidenced in
GRIN2B haploinsufficiency as impaired hippocampal long-term potentiation.
Because the lesion is present throughout development, the deficit is built
into the circuit as it forms rather than imposed on a mature one.
role: effector
biological_scale: CELLULAR
conforms_to: "nmda_receptor_hypofunction#Impaired Activity-Dependent Synaptic Plasticity"
cell_types:
- preferred_term: hippocampal neuron
term:
id: CL:0002608
label: hippocampal neuron
biological_processes:
- preferred_term: regulation of synaptic plasticity
term:
id: GO:0048167
label: regulation of synaptic plasticity
modifier: DECREASED
- preferred_term: long-term synaptic potentiation
term:
id: GO:0060291
label: long-term synaptic potentiation
modifier: DECREASED
locations:
- preferred_term: hippocampal formation
term:
id: UBERON:0002421
label: hippocampal formation
evidence:
- reference: PMID:40024627
reference_title: "Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Chronic spermidine administration in young adult Grin2b+/- mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of Grin2b+/- mice"
explanation: >-
Establishes an LTP deficit in the haploinsufficient mouse and shows it is
pharmacologically reversible, which places the plasticity node on the
causal path rather than alongside it.
downstream:
- target: Impaired Learning and Memory
causal_link_type: DIRECT
description: >-
Hippocampal and cortical plasticity is the cellular substrate of learning,
so a developmental plasticity deficit presents as a cognitive deficit.
- target: Altered Excitatory Circuit Function
causal_link_type: DIRECT
description: >-
Synapses that form and adapt abnormally assemble into cortical circuits
whose excitatory drive and regulation are correspondingly altered.
- name: Altered Excitatory Circuit Function
description: >-
Network-level consequence of building cortical and hippocampal circuits on
abnormal NMDA-receptor-dependent excitatory synapses. This node is the
common origin of the non-cognitive neuropsychiatric features of MRD6 — the
hyperactive, inattentive, stereotypy-prone behavioral profile and disturbed
sleep — and of seizures in the subset who have them. It is deliberately
named for altered circuit function rather than for excitation-inhibition
imbalance: in the loss-of-function arm the primary change is reduced
excitatory drive, so a hyperexcitability framing would misstate the
direction, and seizures here are a variable feature rather than the
defining one.
role: effector
biological_scale: TISSUE
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: modulation of chemical synaptic transmission
term:
id: GO:0050804
label: modulation of chemical synaptic transmission
modifier: ABNORMAL
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: "Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected."
explanation: >-
The founding study's own framing of the step: developmental disturbance of
neuronal electrophysiological balance produces the variable neurological
phenotypes this node feeds.
downstream:
- target: Seizures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In the subset who develop epilepsy, altered excitatory circuit function is
the substrate of seizure generation.
- target: Hyperactivity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Short Attention Span
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Stereotypy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Sleep Disturbance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Autistic Behavior
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Learning and Memory
description: >-
The organism-level convergence point of the chain: degraded acquisition and
retention, which in MRD6 presents as static, non-degenerative intellectual
disability with prominent language impairment rather than as progressive
cognitive loss.
role: consequence
biological_scale: ORGANISM
conforms_to: "nmda_receptor_hypofunction#Learning and Memory Impairment"
biological_processes:
- preferred_term: learning
term:
id: GO:0007612
label: learning
modifier: DECREASED
- preferred_term: memory
term:
id: GO:0007613
label: memory
modifier: DECREASED
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All individuals had mild to severe ID and needed guidance in daily routine."
explanation: >-
The human anchor for the outcome node in a series ascertained specifically
as MRD6 de novo GRIN2B mutation carriers.
downstream:
- target: Intellectual Disability
causal_link_type: DIRECT
- target: Global Developmental Delay
causal_link_type: DIRECT
- target: Language Impairment
causal_link_type: DIRECT
phenotypes:
- category: Neurodevelopmental
name: Intellectual Disability
description: >-
Intellectual disability is present in every affected individual, ranging from
mild to profound. Severity is the principal determinant of functional outcome
and of caregiver burden.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All individuals had mild to severe ID and needed guidance in daily routine."
explanation: >-
Every carrier in a series ascertained as MRD6 had intellectual disability.
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%)."
explanation: >-
Quantifies developmental delay/intellectual disability as universal across
the pooled 105-patient GRIN2B series.
- category: Neurodevelopmental
name: Global Developmental Delay
description: >-
Global developmental delay is apparent in infancy, typically before the
disorder is molecularly diagnosed, and is non-degenerative: the course is
static rather than regressive in the large majority.
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 is present in all affected individuals across the
GRIN2B series.
- category: Neurodevelopmental
name: Language Impairment
description: >-
Delayed and limited expressive language is a characteristic and
disproportionately prominent feature, reported both as delayed language
acquisition in deletion carriers and as a distinct language impairment in
loss-of-function cases. Speech is absent in the most severely affected.
frequency: FREQUENT
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%)."
explanation: >-
Quantifies language impairment in roughly half of the pooled GRIN2B series.
- reference: PMID:23918416
reference_title: "Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia."
explanation: >-
Delayed language acquisition in three GRIN2B deletion carriers, the
haploinsufficiency form of MRD6.
- category: Neurologic
name: Hypotonia
description: >-
Muscular hypotonia is usually evident in the neonatal or infantile period and
often persists, contributing to delayed motor milestones and, in a subset, to
feeding difficulty.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%)."
explanation: >-
Quantifies hypotonia as a near-universal feature of the pooled GRIN2B
series.
- category: Behavioral
name: Hyperactivity
description: >-
Prominent hyperactivity and impulsivity dominate the behavioral profile of
MRD6 and are, alongside inattention, the features most often reported as
driving day-to-day management difficulty.
phenotype_term:
preferred_term: Hyperactivity
term:
id: HP:0000752
label: Hyperactivity
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span."
explanation: >-
Standardized behavioral assessment of MRD6 carriers identifies
hyperactivity as a characteristic feature.
- category: Behavioral
name: Short Attention Span
description: >-
Distractibility and a short attention span are consistently reported on
standardized parent and teacher behavioral rating scales.
phenotype_term:
preferred_term: Short attention span
term:
id: HP:0000736
label: Short attention span
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "prominent hyperactivity, impulsivity, distractibility and a short attention span"
explanation: >-
Short attention span is part of the characteristic MRD6 behavioral profile.
- category: Behavioral
name: Stereotypy
description: >-
Stereotyped, repetitive movements are commonly reported, part of a behavioral
profile that overlaps autism spectrum presentations without always meeting
criteria for them.
phenotype_term:
preferred_term: Motor stereotypy
term:
id: HP:0000733
label: Motor stereotypy
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported."
explanation: >-
Stereotypies are commonly reported in MRD6 carriers.
- category: Behavioral
name: Sleep Disturbance
description: >-
Sleeping problems are commonly reported by caregivers and add materially to
family burden.
phenotype_term:
preferred_term: Sleep disturbance
term:
id: HP:0002360
label: Sleep disturbance
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported."
explanation: >-
Sleeping problems are among the commonly reported MRD6 features.
- category: Neurodevelopmental
name: Autistic Behavior
description: >-
Autism spectrum features and behavioral abnormalities occur in a substantial
minority. Notably, the MRD6 social profile is often described as friendly and
socially disinhibited rather than socially withdrawn, which distinguishes it
from many other syndromic autism presentations.
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 and behavioral issues are common in the GRIN2B
series.
- category: Neurologic
name: Seizures
description: >-
Seizures occur in some but not all individuals — MRD6 is explicitly named
"with or without seizures". Where present they are ordinary epilepsy rather
than the early-onset epileptic encephalopathy of the allelic DEE27 sibling,
and epilepsy is comparatively less frequent in the loss-of-function allelic
class that predominates in MRD6. Frequency is deliberately left unset: the
published percentages come from mixed GRIN2B series spanning both poles of
the allelic series and would misstate the rate for this arm.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GOF variants were more likely to cause epilepsy and microcephaly than LOF variants."
explanation: >-
Establishes that epilepsy is enriched in the gain-of-function class rather
than the loss-of-function class that predominates in MRD6, which is why
seizures are a variable rather than defining feature here.
- category: Neurologic
name: Movement Disorder
description: >-
A hyperkinetic movement disorder — dystonic, dyskinetic or choreiform — is
part of the reported GRIN2B phenotype spectrum, and is one of the features
reported as more severe in loss-of-function missense than in
loss-of-function truncating variants.
phenotype_term:
preferred_term: Hyperkinetic movement disorder
term:
id: HP:0002487
label: Hyperkinetic movements
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: "Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy."
explanation: >-
Movement disorder is part of the presenting spectrum in the 86-patient
cohort.
- category: Ophthalmologic
name: Cerebral Visual Impairment
description: >-
Cortical/cerebral visual impairment occurs in a subset. The lesion is
cortical; the eyes are structurally normal, so this is not an ophthalmologic
abnormality in the usual sense.
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: "Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy."
explanation: >-
Cortical visual impairment is part of the presenting spectrum in the
86-patient cohort.
- category: Neurologic
name: Spasticity
description: >-
Spasticity occurs alongside or instead of hypotonia among the muscle-tone
abnormalities, and is reported predominantly in the more severely affected.
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 of the GRIN2B
series.
- category: Gastrointestinal
name: Feeding Difficulties
description: >-
Feeding difficulties occur in association with the muscle-tone
abnormalities, occasionally requiring tube feeding.
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 accompany the muscle-tone abnormalities.
- category: Craniofacial
name: Mild Facial Dysmorphism
description: >-
Mild, non-specific facial dysmorphic features have been described in
GRIN2B deletion carriers. There is no recognizable gestalt, and MRD6 is not
diagnosable on facial features.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:23918416
reference_title: "Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia."
explanation: >-
Mild facial dysmorphia accompanied intellectual disability in three GRIN2B
deletion carriers.
genetic:
- name: GRIN2B
association: Causative
relationship_type: CAUSATIVE
variant_origin: DE_NOVO
gene_term:
preferred_term: GRIN2B
term:
id: hgnc:4586
label: GRIN2B
notes: >-
GRIN2B (12p13.1) encodes the GluN2B subunit of the NMDA receptor. In MRD6 the
causal alleles are heterozygous and typically de novo, and the mechanism
leans loss-of-function: exonic and whole-gene deletions and truncating
variants act through haploinsufficiency, while missense variants in the
ligand-binding and transmembrane domains reduce surface expression, agonist
potency or open probability. Gain-of-function missense alleles at the same
locus are enriched in the allelic epileptic-encephalopathy entity rather than
in MRD6. Variant-level functional classification is not available for most
reported variants, so this entry records the functional impact at the
allelic-class level rather than asserting it variant by variant.
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: "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 gene-discovery study, performed in an intellectual-disability
cohort, establishing de novo GRIN2B variants as causal.
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variants located in the transmembrane domain predominantly resulted in a GOF effect."
explanation: >-
Locates the gain-of-function class structurally, which is the basis for
treating the loss-of-function class as the MRD6-predominant one.
prevalence:
- population: General population, worldwide
measure_type: POINT_PREVALENCE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No general-population prevalence or birth-prevalence figure for MRD6 could
be sourced. A modelled birth-incidence estimate for de novo GRIN2B disorder
(~5.91 per 100,000 live births) is often quoted from the López-Rivera 2020
incidence catalogue, but that per-gene number lives in a supplementary table
and does not appear in the retrievable text of PMID:32168371, so it is
deliberately not asserted here. The two records below are diagnostic yields
within ascertained clinical cohorts, not population rates, and must not be
read as such.
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 published individuals across the whole GRIN2B series
indicates the population rate is undocumented rather than measured, which
is what this record asserts.
- population: Individuals with intellectual disability (clinical cohorts)
measure_type: POINT_PREVALENCE
prevalence_class: UNKNOWN
rate_per_100000: 750.0
rate_low: 500.0
rate_high: 1000.0
notes: >-
0.5-1% of individuals with intellectual disability, reported for MRD6
specifically. The rate is expressed against the ID-cohort denominator named
in `population`, so it is a diagnostic yield and NOT a general-population
prevalence. `prevalence_class` is deliberately UNKNOWN rather than a numeric
Orphanet band: those bands are read as general-population rarity tiers, and
filling one from a clinic-cohort yield would assert that MRD6 is a common
disease by roughly three orders of magnitude.
evidence:
- reference: PMID:23718928
reference_title: "Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 - 1% in individuals with ID)"
explanation: >-
States the MRD6 frequency within the intellectual-disability population,
naming MRD6 and its OMIM number explicitly rather than the broader GRIN2B
series.
- population: Individuals with neurodevelopmental disorders (large diagnostic cohort)
measure_type: POINT_PREVALENCE
prevalence_class: UNKNOWN
rate_per_100000: 200.0
notes: >-
Share of a large neurodevelopmental-disorder cohort carrying a likely
pathogenic de novo GRIN2B variant. Broader denominator than the ID-cohort
figure above and correspondingly lower, and it covers the whole GRIN2B
series rather than the MRD6 arm alone. As above, this is a diagnostic yield
against the cohort named in `population`, not a population prevalence, so
`prevalence_class` is left UNKNOWN.
evidence:
- reference: PMID:36704660
reference_title: "GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms."
supports: SUPPORT
evidence_source: OTHER
snippet: "the prevalence of de novo GRIN2B variants that are likely pathogenic was 0.2%"
explanation: >-
Gives the GRIN2B yield in a large neurodevelopmental-disorder cohort.
animal_models:
- name: Grin2b heterozygous null mouse
species: Mouse
genotype: Grin2b+/- (constitutive heterozygous null)
publication: PMID:40024627
description: >-
A constitutive heterozygous Grin2b null mouse, the genetic counterpart of the
haploinsufficiency mechanism that causes MRD6 through deletions and truncating
variants. It is the model in which the plasticity deficit and its
pharmacological rescue were demonstrated.
modeled_mechanisms:
- target: Impaired Activity-Dependent Synaptic Plasticity
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
The heterozygous null reproduces the hippocampal long-term potentiation
deficit expected from reduced GluN2B dosage, and the deficit is partially
reversed by a receptor-potentiating agent.
limitations: >-
A constitutive whole-gene null models the deletion and truncating alleles
but not the loss-of-function missense alleles, which may act through
dominant-negative co-assembly rather than dosage alone. Mouse cognitive
readouts are behavioral proxies for human intellectual disability, and the
developmental timing of the GluN2B-to-GluN2A subunit switch differs between
species.
readouts:
- name: Hippocampal long-term potentiation in slices
target: Impaired Activity-Dependent Synaptic Plasticity
direction: RESTORED
interpretation: >-
LTP was deficient in Grin2b+/- slices and partially restored by chronic
spermidine, which is the rescue arm of the plasticity claim.
evidence:
- reference: PMID:40024627
reference_title: "Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Chronic spermidine administration in young adult Grin2b+/- mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of Grin2b+/- mice"
explanation: >-
Reports the LTP measurement and its partial restoration in the
haploinsufficient mouse.
evidence:
- reference: PMID:40024627
reference_title: "Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "a GRIN2B-LoF genetic murine model recapitulating GRD-like synaptic, motor, and cognitive alterations"
explanation: >-
Supports treating the heterozygous null as informative for the synaptic
and cognitive nodes of this entry.
diagnosis:
- name: Molecular Genetic Testing
description: >-
Diagnosis rests on identifying a heterozygous pathogenic GRIN2B variant or an
exon or whole-gene deletion, in practice through trio exome or genome
sequencing or a neurodevelopmental gene panel. Chromosomal microarray remains
necessary to detect the deletion class, which sequence analysis alone can
miss. Establishing that the variant is de novo supports pathogenicity.
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: "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, including the deletion class
that requires copy-number-aware testing.
differential_diagnoses:
- name: GRIN2B-related developmental and epileptic encephalopathy (DEE27)
disease_term:
preferred_term: developmental and epileptic encephalopathy, 27
term:
id: MONDO:0014505
label: developmental and epileptic encephalopathy, 27
description: >-
The allelic sibling entity at the same locus, and the single most important
differential. Both are caused by heterozygous de novo GRIN2B variants and
both feature developmental delay and intellectual disability, so the gene
result does not discriminate them: only the clinical presentation and, where
available, the functional class of the variant do. The two are poles of one
allelic series rather than disjoint diseases, and intermediate presentations
exist.
distinguishing_features:
- Defined by severe early-onset epileptic encephalopathy, in which frequent seizures and epileptiform activity themselves drive developmental impairment; MRD6 is named "with or without seizures" and lacks the encephalopathic course.
- Enriched for gain-of-function variants, which are more likely to cause epilepsy and microcephaly, whereas MRD6 leans loss-of-function (deletions, truncating and hypomorphic missense alleles).
- Gain-of-function variants cluster in the transmembrane domains, giving a structural correlate that partially predicts which arm a novel missense variant belongs to.
- "Opposite mechanism-directed therapy: NMDA-receptor channel blockade (memantine, radiprodil) for the gain-of-function pole, receptor-potentiating strategies for the loss-of-function pole."
evidence:
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GOF variants were more likely to cause epilepsy and microcephaly than LOF variants."
explanation: >-
The variant-class comparison that separates the epileptic pole from the
MRD6 pole.
- reference: PMID:41146259
reference_title: "GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variants located in the transmembrane domain predominantly resulted in a GOF effect."
explanation: >-
Supports the structural correlate in the third distinguishing feature:
transmembrane-domain location predicts the gain-of-function pole.
- reference: PMID:28533163
reference_title: "GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants."
explanation: >-
Supports the fourth distinguishing feature, that receptor blockade is the
gain-of-function pole's mechanism-directed therapy: the GluN2B-selective
blocker retains potency against gain-of-function variants where
non-selective antagonists lose it.
- name: Other GRIN-related neurodevelopmental disorders (GRIN1, GRIN2A, GRIN2D)
description: >-
Disorders of the other NMDA-receptor subunit genes produce overlapping
developmental delay, intellectual disability and epilepsy phenotypes and are
typically on the same diagnostic gene panel. They are separated by the gene
result rather than clinically, which is why panel or exome testing rather
than single-gene testing is the appropriate diagnostic route.
distinguishing_features:
- Distinguished by the causal gene on sequencing, not by clinical features.
- GRIN2A disease is more strongly associated with epilepsy-aphasia spectrum presentations.
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: >-
Both subunit genes produce overlapping intellectual-disability and epilepsy
presentations, which is what makes them a differential for one another.
treatments:
- name: Developmental and Supportive Therapy
description: >-
Management is symptomatic and multidisciplinary: early intervention, physical
and occupational therapy, speech and language therapy, feeding support where
hypotonia causes difficulty, and behavioral intervention for the hyperactive,
inattentive profile. No disease-modifying therapy is approved.
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: >-
Establishes symptomatic, standard-practice management as the basis of care.
- name: Spermidine Supplementation
description: >-
An investigational mechanism-directed therapy aimed specifically at the
loss-of-function arm. Spermidine is the precursor of spermine, a natural
polyamine that acts as a positive allosteric modulator of GluN2B-containing
NMDA receptors, so the strategy is to potentiate hypofunctional receptors
rather than block them. Preclinical support comes from the haploinsufficient
mouse; human experience is limited to two pediatric patients with mild
loss-of-function variants followed for 18 months, so this is an early signal
and not established therapy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: spermidine
term:
id: CHEBI:16610
label: spermidine
target_mechanisms:
- target: GluN2B-Containing NMDA Receptor Hypofunction
treatment_effect: RESTORES
description: >-
Polyamine positive allosteric modulation raises the deficient
NMDAR-mediated current of loss-of-function receptors.
evidence:
- reference: PMID:40024627
reference_title: "Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "18 months of spermidine treatment resulted in the amelioration of adaptive behavior (notably in the younger treated patient), with the absence of noticeable side effects."
explanation: >-
The human arm of the spermidine study, in two children with GRIN2B
loss-of-function variants.
- name: L-Serine Supplementation
description: >-
The other receptor-potentiating strategy for the loss-of-function arm, and
the one with the most human data. L-serine is the precursor of D-serine and
glycine, the NMDA-receptor co-agonists, so supplying it aims to raise the
occupancy of hypofunctional receptors. A phase 2A open-label trial in
children with GRIN loss-of-function variants (NCT04646447) reported
improvement across adaptive-behavior, motor and quality-of-life measures.
The trial was single-arm and enrolled GRIN1 and GRIN2A alongside GRIN2B
variants, so the GRIN2B-specific and placebo-controlled effect is not
established.
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: GluN2B-Containing NMDA Receptor Hypofunction
treatment_effect: RESTORES
description: >-
Supplying the co-agonist precursor raises co-agonist site occupancy at
hypofunctional NMDA receptors.
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: "L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity."
explanation: >-
The phase 2A trial's positive motor and quality-of-life outcomes in GRIN
loss-of-function patients.
- name: Antiseizure Medication
description: >-
For the subset of individuals who develop seizures, standard antiseizure
medication chosen by seizure type. This is symptomatic management rather
than mechanism-directed therapy, and seizures are a variable rather than
defining feature of MRD6.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Seizures
treatment_effect: INHIBITS
description: >-
Symptomatic suppression of seizures in the affected subset.
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 in the GRIN2B series is managed symptomatically per standard
practice.
- name: Genetic Counseling
description: >-
Counseling covers the de novo origin of the variant, the consequently low but
non-zero sib recurrence risk arising from possible parental germline
mosaicism, and the reproductive options that follow from it.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
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: >-
The de novo origin is the fact that determines the recurrence-risk
counseling.
clinical_trials:
- name: NCT04646447
phase: PHASE_II
status: COMPLETED
description: >-
Phase 2A open-label, single-arm trial of L-serine in children aged 2-18 with
GRIN loss-of-function pathogenic variants — the arm of the GRIN allelic
series this entry describes. Enrolled GRIN2B, GRIN1 and GRIN2A variants
together, so it is a GRIN loss-of-function trial rather than a
GRIN2B-specific one.
target_phenotypes:
- preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
- preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: clinicaltrials:NCT04646447
reference_title: "Tolerability and Efficacy of L-Serine in Patients With GRIN-related Encephalopathy"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The investigators will include about 20 spanish patients older than 2 years of age, harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants."
explanation: >-
The registration record confirms the trial enrolls functionally annotated
loss-of-function GRIN variants, which is the allelic class this entry
curates.
discussions:
- discussion_id: grin2b_lof_gof_arm_separability
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is the loss-of-function/gain-of-function axis a reliable partition of the
GRIN2B allelic series into the MRD6 and DEE27 clinical entities, or is it a
statistical enrichment across one continuum that does not support separate
disease entries?
attaches_to:
- pathophysiology#GRIN2B Haploinsufficiency and Loss-of-Function Variation
- pathophysiology#GluN2B-Containing NMDA Receptor Hypofunction
- differential_diagnoses#GRIN2B-related developmental and epileptic encephalopathy (DEE27)
rationale: >-
This entry exists as a separate disease on the strength of a directional
claim: that the loss-of-function allelic class predominates in the
intellectual-disability presentation and the gain-of-function class in the
epileptic-encephalopathy presentation. The supporting comparison is recent
and self-described as the first of its kind, rests on 55 loss-of-function
against 16 gain-of-function patients pooled largely from published case
reports, and reports an enrichment rather than a partition — epilepsy occurs
in the loss-of-function group too. Functional classification is itself
unstable: whether a variant reads as gain- or loss-of-function depends on
whether it is assayed in diheteromeric or triheteromeric receptors, so the
same allele can change class with the assay. If the separability does not
hold up in a larger prospectively phenotyped and uniformly assayed cohort,
the correct outcome would be to merge this entry into a single
GRIN2B-related neurodevelopmental disorder entry with the two presentations
as subtypes.
proposed_experiments:
- experiment_id: exp_grin2b_uniform_assay_phenotype_partition
name: Uniform triheteromeric-assay functional classification against prospective deep phenotyping
description: >-
Assay a large panel of patient GRIN2B variants under a single standardized
protocol that includes triheteromeric GluN1/2A/2B receptors, rather than
pooling diheteromeric results from heterogeneous sources, and test whether
the resulting functional class predicts membership of the
intellectual-disability versus epileptic-encephalopathy presentation in
prospectively and uniformly phenotyped patients.
evidence:
- reference: PMID:35741674
reference_title: "Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "thereby influencing the functional classification of NMDA receptor variants as GoF or LoF mutations"
explanation: >-
Shows the functional classification that this entry's separability argument
depends on is itself assay-dependent, which is the core of the gap.
datasets: []
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: intellectual disability, autosomal dominant 6 · 2026-09-05T19:01:09Z · View source
De-novo curation of MRD6 (MONDO:0013509, GRIN2B hgnc:4586) as the non-encephalopathic arm of the GRIN2B allelic series, resolving claim issue 11066 and deleting the stub. Lump/split decision: curated as DISEASE, not SUBTYPE - distinct MONDO/OMIM identities (613970 vs 616139), separable ID-without-encephalopathy presentation, LOF-leaning mechanism (deletions/truncating/hypomorphic missense) vs the GOF-enriched DEE27 sibling, and opposite mechanism-directed therapy direction; the separability caveat is recorded as an open KNOWLEDGE_GAP discussion and in entry notes. Six-node pathophysiology chain with four nodes conforming (partially, per module notes) to nmda_receptor_hypofunction; the module BDNF arm is deliberately not reproduced for lack of GRIN2B-specific evidence. Deep research: Edison was requested but the provider slug is falcon in this checkout; falcon returned HTTP 402 (out of credits), so the run used the recorded --fallback mechanism and claude_code produced the report (research/Intellectual_Disability_Autosomal_Dominant_6-deep-research-claude_code.md, fell_back/requested_provider recorded in frontmatter). preflight-dr returned SKIP (MONDO records no causal gene for MONDO:0013509); manual check confirmed identity (OMIM 613970 in report, GRIN2B=41 mentions, no gene drift). The report's one unresolved reference (DOI:10.1016/j.ymgme.2023.107673) was not cited, and neither was its off-topic-flagged PMID:8789948 (Grin2b homozygous-null mouse; the heterozygous Grin2b+/- model from PMID:40024627 was used instead as the better match for a dominant haploinsufficiency disorder). Evidence: 40/40 snippets verified against references_cache (PMIDs 20890276, 23718928, 23918416, 27818011, 28377535 sibling-shared, 29851452 GeneReviews tagged, 29937144, 35741674, 36704660, 40024627, 41146259); mixed-source PMID:40024627 split into IN_VITRO/MODEL_ORGANISM/HUMAN_CLINICAL items per grading rules. Validation: just validate PASS, count-verified-snippets 40/40, validate-terms PASS, check-duplicate-keys/entity-refs/causal-targets/qualifier-terms/enum-values PASS, check-folded-hyphens/snippet-length/title-snippets/snippet-grading PASS (one short snippet fixed during the loop), validate-disorders run once at the end.
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):
| Resource | ID |
|---|---|
| OMIM (phenotype) | #613970 — "Intellectual developmental disorder, autosomal dominant 6, with or without seizures; MRD6" |
| OMIM (gene) | 138252 (GRIN2B) |
| MONDO | MONDO:0013509 — intellectual disability, autosomal dominant 6 |
| MedGen/UMLS | C3151411 |
| GARD | 12851 |
| Allelic OMIM phenotype | #616139 — Developmental and epileptic encephalopathy 27 (DEE27), same gene |
| Orphanet | No dedicated ORPHA code for MRD6; subsumed under autosomal dominant non-syndromic intellectual disability (ORPHA:178469 group); GRIN2B also listed as a gain-of-function gene for Infantile epileptic spasms syndrome (ORPHA:697160, per Orphadata gene table) |
| ICD-10 / ICD-11 | No disease-specific code; coded as disorders of intellectual development (ICD-10 F70–F79; ICD-11 6A00) ± epilepsy codes |
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).
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.
Frequencies below are from the GeneReviews GRIN2B-NDD chapter (NBK501979, Platzer & Lemke) drawing on the 86-patient Platzer 2017 cohort (PMID:28377535).
| Phenotype | Frequency | Onset | Severity/course | Suggested HP term |
|---|---|---|---|---|
| Developmental delay / intellectual disability | 100% (mild ~15%, severe–profound ~61%) | infancy | stable, non-degenerative; regression rare (~7%) | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability (suggest) |
| Muscular hypotonia | ~56% (15% of these tube-fed) | neonatal/infantile | often persistent | HP:0001252 Hypotonia (suggest) |
| Epilepsy (various types incl. infantile spasms, focal, generalized) | ~51% | birth–9 y | ~half drug-resistant | HP:0001250 Seizure; HP:0012469 Infantile spasms (suggest) |
| Autism spectrum disorder / behavioral abnormalities | ~26% | early childhood | chronic | HP:0000717 Autism; HP:0000708 Abnormal behavior (suggest) |
| Spasticity | ~23% (only in severe ID) | childhood | chronic | HP:0001257 Spasticity (suggest) |
| Microcephaly | ~18% (severe ID only) | congenital/postnatal | stable | HP:0000252 Microcephaly (suggest) |
| Malformation of cortical development (polymicrogyria-like, intermediate with tubulinopathy pattern) | ~13% (6/48 in Platzer series) | congenital | structural | HP:0002126 Polymicrogyria (suggest) |
| Movement disorder (dystonic, dyskinetic, choreiform) | ~10% | infancy/childhood | chronic | HP:0001332 Dystonia; HP:0002072 Chorea (suggest) |
| Cortical visual impairment | ~8% | infancy | chronic | HP:0100704 Cerebral visual impairment (suggest) |
| Feeding difficulties | subset of hypotonic patients | neonatal | may need gastrostomy | HP:0011968 Feeding difficulties (suggest) |
| Macrocephaly (12p13 deletion cases) | occasional | infancy | — | HP:0000256 Macrocephaly (suggest); PMID:27656287 |
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).
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).
Causal chain (numbered; branch points marked):
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).
No disease-modifying therapy is approved; management is symptomatic (GeneReviews NBK501979). Suggested NCIT bindings marked (suggest).
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
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 15 |
| Unresolved (possible confabulation) | 1 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 15 |
| On topic | 11 |
| Off topic | 1 |
These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:
DOI:10.1016/j.ymgme.2023.107673 (1 mention) - Identifier did not resolve to a recordThese identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:8789948 (5 mentions) - Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice.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.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 46 |
| Resolved | 42 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 4 |
| Terms whose name was checked | 1 |
| Terms named correctly | 0 |
| Terms named as a different term | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
NCIT:C15302 (1 mention) - the report calls it "Developmental/supportive care — early-intervention programs, physical therapy"; NCIT calls it Physical Therapy**Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.