| Domain | Core finding/statistic | Suggested ontology terms | Evidence type/source |
|---|---|---|---|
| Disease identity | GRIN2A-related disorder spans mild focal epilepsy/speech disorder to severe developmental and epileptic encephalopathy within the epilepsy-aphasia spectrum; largest aggregated cohort included 248 affected individuals. Orphanet entry referenced as 289266 in trial registry material. (pqac-00000000, pqac-00000011) | MONDO: GRIN2A-related disorder (if mapped); Orphanet: 289266; HP:0001250 Seizure; HP:0000750 Delayed speech and language development | Human aggregated cohort; trial registry background (Brain 2019; ClinicalTrials.gov) |
| Gene/protein | Causal gene is **GRIN2A** encoding GluN2A, an NMDA receptor subunit; pathogenic variation affects receptor function, trafficking, and localization. (pqac-00000009, pqac-00000010) | HGNC: GRIN2A; NCBI Gene: GRIN2A; UniProt: GluN2A; GO:0004972 NMDA glutamate receptor activity | Human molecular genetics; review/in vitro mechanistic synthesis |
| Epilepsy/EEG | In the 2019 cohort, 27/219 (12.3%) had no seizures; among 152 with EEG, 143/152 (94.1%) had epileptiform discharges, including centrotemporal spikes (34), multifocal discharges (28), and CSWS/SWAS (51). (pqac-00000002) | HP:0001250 Seizure; HP:0011175 Focal-onset seizure; HP:0010848 Abnormality of EEG; HP:0011185 Centrotemporal spike waves; HP:0011187 Continuous spike-wave during slow-wave sleep | Human cohort (Brain 2019) |
| Speech-language | Speech disorder was the dominant phenotype: 129/140 (92.1%) had impairment; reported subgroups included moderate dysarthria/dyspraxia (55), aphasia with speech loss (26), delayed speech development (26), and temporary regression (8). (pqac-00000002) | HP:0000750 Delayed speech and language development; HP:0002167 Dysarthria; HP:0002376 Developmental regression; HP:0031988 Aphasia | Human cohort |
| ID/development | Intellectual disability/developmental delay present in 62.7% overall; severity ranged from none to profound, with misTMD+linker variants associated with markedly greater severity than misATD+LBD variants. (pqac-00000001, pqac-00000002) | HP:0001249 Intellectual disability; HP:0011342 Developmental delay; HP:0010864 Global developmental delay | Human cohort with genotype-phenotype analysis |
| Motor/behavior | Hypotonia in 40/139 (28.8%); movement disorders in 19/72 (26.4%), including ataxic/dystonic/spastic/choreatic features; neuropsychiatric comorbidity in 17/70 (24.3%), including ADHD (6), autism (6), schizophrenia (2), anxiety (1). (pqac-00000002) | HP:0001252 Hypotonia; HP:0001251 Ataxia; HP:0001332 Dystonia; HP:0002317 Unsteady gait/ataxia-related; HP:0007018 Attention deficit hyperactivity disorder; HP:0000717 Autism | Human cohort |
| Anatomy | Imaging abnormalities were reported in 12/85 (14.1%) in the human cohort; mouse knockout imaging showed transient abnormalities in neocortex, corpus callosum, hippocampus, and thalamus, strongest around postnatal day 30. (pqac-00000002, pqac-00000008) | UBERON:0000955 brain; UBERON:0001950 cerebral cortex/neocortex; UBERON:0000956 corpus callosum; UBERON:0002421 hippocampus; UBERON:0001897 thalamus | Human cohort; mouse MRI/DTI model |
| Mechanism (GoF/LoF) | Variant class/domain predicts function and phenotype: missense variants in transmembrane/linker regions are associated with severe developmental phenotypes and NMDAR gain-of-function; missense variants in ATD/LBD and null variants more often associate with NMDAR loss-of-function and milder developmental phenotypes. Severe GoF can also result from specific missense variants such as L812M. (pqac-00000000, pqac-00000003) | GO:0004972 NMDA glutamate receptor activity; GO:0050890 cognition/synaptic signaling-related; SO:0001583 missense_variant; SO:0001587 stop_gained; SO:0001909 frameshift_variant | Human cohort integrated with electrophysiology; case functional study |
| Protein/trafficking dysfunction | A de novo **P1199Rfs*32** frameshift truncating the GluN2A CTD caused impaired PSD-95 binding, preserved Scribble1 interaction, increased extrasynaptic expression, fewer synapses, decreased spine density, and was interpreted as loss-of-function. (pqac-00000009) | GO:0098978 glutamatergic synapse; GO:0043197 dendritic spine; GO:0006897 endocytosis/recycling trafficking; HP:0001250 Seizure | Human case plus heterologous-cell and rat-neuron in vitro study |
| Diagnosis | Recommended diagnosis is molecular: pathogenic/likely pathogenic **GRIN2A** variant in an individual with epilepsy, sleep-activated epileptiform EEG/SWAS, speech-language disorder, and/or developmental impairment; functional annotation is important because treatment direction differs for GoF vs LoF variants. (pqac-00000001, pqac-00000014) | NCIT: Genetic Testing; HP:0010848 Abnormality of EEG; HP:0000750 Delayed speech and language development | Human cohort; retrospective treatment series |
| Inheritance | Unlike several other GRIN-associated disorders, inherited variants are common: 60.2% of GRIN2A variants were inherited overall; all 32 misTMD+linker variants were de novo, while 18/47 misATD+LBD variants were de novo. Apparent penetrance is incomplete, with only three individuals reported as apparently normal. (pqac-00000001, pqac-00000002) | HP:0000006 Autosomal dominant inheritance; HP:0003829 Variable expressivity; HP:0003828 Reduced penetrance | Human cohort |
| Temporal course | EAS/GRIN2A phenotypes are age-dependent childhood disorders; in mouse knockout, structural abnormalities were transient and most evident at ~1 month, paralleling the childhood onset and variable adolescent outcome described for EAS. (pqac-00000008) | HP:0011463 Childhood onset; HP:0002376 Developmental regression; HP:0012378 Episodic course | Mouse model with human syndrome framing |
| Recent SWAS relevance | In a 2024 D/EE-SWAS study, genetic etiology was found in 31/91 (34%) of the core cohort; GRIN genes are part of the etiologic landscape of SWAS disorders, reinforcing GRIN2A testing in relevant EEG-language-regression phenotypes. (pqac-00000015) | HP:0011187 Continuous spike-wave during slow-wave sleep; HP:0001288 Aphasia; HP:0001249 Intellectual disability | Human 2024 syndrome cohort |
| Treatment | Precision treatment remains experimental and mechanism-dependent. In a 10-patient retrospective GRIN2A/GRIN2B series, among 9 LoF/null cases, L-serine was associated with improvement in behavior in 8/9 (89%), development in 4/9 (44%), and EEG or seizure frequency in 4/9 (44%); no side effects were reported in these 9. A GoF case worsened transiently with L-serine. (pqac-00000014) | NCIT:C61742 Serine; NCIT:Anticonvulsant Therapy; HP:0010848 Abnormality of EEG | Human retrospective n-of-1/case-series evidence |
| Clinical trials | **NCT04646447**: L-serine in GRIN-related encephalopathy, interventional single-group, estimated enrollment 20, last known recruiting, focused on LoF variants. **NCT05818943** Honeycomb: radiprodil (NR2B negative allosteric modulator), phase 1, open-label, active not recruiting, estimated enrollment 24, for pediatric GoF GRIN-related disorder. (pqac-00000011, pqac-00000012, pqac-00000013) | NCIT:C61742 Serine; NCIT:C000626801 radiprodil; NCIT:Clinical Trial | Trial registry |
| Animal/cellular models | **Grin2a KO mouse**: transient microstructural brain anomalies and epileptiform discharges in third postnatal week. **Grin2a N615S mouse**: voltage-independent Ca2+ signaling caused audiogenic seizures, exploratory hyperactivity, attentional/cognitive abnormalities, and altered hippocampal activity. **Rat primary neurons/heterologous cells**: P1199Rfs*32 caused trafficking/synaptic defects. (pqac-00000008, pqac-00000016, pqac-00000009) | MGI:Grin2a; GO:0007611 learning or memory; GO:0051930 regulation of sensory perception; CL:0000540 neuron | Mouse model; in vitro neuronal/cell-system evidence |
| Major evidence gaps | No robust prevalence/incidence estimates specific to GRIN2A-related epileptic encephalopathy/ID were identified; no standardized diagnostic criteria unique to GRIN2A disorder; no approved disease-modifying therapy; treatment evidence remains small, retrospective, and mechanism-stratified; limited data on biomarkers, long-term prognosis, and protective/environmental modifiers. (pqac-00000001, pqac-00000014, pqac-00000011, pqac-00000012) | NCIT:Evidence Gap; HP:0000007 Autosomal dominant; GO:0007268 synaptic transmission | Evidence synthesis across cohort, case series, and trial registries |


*Table: This table maps the main disease-characteristic domains for GRIN2A-related epileptic encephalopathy/intellectual disability to concise evidence-backed findings and suggested ontology terms. It is designed as a compact knowledge-base scaffold that distinguishes cohort, mechanistic, model, and trial-registry evidence.*