| Evidence domain | Key finding with exact quantitative values where available | Evidence type | Source/date/DOI |
|---|---|---|---|
| Contemporary genotype–phenotype spectrum | Among **25 patients from 23 families** carrying 17 functionally abnormal variants, all had global developmental impairment: **9/25 moderate**, **12/25 severe**; **12/25** had seizures, **13/25** hypotonia, **10/25** hypertonia, and **14/25** movement disorders, including hyperekplexia or nonepileptic erratic myoclonus in **8/25**. Testing of one frameshift and 43 missense variants found **31 function-altering LoF/GoF variants** and **13 apparently neutral variants**. Median seizure onset was **1 month for GoF** versus **16 months for LoF**. | Human clinical cohort; in-vitro electrophysiology | Rinaldi et al., *Brain*; online **2023-12-01**, 2024 volume; [DOI 10.1093/brain/awad403](https://doi.org/10.1093/brain/awad403) (pqac-00000000) |
| Structural variant and prenatal diagnosis | A hemizygous **GRIA3 exon 5–12 deletion** was found in an affected male with intellectual disability, schizophrenia, brain atrophy, seizures, and episodic irritability. The pregnant woman and maternal grandmother were heterozygous; amniotic-fluid testing detected the familial deletion in the fetus. | Human pedigree; prenatal molecular diagnosis | Wang et al., *Biomedical Journal of Scientific & Technical Research*; published **2023-09-15**; [DOI 10.26717/BJSTR.2023.52.008322](https://doi.org/10.26717/BJSTR.2023.52.008322) (pqac-00000008) |
| Female developmental and epileptic encephalopathy | A 13-year-old girl carried de novo heterozygous **NM_007325.5:c.1982T>C, p.Met661Thr**, absent from several population databases and classified **likely pathogenic**. Hypertonia was present at birth; seizures began at **3 months**. Carbamazepine and ethosuximide were ineffective; lamotrigine, clobazam, levetiracetam, and lacosamide gradually controlled seizures. | Human clinical case; WES and segregation | Okano et al., *Human Genome Variation*; published **2023-02-02**; [DOI 10.1038/s41439-023-00232-1](https://doi.org/10.1038/s41439-023-00232-1) (pqac-00000012) |
| Genotype-guided symptomatic treatment | A boy with de novo hemizygous **GRIA3 c.1844C>T, p.Ala615Val** had neurodevelopmental impairment, seizures, hypertonia, and hyperreflexia. **Carbamazepine ameliorated seizures and hypertonia**. Patch-clamp recordings showed slower receptor desensitization and deactivation, supporting GoF. | Human case; in-vitro electrophysiology; transgenic fly | Hamanaka et al., *Human Genetics*; published online **2022-01-15**; [DOI 10.1007/s00439-021-02416-7](https://doi.org/10.1007/s00439-021-02416-7) (pqac-00000013) |
| Sleep–wake phenotype and allelic mouse model | Two brothers with severe developmental delay and **p.Ala653Thr** had wake periods up to **106 hours** and sleep periods up to **48 hours**. In vitro, the variant stabilized the channel in a closed conformation. CRISPR knock-in hemizygous mice had fewer brief sleep/activity bouts and enhanced period lengthening under constant light. | Human pedigree; in vitro; CRISPR knock-in mouse | Davies et al., *Human Molecular Genetics*; advance publication **2017-07-14**; [DOI 10.1093/hmg/ddx270](https://doi.org/10.1093/hmg/ddx270) (pqac-00000010) |
| Knockout behavior and monoamines | Compared with wild-type littermates (**n=14**), knockout mice (**n=13**) showed increased aggression (**p=0.011**), sociality (**p=0.01**), male–male interaction (**p=0.005**), peripheral activity (**p=0.037**), and minor rotarod impairment (**p=0.016**). Striatal dopamine increased (**p=0.034**) and olfactory-bulb serotonin turnover decreased (**p=0.002**). | Germline knockout mouse; behavioral and neurochemical assays | Adamczyk et al., *Behavioural Brain Research*; **2012-04-01**; [DOI 10.1016/j.bbr.2012.01.007](https://doi.org/10.1016/j.bbr.2012.01.007) (pqac-00000014) |
| AMPAR interaction proteomics | Hippocampal proteomics in wild-type and **Gria3**-knockout mice showed that GluA2/3 receptors most strongly co-purified with **CNIH-2, TARP-γ2/Stargazin, and Noelin-1/OLFM1**, identifying subtype-specific partners involved in receptor trafficking and gating. | Mouse hippocampal interaction proteomics | van der Spek et al., *Cells*; published **2022-11-17**; [DOI 10.3390/cells11223648](https://doi.org/10.3390/cells11223648) (pqac-00000015) |
| Brain-region-specific molecular profiling | Bulk RNA-seq across six brain regions at **1 and 3 months** found **153 regional DEG calls/148 unique DEGs at 1 month** and **209/201 at 3 months**, with downregulated activity-regulated genes and region-specific immune, glial, and oligodendrocyte-pathway changes. Synaptic proteome composition was also altered. | Mouse transcriptomics and synaptic proteomics; **non-peer-reviewed preprint** | Huang et al., *bioRxiv*; posted **2024-11-17**; [DOI 10.1101/2024.11.15.623468](https://doi.org/10.1101/2024.11.15.623468) (pqac-00000009) |


*Table: Compact evidence matrix covering clinical genotype–phenotype findings, prenatal diagnosis, functional studies, treatment observations, and animal or omics models relevant to GRIA3-related syndromic X-linked intellectual disability 94.*