GRIN2A – Neurodevelopmental Disorder

GRIN2A encodes the GluN2A subunit of the N-methyl-D-aspartate receptor. Heterozygous pathogenic variants in GRIN2A underlie an autosomal dominant neurodevelopmental disorder spanning isolated speech impairment and mild epilepsy to severe developmental and epileptic encephalopathies (PMID:30544257). The clinical spectrum often includes speech delay/apraxia, ataxia, drooling and global developmental delay, with centrotemporal spike‐and‐wave discharges on EEG.

Genetic evidence for GRIN2A–neurodevelopmental disorder is strong. A multicenter cohort study identified 248 individuals harboring pathogenic or likely pathogenic GRIN2A variants, including missense, splice‐site, nonsense and frameshift alleles (PMID:30544257). Familial segregation in two independent pedigrees—a novel N‐terminal null variant in two sisters and their mildly affected mother, and a de novo frameshift c.1717del (p.Val573PhefsTer16) with incomplete penetrance in the parent—supports autosomal dominant inheritance with haploinsufficiency (PMID:35367634; PMID:40688221).

The variant spectrum is broad: pathogenic missense changes cluster in transmembrane and linker domains (gain‐of‐function) or in amino‐terminal/ligand‐binding domains (loss‐of‐function), while null alleles uniformly lead to haploinsufficiency. Recurrent de novo missense variants and multiple loss‐of‐function alleles have been observed across diverse populations, with consistent genotype–phenotype correlations.

Functional studies yield concordant evidence for both gain‐ and loss‐of‐function mechanisms. Null and misATD+LBD variants produce reduced current density and prolonged decay in Grin2a+/- rat cortical neurons without GluN2B upregulation (PMID:30544257), whereas misTMD+Linker variants enhance agonist potency, decrease Mg2+ block and prolong synaptic responses in Xenopus oocytes and mammalian cells (PMID:24504326). Positive allosteric modulators can partially restore function in loss‐of‐function variants, highlighting therapeutic avenues.

Conflicting evidence is limited to the GluN2A R586K variant, which exhibited no functional effect on receptor properties and is unlikely to contribute to pathogenesis (PMID:28459106). This single non‐contributory finding does not outweigh the extensive pathogenic data.

Integration of genetic, segregation and mechanistic data supports a Strong ClinGen classification for GRIN2A in autosomal dominant neurodevelopmental disorder. Early GRIN2A testing in children with speech delay or epilepsy-aphasia phenotypes enables precise diagnosis and guides variant‐specific therapeutic strategies.

Key Take-home: Heterozygous GRIN2A variants should be considered in pediatric neurodevelopmental syndromes with speech impairment or epileptic features, and functional classification can inform precision medicine.

References

• Brain • 2019 • GRIN2A-related disorders: genotype and functional consequence predict phenotype. PMID:30544257
• European journal of medical genetics • 2022 • Mild neurological phenotype in a family carrying a novel N-terminal null GRIN2A variant. PMID:35367634
• Translational pediatrics • 2025 • Neurodevelopmental disorder due to a frameshift mutation in the GRIN2A gene: a case report. PMID:40688221
• Wellcome open research • 2017 • Functional assessment of the NMDA receptor variant GluN2A R586K. PMID:28459106

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