GRIN2A

Gene Facts

• HGNC Symbol: GRIN2A (HGNC:4585)
• HGNC Name: glutamate ionotropic receptor NMDA type subunit 2A
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: NMDAR2A
• Alias symbols: GluN2A, NR2A
• %HI: 13.34
• pLI: 1
• LOEUF: 0.27
• Cytoband: 16p13.2
• Genomic Coordinates:

  GRCh37/hg19:	chr16:9847261-10276765
  GRCh38/hg38:	chr16:9753404-10182908

• MANE Select Transcript: NM_001134407.3 ENST00000330684.4
• Function: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:8768735, PubMed:26919761, PubMed:26875626, PubMed:28105280). Sensitivity to glutamate and channel kinetics depend... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-24459
• ClinGen Curation ID: CCID:007252
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/27/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• complex neurodevelopmental disorder

HI Evidence

• PUBMED: 20890276
  Endele et al. (2010) describes a 4-year-old male with mild to moderate intellectual disability, abnormal EEG, behavioral anomalies, muscular hypotonia, and facial dysmorphism with a heterozygous c.652C>T (p.Q218X) variant in the GRIN2A gene (subject 6-1). Proband’s mother (subject 6-2) and maternal grandmother (subject 6-3) also carried the c.652C>T (p.Q218X) variant, and both had a history of seizures during early childhood and learning difficulties. RNA analysis of the proband revealed monoallelic expression of the wild-type allele, suggesting that GRIN2A transcripts with the p.Q218X were efficiently degraded by nonsense-mediated mRNA decay. This variant was not observed in 360 controls.
• PUBMED: 23933820
  Lesca et al (2013) describes a male proband with autism and continuous spike and waves during slow-wave sleep syndrome (CSWSS, epileptic encephalopathy) with a heterozygous nonsense variant in GRIN2A (p.Tyr1387X). The proband’s mother and paternal uncle both experienced seizures in childhood that resolved before adulthood (family 4). The proband’s mother was found to be a carrier of the p.Tyr1387X variant; the paternal uncle was not tested. The authors also describe three brothers with CSWSS and mild verbal dyspraxia with a heterozygous 75-kb deletion, deleting exons 1-2 of GRIN2A (family 2). The deletion was inherited from the unaffected mother. The authors go on to describe two brothers and a sister with Landau-Kleffner syndrome (LKS) and verbal dyspraxia with a heterozygous 15-kb deletion, deleting exon 10 of the GRIN2A (family 3). The deletion was inherited from the mother with benign childhood epilepsy.
• PUBMED: 23933819
  Lemke et al (2013) describes three independent families with nonsense variants in GRIN2A and three independent families with frameshift variants in GRIN2A. Family Brn-index2 includes a female proband (III.2) with Landau-Kleffner syndrome with a heterozygous c.2041C>T (p.R681X) variant. This variant was inherited from the mother (ii.2) with learning disabilities. The variant was also observed in two maternal aunts, one with learning disabilities (ii.5) the other unaffected (ii.4). Family Hel-1 includes a male (II.3) and female (II.2) sibling with continuous spike and waves during slow-wave sleep syndrome and Panayiotopoulos syndrome, respectively with a heterozygous c.1001T>A (p.L334X) variant. This variant was inherited from the mother (I.1) with partial epilepsy. Family Hel-5 includes a male (II.2) and female (II.1) sibling with benign epilepsy with centrotemporal spikes/continuous spike and waves during slow-wave sleep syndrome and centrotemporal spikes, respectively with a heterozygous c.2829C>G (p.T943X) variant. This variant was inherited from the mother (I.1) with benign epilepsy with centrotemporal spikes. Family Lon-2 includes a male proband (II.1) with continuous spike and waves during slow-wave sleep syndrome with a heterozygous c.2334_2338delCTTGC (p.L779Sfs*5) variant. This variant was inherited from the father (I.2) with unknown phenotype. Family D202 includes a male (II.1) and female (II.2) sibling with benign epilepsy with centrotemporal spikes and a heterozygous c.90delTinsTT (p.P31Sfs*107) variant. This variant was inherited from an unaffected mother (I.2). The father (I.1) was observed to have two wild-type alleles, but presented with benign epilepsy with centrotemporal spikes. The female sibling’s monozygotic twin (II.3) was found to have the variant with unknown phenotype. Family E256 includes two male siblings (II.1 and II.2)with benign epilepsy with centrotemporal spikes and a heterozygous c.1585delG (p.V529Wfs*22) variant. This variant was inherited from a mother (I.2) with benign epilepsy with centrotemporal spikes. Three probands were described having variable deletions of GRIN2A which appeared to delete exon 2-11 (EPW1111-1), exon 9-11 (NB3), and exon 1 (72-3), respectively (supplementary table 3 and supplementary figure 4). These probands presented with benign epilepsy with centrotemporal spikes (EPW1111-1 and 72-3) and atypical benign partial epilepsy (NB3). Parental testing was not performed. The authors speculate that families in which the variant was inherited from an unaffected parent may represent incomplete penetrance or mosaicism.
• PUBMED: 23933818
  Carvill et al (2013) describes a three-generation family with autosomal dominant rolandic epilepsy with speech dyspraxia with a heterozygous 5’ splice site c.1007+1G>A (predicted p.F139Ifs*15) variant in GRIN2A (family A). A second, independent family was found to have the same variant (family C), but with syndrome of epileptic encephalopathy with continuous spike and wave during slow-wave sleep. The variant was also found to segregate with phenotype in both families and was not observed in 6,500 control exomes.
• PUBMED: 28109652
  Stülpnagel et al (2017) describes three unrelated probands with heterozygous truncation variants in GRIN2A. Patient 2 was diagnosed with continuous spike waves during slow wave sleep with a heterozygous c.1586delT (p.F528Gfs*22) variant. Patient 10 was diagnosed with atypical benign partial epilepsy with a heterozygous c.1818G>A (p.W606X) variant. Patient 4 was diagnosed with Landau Kleffner Syndrome with a de novo heterozygous c.2407G>T (p.G803*) variant.

• HI Evidence Comments: Heterozygous null variants in GRIN2A have been associated with various neurodevelopmental presentations, including speech disorders, epilepsy (including Landau-Kleffner syndrome, epileptic encephalopathy with continuous spike-and-wave during sleep, childhood epilepsy with centrotemporal spikes, etc.), developmental delays, and intellectual disabilities. Incomplete penetrance and variable expressivity have been observed; presentations/severity may also vary within families. See GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK385627/) for additional information. Other relevant information includes: PMID 20384727: Reutlinger et al (2010) describes three individuals with epilepsy, developmental disabilities, and variable dysmorphic features or congenital anomalies who each had overlapping deletions involving GRIN2A and surrounding genes. When the three deletions were compared, GRIN2A was found to be the only gene located within the smallest region of overlap. Two of the three deletions were de novo; inheritance was not assessed for the third. PMID 28182669: Gao et al (2017) describes an 11-year-old female with partial seizures with seizures restricted to periods of sleep. In addition, the proband exhibited developmental delay with motor and cognitive function regression, especially verbal dyspraxia. Proband was found to have c.S191G>A (p.D731N) variant in GRIN2A. The same variant was observed in two additional unrelated probands reported elsewhere (Family 8, PMID: 23933820, Lesca et al (2013); Family 1, PMID: 25046240, Dyment et al (2015)). The authors conclude, “Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition. The combined effects reduce NMDAR function.” PMID 26633542: Retterer et al (2016) reports the diagnostic yield of whole-exome sequencing in 3,040 consecutive cases at a single clinical laboratory. Within their cohort they identified two individuals with truncating variants in GRIN2A (c.2848C>T, p.Q950* and c.627delC, p.F210Lfs*10) presenting with either “abnormality of the nervous system” or “seizures”, respectively. PMID 29358611: Bobbili et al (2018) reports on whole-exome sequencing of 194 unrelated patients with typical and atypical Rolandic epilepsy and 567 ethnically matched population controls. Within their cohort they identified an individual with a c.1344_1345insCCTA (p.G449Pfs*4) variant in GRIN2A. PMID 30544257: Strehlow et al (2019) reviewed the genotype and phenotypes of previously published and unpublished patients with GRIN2A variants in regards to intellectual development, seizures/electroencephalography, language/speech, other neurological and psychiatric phenotypes, and MRI findings. The authors concluded that, “null variants lead to less severe developmental phenotypes”.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity