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Genetic epilepsy syndromes

Gene: GRIA2

Amber List (moderate evidence)

GRIA2 (glutamate ionotropic receptor AMPA type subunit 2)
EnsemblGeneIds (GRCh38): ENSG00000120251
EnsemblGeneIds (GRCh37): ENSG00000120251
OMIM: 138247, Gene2Phenotype
GRIA2 is in 2 panels

3 reviews

Helen Lord (Oxford Medical Genetics Laboratories)

I don't know

Not linked to disease on OMIM. Nothing on HGMDPro assocated with epilepsy phenotype. Salpietro et al, 2019 (31300657) - het de novo GRIA2 variants in 28 unrelated individuals with ID, ASD, Rett syndrome-like features, and seizures or developmental epileptic encephalopathy 12/28 cases had seizures (43% of cases).
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Rebecca Foulger (Genomics England curator)

I don't know

Comment on list classification: Changed rating of GRIA2 from Grey to Amber based on Amber post-Webex review from Helen Lord. Currently insufficient evidence for a diagnostic rating.
Created: 9 Sep 2019, 11:21 a.m. | Last Modified: 9 Sep 2019, 11:21 a.m.
Panel Version: 1.324
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
GRIA2 is not yet associated with a disorder in OMIM or Gene2Phenotype.
Created: 7 Aug 2019, 8:34 p.m. | Last Modified: 7 Aug 2019, 8:34 p.m.
Panel Version: 1.194
PMID:8938126- animal model doesn't report seizures: GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.
Created: 7 Aug 2019, 8:33 p.m. | Last Modified: 15 Aug 2019, 8:34 a.m.
Panel Version: 1.224
PMID:31300657: As noted by Konstantinos Varvagiannis, Salpietro et al., 2019 report 28 unrelated individuals recruited through different studies (including Decipher) with ID and neurodevelopmental anomalies, and heterozygous de novo variants in GRIA2. 12/28 individuals had seizures, though in one case only one seizure episode was recorded (patient 23) and in one case the only seizures were febrile (patient 5). For the seizure patients, missense variants were most frequently reported (Supplementary Table 1) with patient 25 harbouring a microdeletion spanning multiple genes, including GRIA2.
Created: 7 Aug 2019, 8:29 p.m. | Last Modified: 7 Aug 2019, 8:29 p.m.
Panel Version: 1.193

Konstantinos Varvagiannis (Other)

I don't know

There is a recent publication by Salpietro et al. (2019 - PMID: 31300657) reporting on 28 unrelated individuals. Seizures were observed in 12/28 (~40%), so the gene may also be relevant for the current panel.

The phenotype overall corresponds to a NDD disorder with DD, ID (universal feature in those with appropriate age for evaluation, relevant severity), ASD, Rett-like features and seizures. All types of variants were reported (15 missense, 2 splice-site, 1 in-frame del, 1 stopgain, 2 frameshift ones, 3 CNVs spanning GRIA2 and other genes, the latter more tolerant to LoF). The role of this gene (encoding AMPA receptor GluA2 subunit), functional studies (loss of function demonstrated for the majority of mutations, though by multiple molecular mechanisms), overlapping phenotype with disorders due to other ionotropic glutamate receptor subunit genes (eg. GRIA3/4 - ID with or without seizures), animal models (PMID cited: 8938126) are among the arguments provided.
Sources: Literature
Created: 7 Aug 2019, 5:42 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual disability; Seizures; Autism

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Amber
Phenotypes
  • Intellectual disability
  • Seizures
  • myoclonic seizures
  • status epilepticus
  • tonic-clonic seizures
  • focal seizures
OMIM
138247
Clinvar variants
Variants in GRIA2
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to GRIA2.

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to GRIA2.

9 Sep 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: gria2 has been classified as Amber List (Moderate Evidence).

7 Aug 2019, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: GRIA2 were changed from Intellectual disability; Seizures; Autism to Intellectual disability; Seizures; myoclonic seizures; status epilepticus; tonic-clonic seizures; focal seizures

7 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: GRIA2 was added gene: GRIA2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: GRIA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GRIA2 were set to 31300657 Phenotypes for gene: GRIA2 were set to Intellectual disability; Seizures; Autism Penetrance for gene: GRIA2 were set to unknown Review for gene: GRIA2 was set to AMBER