GRIN2A
Homo sapiens
Gene Name: glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Aliases: EPND, FESD, GluN2A, LKS, NMDAR2A, NR2A
Chromosome No: 16
Chromosome Band: 16p13.2
Genetic Category: Genetic Association--Rare single gene variant-Syndromic-Multigenic CNV-Functional-Rare single gene variant/Functional
Aliases: EPND, FESD, GluN2A, LKS, NMDAR2A, NR2A
Chromosome No: 16
Chromosome Band: 16p13.2
Genetic Category: Genetic Association--Rare single gene variant-Syndromic-Multigenic CNV-Functional-Rare single gene variant/Functional
Summary Statistics:
ASD Reports: 63
Recent Reports: 13
Annotated variants: 215
Associated CNVs: 4
Evidence score: 4
ASD Reports: 63
Recent Reports: 13
Annotated variants: 215
Associated CNVs: 4
Evidence score: 4
| Associated Disorders: |
|
Relevance to Autism
Genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).
Molecular Function
This gene encodes a member of the glutamate-gated ion channel protein family. The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit. NMDA receptors are both ligand-gated and voltage-dependent, and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades. Disruption of this gene is associated with focal epilepsy and speech disorder with or without cognitive disability.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.
ASD
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Positive Association
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
ASD, ADHD, BPD, MDD, SCZ
Support
Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.
ASD
Support
Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression
ASD
Developmental regression, epilepsy/seizures
Support
A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.
Psychomotor retardation
Support
Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.
Epilepsy
Support
Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies
DD, epilepsy/seizures
Support
Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility.
ASD, SCZ
Support
Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.
DD, ID, epilepsy/seizures
Support
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
ID, epilepsy/seizures
Support
A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.
Epilepsy/seizures, DD
Support
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Epilepsy
ID
Support
Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A
Epilepsy/seizures
DD, ID
Support
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
Epilepsy/seizures
Support
Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation.
DD, epilepsy/seizures
Support
Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation
Childhood apraxia of speech
DD
Support
Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy.
DD, epilepsy/seizures
Support
De novo GRIN2A variants associated with epilepsy and autism and literature review
ASD, DD, ID, epilepsy/seizures
ADD
Support
Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit.
Support
Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.
ASD
Support
Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability
ID
Marfanoid habitus
Support
Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.
Epilepsy/seizures
DD, ID
Support
Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID
Support
Diagnostic exome sequencing in persons with severe intellectual disability.
ID
Epilepsy, ASD
Support
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders
ASD
ADHD, DD, ID
Support
Autism risk in offspring can be assessed through quantification of male sperm mosaicism.
ASD
Support
Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.
Support
Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study
ADHD, epilepsy/seizures
Support
Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.
ASD, SCZ
Support
Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing
Pediatric Acute-Onset Neuropsychiatric Syndrome (P
Learning disability
Support
De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Support
An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking
Support
Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.
Specific language impairment
Support
Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...
Epilepsy
ADHD
Support
Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy
Epilepsy/seizures
DD
Support
A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder.
DD, ID
Movement disorder
Highly Cited
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
Highly Cited
Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.
Recent Recommendation
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Epilepsy
DD, ID
Recent Recommendation
Rare coding variants in ten genes confer substantial risk for schizophrenia
Schizophrenia
Recent Recommendation
GRIN2A mutations cause epilepsy-aphasia spectrum disorders.
Epilepsy
Recent recommendation
GRIN2A-related disorders: genotype and functional consequence predict phenotype.
DD/ID, epilepsy/seizures
Recent Recommendation
NMDA receptor function: subunit composition versus spatial distribution.
Recent Recommendation
Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.
Epilepsy/seizures
Recent Recommendation
Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors.
Recent Recommendation
Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.
ID
ASD, epilepsy/seizures
Recent Recommendation
Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses.
Recent Recommendation
Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.
Recent Recommendation
Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons.
Recent Recommendation
GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.
Epilepsy
Rare
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
GEN110R014
splice_site_variant
c.1007+1G>A
p.Phe139IlefsTer15
Familial
Maternal and paternal
Multi-generational
GEN110R015
splice_site_variant
c.1007+1G>A
p.Phe139IlefsTer15
Familial
Paternal
Simplex
GEN110R016
initiator_codon_variant
c.2T>C
p.Met1?
Familial
Paternal
Multiplex
GEN110R017
missense_variant
c.1592C>T
p.Thr531Met
Familial
Maternal
Multiplex
GEN110R019
stop_gained
c.2041C>T
p.Arg681Ter
Familial
Maternal
Extended multiplex
GEN110R030
frameshift_variant
c.2334_2338del
p.Leu779SerfsTer5
Familial
Paternal
Simplex
GEN110R033
missense_variant
c.236C>G
p.Pro79Arg
Familial
Maternal
Multi-generational
GEN110R039
missense_variant
c.2113A>G
p.Met705Val
Familial
Maternal
Multiplex
GEN110R041
missense_variant
c.2200G>C
p.Val734Leu
Familial
Paternal
Multiplex
GEN110R044
missense_variant
c.2710A>T
p.Ile904Phe
Familial
Paternal
Multiplex
GEN110R045
frameshift_variant
c.90dup
p.Pro31SerfsTer107
Familial
Maternal
Multi-generational
GEN110R046
frameshift_variant
c.1585del
p.Val529TrpfsTer22
Familial
Maternal
Multiplex
GEN110R047
inframe_deletion
c.1639_1641del
p.Ser547del
Unknown
Not maternal
Multiplex
GEN110R052
splice_site_variant
c.1123-2A>G
Familial
Maternal
Multi-generational
GEN110R055
stop_gained
c.4161C>A
p.Tyr1387Ter
Familial
Maternal
Extended multiplex
GEN110R061
missense_variant
c.2146G>A
p.Ala716Thr
Familial
Maternal
Multi-generational
GEN110R071
stop_gained
c.652C>T
p.Gln218Ter
Familial
Maternal
Multi-generational
GEN110R077
frameshift_variant
c.1586del
p.Val529GlyfsTer22
Unknown
Multi-generational
GEN110R089
missense_variant
c.2063G>C
p.Gly688Ala
De novo
Possible multi-generational
GEN110R102
missense_variant
c.1928C>A
p.Ala643Asp
De novo (germline mosaicism)
Multiplex
GEN110R143
frameshift_variant
NM_001009184.2:c.445_448delGCGTins69
p.Ala149SerfsTer8
Unknown
GEN110R152
splice_site_variant
c.1123-1G>T
Familial
Maternal
Multi-generational
GEN110R157
frameshift_variant
c.1686del
p.Phe562LeufsTer2
Familial
Paternal
GEN110R162
stop_gained
c.2041C>T
p.Arg681Ter
Familial
Paternal
Multi-generational
GEN110R165
frameshift_variant
c.2341_2343delinsAT
p.Gln781IlefsTer27
Unknown
Common
Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
GEN110C003
3_prime_UTR_variant
rs1014531
c.*1212C>T;c.*1418C>T
IMGSAC
Discovery
GEN110C004
intron_variant
rs8058295
c.2168+4735G>T;c.2324+4735G>T;c.1697+4735G>T
A/C
Pyschiatrics Genomic Consortium (PGC): 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls
Discovery
GEN110C005
intron_variant
rs7191183
c.2169-7736A>G;c.2325-7736A>G;c.1698-7736A>G
40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets)
Discovery
