Human Gene Module / Chromosome 11 / GRIK4

GRIK4Glutamate receptor, ionotropic, kainate 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
9 / 0
Aliases
GRIK4, EAA1,  GRIK,  GluK4,  KA1
Associated Syndromes
-
Chromosome Band
11q23.3
Associated Disorders
-
Relevance to Autism

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIK4 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features Aller MI , et al. (2015) No -
3 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities Koromina M , et al. (2019) No -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- p.Leu825Trp missense_variant Unknown - Unknown 31844109 Koromina M , et al. (2019)
- p.Tyr555Asn missense_variant Unknown - Unknown 31844109 Koromina M , et al. (2019)
c.1856G>A p.Arg619His missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
c.293C>A p.Ser98Ter stop_gained Unknown - Unknown 31844109 Koromina M , et al. (2019)
c.398G>T p.Arg133Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1804G>A p.Gly602Arg missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.-50-6585G>T - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2713_2727delinsGCT p.Leu905_Glu908del inframe_deletion Unknown - - 28554332 Bowling KM , et al. (2017)
c.601del p.Thr201ProfsTer29 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

1/1/2020
3
icon
3

Decreased from 3 to 3

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

Reports Added
[Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities.2019]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
5
icon
4

Decreased from 5 to 4

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). A compound heterozygous mutation in GRIK4 consisting of a rare potentially damaging missense variant and a rare in-frame deletion variant was identified in an individual presenting with intellectual disability, seizures, autism spectrum disorder, and speech delay (Bowling et al., 2017).

4/1/2017
5
icon
5

Decreased from 5 to 5

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Reports Added
[Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2015
icon
5

Increased from to 5

Description

Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Krishnan Probability Score

Score 0.49157801071691

Ranking 5391/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.63084615815737

Ranking 4841/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.91959544268449

Ranking 9029/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.24947321486877

Ranking 16372/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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