Human Gene Module / Chromosome X / GLRA2

GLRA2glycine receptor, alpha 2

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
5 / 14
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
Xp22.2
Associated Disorders
SCZ
Relevance to Autism

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011). Rare variants experimentally shown to affect GLRA2 function in vitro and in vivo were identified in ASD probands in Pilorge et al., 2015.

Molecular Function

A ligand-gated channel mediating a chloride-dependent inhibitory neurotransmission

Reports related to GLRA2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Alternative splicing generates two variants of the alpha 1 subunit of the inhibitory glycine receptor. Malosio ML , et al. (1991) No -
2 Recent Recommendation Glycinergic transmission in the Mammalian retina. Wssle H , et al. (2009) No -
3 Recent Recommendation Differential expression of glycine receptor subunits in the rat basolateral and central amygdala. Delaney AJ , et al. (2009) No -
4 Recent Recommendation Ginkgolide X is a potent antagonist of anionic Cys-loop receptors with a unique selectivity profile at glycine receptors. Jensen AA , et al. (2010) No -
5 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Piton A , et al. (2010) Yes SCZ
6 Support Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. Chahrour MH , et al. (2012) Yes -
7 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
8 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
10 Recent Recommendation Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism. Pilorge M , et al. (2015) Yes -
11 Support Structure-Function Analysis of the GlyR 2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function. Zhang Y , et al. (2017) No -
12 Support 2-glycine receptors modulate adult hippocampal neurogenesis and spatial memory. Lin MS , et al. (2017) No -
13 Support Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic ... Comhair J , et al. (2018) No -
14 Highly Cited Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs. Racca C , et al. (1997) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Simplex 26370147 Pilorge M , et al. (2015)
c.16G>C p.Val6Leu missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1049G>T p.Arg350Leu missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.407A>G p.Asn136Ser missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.458G>A p.Arg153Gln missense_variant De novo - Multiplex 26370147 Pilorge M , et al. (2015)
c.1261A>G p.Ile421Val missense_variant Familial - Multiplex 22511880 Chahrour MH , et al. (2012)
c.887C>T p.Thr296Met missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
4

Minimal Evidence

5

Score Delta: Score remained at 5.4

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2017
5
icon
5

Score remained at 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

7/1/2017
5
icon
5

Score remained at 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

1/1/2015
5
icon
5

Score remained at 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

7/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Krishnan Probability Score

Score 0.5019027997471

Ranking 1994/25841 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.
ExAC Score

Score 0.90858763229945

Ranking 3157/18225 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
Sanders TADA Score

Score 0.72931669676599

Ranking 1368/18665 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).
Larsen Cumulative Evidence Score

Score 5

Ranking 280/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.060924754799852

Ranking 6962/20870 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.
CNVs associated with GLRA2(1 CNVs)
Xp22.2 16 Deletion-Duplication 24  /  86
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