Human Gene Module / Chromosome X / GPC4

GPC4glypican 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 2
Rare Variants / Common Variants
2 / 0
Aliases
GPC4, K-glypican
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
Xq26.2
Associated Disorders
-
Relevance to Autism

Previously unreported homozyous variants in the same human accelerated region (HAR) within an intron of the GPC4 gene were identified in individuals affected with ASD and ID from two unrelated consanguineous families; interaction data revealed interactions between this HAR and the GPC4 promoter in adult human brain tissue, and luciferase reporter assays demonstrated that both variants reduced regulatory activity in N2A cells (Doan et al., 2016).

Molecular Function

This gene encodes a cell surface proteoglycan that bears heparan sulfate and may be involved in the development of kidney tubules and of the central nervous system.

Reports related to GPC4 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
2 Recent Recommendation Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation. Farhy-Tselnicker I , et al. (2017) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
T>C - intron_variant;intron_variant Familial Both parents Unknown 27667684 Doan RN , et al. (2016)
delT - intron_variant;intron_variant Familial Both parents Unknown 27667684 Doan RN , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Score remained at 3.4

3

Suggestive Evidence

See all Category 3 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
3
icon
3

Score remained at 3

Description

Previously unreported homozyous variants in the same human accelerated region (HAR) within an intron of the GPC4 gene were identified in individuals affected with ASD and ID from two unrelated consanguineous families; interaction data revealed interactions between this HAR and the GPC4 promoter in adult human brain tissue, and luciferase reporter assays demonstrated that both variants reduced regulatory activity in N2A cells (Doan et al., 2016).

10/1/2016
icon
3

Increased from to 3

Description

Previously unreported homozyous variants in the same human accelerated region (HAR) within an intron of the GPC4 gene were identified in individuals affected with ASD and ID from two unrelated consanguineous families; interaction data revealed interactions between this HAR and the GPC4 promoter in adult human brain tissue, and luciferase reporter assays demonstrated that both variants reduced regulatory activity in N2A cells (Doan et al., 2016).

Krishnan Probability Score

Score 0.49103297284304

Ranking 5835/25841 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 0.94847697481638

Ranking 2715/18225 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 0.93622413019359

Ranking 13127/18665 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).
Zhang D Score

Score 0.13925807444939

Ranking 5370/20870 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 GPC4(1 CNVs)
Xq26.2 12 Deletion-Duplication 19  /  41
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