Human Gene Module / Chromosome 12 / WNT1

WNT1Wingless-type MMTV integration site family, member 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
4 / 1
Aliases
WNT1, BMND16,  INT1,  OI15
Associated Syndromes
-
Chromosome Band
12q13.12
Associated Disorders
-
Relevance to Autism

A missense variant in the WNT1 gene (p.Ser88Arg) that results in increased activity was found to be overrepresented in a combined sample of ASD cases compared to controls [8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048] (Martin et al., 2013). Prenatal valproate exposure in rats, which is used as an induced animal model of ASD, increases WNT1 expression (Wang et al., 2010; Go et al., 2012).

Molecular Function

This gene is a member of the WNT gene family, which consists of structurally related genes which encode secreted signaling proteins involved in multiple developmental processes. Studies in mouse indicate that the Wnt1 protein plays a role in CNS development and functions in the induction of the mesencephalon and cerebellum.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to WNT1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Demethylation of specific Wnt/?-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure Wang Z , et al. (2010) No -
2 Recent Recommendation Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3?/?-catenin pathway Go HS , et al. (2012) No -
3 Primary A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation Martin PM , et al. (2013) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Chan AJS et al. (2022) Yes Autosomal recessive osteogenesis imperfecta type X
6 Recent Recommendation - Li Y et al. (2023) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.456G>T p.Thr152%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.104+1G>A - splice_site_variant Familial Both parents Simplex 37658228 Li Y et al. (2023)
c.793C>T p.Arg265Cys missense_variant Familial Unknown Simplex 24002087 Martin PM , et al. (2013)
c.287_300del p.Gln96ProfsTer54 frameshift_variant Familial Both parents - 36309498 Chan AJS et al. (2022)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.264T>A p.Ser88Arg missense_variant - - - 24002087 Martin PM , et al. (2013)
SFARI Gene score
2

Strong Candidate

A missense variant in the WNT1 gene (p.Ser88Arg) that results in increased activity was found to be overrepresented in a combined sample of ASD cases compared to controls [8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048] (Martin et al., 2013). Prenatal valproate exposure in rats, which is used as an induced animal model of ASD, increases WNT1 expression (Wang et al., 2010; Go et al., 2012).

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

A missense variant in the WNT1 gene (p.Ser88Arg) that results in increased activity was found to be overrepresented in a combined sample of ASD cases compared to controls [8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048] (Martin et al., 2013). Prenatal valproate exposure in rats, which is used as an induced animal model of ASD, increases WNT1 expression (Wang et al., 2010; Go et al., 2012).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A missense variant in the WNT1 gene (p.Ser88Arg) that results in increased activity was found to be overrepresented in a combined sample of ASD cases compared to controls [8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048] (Martin et al., 2013). Prenatal valproate exposure in rats, which is used as an induced animal model of ASD, increases WNT1 expression (Wang et al., 2010; Go et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2017
icon
4

Increased from to 4

Description

A missense variant in the WNT1 gene (p.Ser88Arg) that results in increased activity was found to be overrepresented in a combined sample of ASD cases compared to controls [8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048] (Martin et al., 2013). Prenatal valproate exposure in rats, which is used as an induced animal model of ASD, increases WNT1 expression (Wang et al., 2010; Go et al., 2012).

Krishnan Probability Score

Score 0.49502848495868

Ranking 3263/25841 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 0.10187896232073

Ranking 7825/18225 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 0.93063657566642

Ranking 11482/18665 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
Larsen Cumulative Evidence Score

Score 9

Ranking 216/461 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.
Original Source
Zhang D Score

Score -0.087241335348489

Ranking 11851/20870 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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