Human Gene Module / Chromosome 4 / WDFY3

WDFY3WD repeat and FYVE domain containing 3

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
37 / 0
Aliases
WDFY3, ALFY,  ZFYVE25
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
4q21.23
Associated Disorders
-
Relevance to Autism

A de novo nonsense variant in the WDFY3 gene was identified in a male ASD proband from the Simons Simplex Collection (Iossifov et al., 2012). Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (Orosco et al., 2014).

Molecular Function

This gene encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of these aggregated proteins. However, it is not necessary for starvation-induced macroautophagy.

Reports related to WDFY3 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology. Orosco LA , et al. (2014) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
6 Recent Recommendation ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size. Kadir R , et al. (2016) No -
7 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
8 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
9 Support Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t... Nilsson D , et al. (2016) Yes Chiari I-anomaly
10 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
11 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
12 Support Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy. Napoli E , et al. (2018) No -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2932A>T p.Arg978Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.9397G>A p.Ala3133Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1463A>T p.Lys488Met missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.8319T>A p.Tyr2773Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10435C>T p.Arg3479Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10072C>T p.Arg3358Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10072C>T p.Arg3358Trp missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2773C>T p.Arg925Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.383C>T p.Thr128Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.132G>C p.Gln44His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8435G>A p.Arg2812His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9445C>T p.Arg3149Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8878C>T p.Arg2960Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.548G>A p.Arg183Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.197C>T p.Pro66Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9622G>A p.Glu3208Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4064T>C p.Leu1355Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.85C>T p.Arg29Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1792C>T p.Leu598Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3382C>T p.Arg1128Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.8090G>A p.Arg2697Lys missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.9726+1G>- - splice_site_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.5278C>T p.Gln1760Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.881G>A p.Ser294Asn missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.5525dup p.Leu1842PhefsTer52 frameshift_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.881G>A p.Ser294Asn missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.8268G>A p.Met2756Ile missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3040G>A p.Gly1014Arg missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.6347T>A p.Leu2116Gln missense_variant Unknown - - 27824329 Wang T , et al. (2016)
- - translocation De novo - - 27862604 Nilsson D , et al. (2016)
c.2765C>T p.Pro922Leu missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.1948G>A p.Gly650Arg missense_variant De novo - Multiplex 28263302 C Yuen RK , et al. (2017)
C>G p.? splice_site_variant Familial - Simplex 28263302 C Yuen RK , et al. (2017)
c.9711_9714del p.Ser3237fs frameshift_variant Unknown - Multiplex 28263302 C Yuen RK , et al. (2017)
c.10570C>T p.Arg3524Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.3382C>T p.Arg1128Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.8864_8867dupTTGG p.Phe2957Trpfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

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.

4/1/2017
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant was identifed in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016, while a fourth de novo LoF variant was observed in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

1/1/2017
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant was identifed in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016, while a fourth de novo LoF variant was observed in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

10/1/2016
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant was identifed in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016, while a fourth de novo LoF variant was observed in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

4/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012).

Krishnan Probability Score

Score 0.57936438906494

Ranking 593/25841 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 1

Ranking 4/18225 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
Iossifov Probability Score

Score 0.994

Ranking 19/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.020362116716918

Ranking 34/18665 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 40

Ranking 49/461 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 0.27176873943254

Ranking 3158/20870 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 WDFY3(1 CNVs)
4q21.23 5 Deletion 11  /  31
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
DPYSL4 Dihydropyrimidinase-related protein 4 Human Protein Binding 10570 O14531
SLC2A12 Solute carrier family 2, facilitated glucose transporter member 12 Human Protein Binding 154091 Q8TD20
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