Human Gene Module / Chromosome 4 / WDFY3

WDFY3WD repeat and FYVE domain containing 3

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
19 / 24
Rare Variants / Common Variants
75 / 0
EAGLE Score
17.2
Strong Learn More
Aliases
WDFY3, ALFY,  ZFYVE25
Associated Syndromes
-
Chromosome Band
4q21.23
Associated Disorders
DD/NDD, ADHD, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

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). Transmission and de novo association (TADA) analysis of ASD cases and controls from the Autism Sequencing Consortium and the Simons Simplex Collection in Sanders et al., 2015 identified WDFY3 as an ASD candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified WDFY3 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to WDFY3 (24 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 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
7 Recent Recommendation ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size Kadir R , et al. (2016) No -
8 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
10 Support Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation Nilsson D , et al. (2016) Yes Chiari I-anomaly
11 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
12 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
13 Support Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy Napoli E , et al. (2018) No -
14 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
15 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes DD, epilepsy/seizures
16 Recent Recommendation Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size Le Duc D , et al. (2019) No ASD, ADHD
17 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
18 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
19 Support - Mahjani B et al. (2021) Yes -
20 Support - Chen S et al. (2021) Yes Epilepsy/seizures
21 Support - Schaaf ZA et al. (2022) No -
22 Recent Recommendation - Zhou X et al. (2022) Yes -
23 Support - Costa CIS et al. (2023) Yes -
24 Support - Wang J et al. (2023) Yes -
Rare Variants   (75)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27862604 Nilsson D , et al. (2016)
- - copy_number_loss De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.6073+2T>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.8501C>G p.Ser2834Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.5278C>T p.Gln1760Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.9505C>T p.Arg3169Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.1856C>T p.Thr619Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1900G>C p.Val634Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2296A>G p.Ser766Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.881G>A p.Ser294Asn missense_variant De novo - - 27824329 Wang T , et al. (2016)
C>G p.? splice_site_variant Familial - Simplex 28263302 C Yuen RK et al. (2017)
c.8320T>A p.Trp2774Arg missense_variant De novo - - 34800434 Chen S et al. (2021)
c.3007C>T p.Arg1003Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4141C>T p.Arg1381Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7728A>G p.Ile2576Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8399T>G p.Leu2800Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.10156T>C p.Trp3386Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6347T>A p.Leu2116Gln missense_variant Unknown - - 27824329 Wang T , et al. (2016)
c.9726+1del - splice_site_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.9312G>A p.Val3104%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.8596+6T>C - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8320T>A p.Trp2774Arg missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.841G>T p.Glu281Ter stop_gained De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.863G>T p.Cys288Phe missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.3382C>T p.Arg1128Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.5242C>T p.Arg1748Ter stop_gained De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.7917C>A p.Tyr2639Ter stop_gained De novo - Simplex 37280359 Costa CIS et al. (2023)
c.9231T>G p.Ser3077= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1681A>G p.Asn561Asp missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.10570C>T p.Arg3524Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.3382C>T p.Arg1128Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2932A>T p.Arg978Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.4141C>T p.Arg1381Trp missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.4715T>G p.Phe1572Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.881G>A p.Ser294Asn missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.8878C>T p.Arg2960Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9445C>T p.Arg3149Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6543del p.Asp2182MetfsTer16 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2765C>T p.Pro922Leu missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.85C>T p.Arg29Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.10179G>A p.Arg3393%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3040G>A p.Gly1014Arg 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.6610T>C p.Trp2204Arg missense_variant De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.7672G>A p.Gly2558Ser missense_variant De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.8467C>T p.Arg2823Trp missense_variant De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.197C>T p.Pro66Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1948G>A p.Gly650Arg missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.8090G>A p.Arg2697Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.548G>A p.Arg183Gln missense_variant Unknown - Unknown 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.1792C>T p.Leu598Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9397G>A p.Ala3133Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.4064T>C p.Leu1355Ser 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.9445C>T p.Arg3149Ter stop_gained Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.545G>A p.Arg182His missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1978G>C p.Ala660Pro missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.8268G>A p.Met2756Ile missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.9496C>T p.Arg3166Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.8319T>A p.Tyr2773Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5525dup p.Leu1842PhefsTer52 frameshift_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1990del p.Ser664LeufsTer2 frameshift_variant De novo - Multiplex 31327001 Le Duc D , et al. (2019)
c.749A>G p.Asn250Ser missense_variant De novo - Multi-generational 31327001 Le Duc D , et al. (2019)
c.132G>C p.Gln44His missense_variant Familial Maternal 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.2773C>T p.Arg925Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8435G>A p.Arg2812Lys missense_variant Familial Maternal 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.10435C>T p.Arg3479Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7375_7376dup p.Ser2459ArgfsTer30 frameshift_variant De novo - Simplex 31327001 Le Duc D , et al. (2019)
c.10072C>T p.Arg3358Trp missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.9711_9714del p.Asp3238GlufsTer25 frameshift_variant Unknown - Multiplex 28263302 C Yuen RK et al. (2017)
c.8865_8866insTGGT p.Gly2956TrpfsTer5 frameshift_variant De novo - Multiplex 28554332 Bowling KM , et al. (2017)
c.9017_9027del p.Asp3006AlafsTer21 frameshift_variant Familial Paternal Multi-generational 31327001 Le Duc D , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

1/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
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).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
2
icon
2

Decreased from 2 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).

Reports Added
[Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2019
2
icon
2

Decreased from 2 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).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
1/1/2019
2
icon
2

Decreased from 2 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).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2018
2
icon
2

Decreased from 2 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).

Reports Added
[Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy.2018]
4/1/2017
2
icon
2

Decreased from 2 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).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.2016] [Genome-wide characteristics of de novo mutations in autism2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t...2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
2
icon
2

Decreased from 2 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).

Reports Added
[Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t...2016]
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).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
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).

Reports Added
[Genome-wide characteristics of de novo mutations in autism2016]
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).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.2016]
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).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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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