Human Gene Module / Chromosome 10 / WAC

WACWW domain containing adaptor with coiled-coil

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
15 / 30
Rare Variants / Common Variants
62 / 0
EAGLE Score
15
Strong Learn More
Aliases
WAC, RP11-48B24.1,  BM-016,  PRO1741,  Wwp4
Associated Syndromes
DeSanto-Shinawi syndrome, Desanto-Shinawi syndrome, DD
Chromosome Band
10p12.1
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. 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 WAC as an ASD candidate gene with a false discovery rate (FDR) 0.01; a FDR 0.01 was replicated for this gene following TADA analysis in Satterstrom et al., 2020. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012). 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 WAC as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription. Regulates the cell-cycle checkpoint activation in response to DNA damage. Positive regulator of amino acid starvation-induced autophagy. May negatively regulate the ubiquitin proteasome pathway.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to WAC (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11 Wentzel C , et al. (2011) No -
2 Support Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion Okamoto N , et al. (2012) No -
3 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No -
4 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
6 Recent Recommendation WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome DeSanto C , et al. (2015) No Hypotonia, behavioral problems
7 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder Tammimies K , et al. (2015) Yes -
8 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
9 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
10 Recent Recommendation De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila Lugtenberg D , et al. (2016) No ASD
11 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
12 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
13 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
14 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
15 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Behavioral anomalies, hypotonia
16 Support Three patients with DeSanto-Shinawi syndrome: Further phenotypic delineation Uehara T , et al. (2018) No -
17 Support DeSanto-Shinawi Syndrome: First Case in South America Vanegas S , et al. (2018) No -
18 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
19 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
20 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
21 Support - Brunet T et al. (2021) No -
22 Support - Morales JA et al. (2022) No ASD
23 Support - Álvarez-Mora MI et al. (2022) Yes -
24 Support - Woodbury-Smith M et al. (2022) Yes -
25 Support - Toledo-Gotor C et al. (2022) No Autistic features, stereotypy
26 Support - Zhou X et al. (2022) Yes -
27 Support - Shimelis H et al. (2023) Yes Depressive disorder, anxiety disorder
28 Support - Spataro N et al. (2023) Yes ADHD, epilepsy/seizures
29 Support - Sheth F et al. (2023) Yes DD, ID
30 Support - Tamam Khalaf et al. (2024) No -
Rare Variants   (62)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 26757981 Lugtenberg D , et al. (2016)
c.274+5G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1874+1G>T - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.498-2A>G - splice_site_variant De novo - - 29158550 Popp B , et al. (2017)
c.1841T>G p.Val614Gly stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1864C>T p.Arg622Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss Unknown - Simplex 35266333 Toledo-Gotor C et al. (2022)
c.1438-1G>T - splice_site_variant De novo - - 36980980 Spataro N et al. (2023)
c.1216C>T p.Gln406Ter stop_gained De novo - - 29663678 Uehara T , et al. (2018)
c.1837C>T p.Arg613Ter stop_gained De novo - - 29663678 Uehara T , et al. (2018)
c.1303C>T p.Gln435Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.374C>A p.Ser125Ter stop_gained De novo - - 26264232 DeSanto C , et al. (2015)
c.1746+1G>A - splice_site_variant De novo - - 29928181 Vanegas S , et al. (2018)
c.1289-2A>T - splice_site_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.493G>A p.Glu165Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1721G>A p.Trp574Ter stop_gained De novo - - 26264232 DeSanto C , et al. (2015)
c.1852C>T p.Gln618Ter stop_gained De novo - - 26264232 DeSanto C , et al. (2015)
c.1078C>A p.Pro360Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1268C>T p.Ala423Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1294C>T p.Pro432Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1391C>T p.Pro464Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1760G>A p.Arg587His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1766A>G p.Glu589Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.139C>T p.Arg47Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1291C>T p.Gln431Ter stop_gained Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.329C>A p.Ser110Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1648C>T p.Arg550Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.381+4_381+7del - splice_site_variant De novo - - 35018708 Morales JA et al. (2022)
c.572T>C p.Val191Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.140G>A p.Arg47Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.285del p.Ser96LeufsTer96 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.971C>T p.Thr324Met missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1425del p.Ser476HisfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1415C>T p.Pro472Leu missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.1039C>T p.Pro347Ser missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.811C>T p.Gln271Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1538G>A p.Arg513Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1859C>G p.Thr620Ser missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1553C>T p.Ser518Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.541_542del p.Phe181ProfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.112del p.Ser38AlafsTer154 frameshift_variant De novo - - 26264232 DeSanto C , et al. (2015)
c.1506dup p.Lys503GlnfsTer6 frameshift_variant De novo - - 35018708 Morales JA et al. (2022)
c.1171dup p.Thr391AsnfsTer15 frameshift_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.265dup p.Arg89LysfsTer21 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1894_1896del p.Gln632del inframe_deletion De novo - Unknown 33619735 Brunet T et al. (2021)
c.356dup p.Asn119LysfsTer2 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.485_486del p.Glu162ValfsTer3 frameshift_variant De novo - - 35018708 Morales JA et al. (2022)
c.1393A>G p.Ile465Val missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1480_1483del p.Ala494HisfsTer5 frameshift_variant De novo - - 29663678 Uehara T , et al. (2018)
c.312_313dup p.Ser105ThrfsTer88 frameshift_variant De novo - - 26264232 DeSanto C , et al. (2015)
c.1415del p.Pro472LeufsTer13 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.263_266del p.Glu88GlyfsTer103 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.578_587del p.Gln193ProfsTer135 frameshift_variant De novo - - 26325558 Tammimies K , et al. (2015)
c.1885_1886del p.Leu629GlufsTer5 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.220_221delinsAAA p.Gly74LysfsTer4 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.263_266del p.Glu88GlyfsTer103 frameshift_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.523_524del p.Lys175AspfsTer10 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.898_901del p.Ala300ArgfsTer30 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1474_1475del p.Gln492ValfsTer10 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1852C>T p.Gln618Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1280_1281delinsGAG p.Ser427Ter frameshift_variant De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[New Scoring Scheme]
1/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

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

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[DeSanto-Shinawi Syndrome: First Case in South America.2018]
10/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[Exome Pool-Seq in neurodevelopmental disorders.2017]
4/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitula...2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [De novo mutations in moderate or severe intellectual disability.2014] [Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11.2011] [Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.2012]
1/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains two genes, WAC and BAMBI.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains two genes, WAC and BAMBI.

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
2
icon
2S

Decreased from 2 to 2S

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains two genes, WAC and BAMBI.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitula...2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.2016]
7/1/2015
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitula...2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015]
10/1/2014
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3

Increased from to 3

Description

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Krishnan Probability Score

Score 0.58194217225824

Ranking 565/25841 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 0.99989194262797

Ranking 686/18225 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 0.985

Ranking 34/239 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 0.0077091528407241

Ranking 27/18665 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 12

Ranking 167/461 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 0.56792478638761

Ranking 185/20870 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
ACC Acetyl-CoA carboxylase Fruit Fly Protein Binding 35761 A1Z784
betaTub85D beta-Tubulin at 85D Fruit Fly Protein Binding 41124 P61857
CG2875 CG2875 gene product from transcript CG2875-RC Fruit Fly Protein Binding 31326 Q9W4R1
CG3491 CG3491 gene product from transcript CG3491-RA Fruit Fly Protein Binding 34870 Q9V453
CG8771 CG8771 gene product from transcript CG8771-RB Fruit Fly Protein Binding 36397 A0A0B4K859
FASN2 Fatty acid synthase 2 Fruit Fly Protein Binding 117361 M9PB21
Hem HEM-protein Fruit Fly Protein Binding 40462 P55162
l(1)G0334 lethal (1) G0334 Fruit Fly Protein Binding 31406 Q7KVX1
pont pontin Fruit Fly Protein Binding 53439 Q9VH07
pug pugilist Fruit Fly Protein Binding 41279 O96553
RAB1C RAB1C, member RAS oncogene family pseudogene Human Protein Binding 441400 Q92928
RAPTOR regulatory associated protein of mTOR Human Protein Binding 31543 Q8N122
rept reptin Fruit Fly Protein Binding 40092 Q9V3K3
sli slit Fruit Fly Protein Binding 36746 P24014
smid smallminded Fruit Fly Protein Binding 38824 Q9VS62
Tor Target of rapamycin Fruit Fly Protein Binding 47396 Q9VK45
Vha100-2 Vacuolar H[+] ATPase 100kD subunit 2 Fruit Fly Protein Binding 42216 Q9VE75
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