Human Gene Module / Chromosome 10 / WAC

WACWW domain containing adaptor with coiled-coil

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
28 / 0
Aliases
WAC, RP11-48B24.1,  BM-016,  PRO1741,  Wwp4
Associated Syndromes
DeSanto-Shinawi syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
10p12.1
Associated Disorders
ASD
Relevance to Autism

Two de novo loss-of-function variants in the WAC gene have been identified in ASD probands from the Simons Simplex Collection (refs). A third de novo loss-of-function variant in this gene was identified in an ASD proband in Tammimies et al., 2015.

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.

Reports related to WAC (16 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 recapitula... 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 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
10 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
11 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
12 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) No -
13 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
14 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No Behavioral anomalies, hypotonia
15 Support Three patients with DeSanto-Shinawi syndrome: Further phenotypic delineation. Uehara T , et al. (2018) No -
16 Support DeSanto-Shinawi Syndrome: First Case in South America. Vanegas S , et al. (2018) No -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.263_266delAGAG 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.Ile300fs frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1852C>T p.Gln618Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1721G>A p.Trp574Ter stop_gained De novo - - 26264232 DeSanto C , et al. (2015)
c.267_268dup p.Asp90TrpfsTer103 frameshift_variant De novo - - 26264232 DeSanto C , et al. (2015)
c.374C>A p.Ser125Ter 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.112delA p.Ser38AlafsTer154 frameshift_variant De novo - - 26264232 DeSanto C , et al. (2015)
c.576_585delGCAAGCAACA p.Gln192fsTer31 frameshift_variant De novo - - 26325558 Tammimies K , et al. (2015)
c.139C>T p.Arg47Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.382-?_1944+?del - copy_number_loss De novo - - 26757981 Lugtenberg D , et al. (2016)
c.329C>A p.Ser110Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1885_1886del p.Leu629GlufsTer5 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.356dup p.Asn119LysfsTer2 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1648C>T p.Arg550Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1415del p.Pro472LeufsTer13 frameshift_variant De novo - - 26757981 Lugtenberg D , et al. (2016)
c.1648C>T p.Arg550Ter stop_gained De novo - - 26757981 Lugtenberg D , et al. (2016)
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)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
c.220_221delAAinsAAA p.Asn74LysfsTer2 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1163_1164del;c.1337_1338del;c.1472_1473del p.Ser388fs;p.Ser446fs;p.Ser491fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.498-2A>G p.? splice_site_variant De novo - - 29158550 Popp B , et al. (2017)
c.1661_1664delCATT p.Ser554Ter frameshift_variant De novo - - 29663678 Uehara T , et al. (2018)
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.1437+1G>A p.? splice_site_variant De novo - - 29928181 Vanegas S , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Score remained at 2.1 + S

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.

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."

4/1/2018
2S
icon
2.1 + S

Score remained at 2.1 + S

Description

2S

10/1/2017
2S
icon
2S

Score remained at 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).

4/1/2017
2S
icon
2S

Score remained at 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).

1/1/2017
2S
icon
2S

Score remained at 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.

10/1/2016
2S
icon
2S

Score remained at 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.

1/1/2016
2
icon
2S

Score remained at 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.

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.

1/1/2015
3
icon
3

Decreased from 3 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).

10/1/2014
icon
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.
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
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
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).
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.
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.
CNVs associated with WAC(1 CNVs)
10p12.1 15 Deletion-Duplication 26  /  62
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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