Human Gene Module / Chromosome 16 / WWOX

WWOXWW domain containing oxidoreductase

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
36 / 0
Aliases
WWOX, D16S432E,  EIEE28,  FOR,  FRA16D,  HHCMA56,  PRO0128,  SCAR12,  SDR41C1,  WOX1
Associated Syndromes
-
Chromosome Band
16
Associated Disorders
DD/NDD, ID, EPS
Relevance to Autism

Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6).

Molecular Function

This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Rat
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to WWOX (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy Suzuki H , et al. (2009) No -
2 Support The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation Mallaret M , et al. (2013) No -
3 Support The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration Abdel-Salam G , et al. (2014) No -
4 Support WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation Mignot C , et al. (2014) No -
5 Primary Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families Leppa VM , et al. (2016) Yes -
6 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
7 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, ID, epilepsy/seizures
8 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) No Hypotonia
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support - Zou D et al. (2021) No -
11 Support - Woodbury-Smith M et al. (2022) Yes -
12 Support - Wang Q et al. (2022) No -
13 Support - Zhou X et al. (2022) Yes -
14 Support - Luigi Vetri et al. (2024) No -
15 Support - Purvi Majethia et al. (2024) No -
16 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 34145886 Zou D et al. (2021)
- - copy_number_gain Unknown - - 27569545 Leppa VM , et al. (2016)
c.*110T>G - 3_prime_UTR_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal - 27569545 Leppa VM , et al. (2016)
c.178-61369T>C - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.718-253123T>C - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.754G>A p.Val252Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 25411445 Mignot C , et al. (2014)
- - copy_number_loss Familial Paternal Simplex 25411445 Mignot C , et al. (2014)
- - copy_number_gain Familial Maternal Simplex 27569545 Leppa VM , et al. (2016)
- - copy_number_gain Familial Paternal Simplex 27569545 Leppa VM , et al. (2016)
- - copy_number_loss Familial Maternal Simplex 27569545 Leppa VM , et al. (2016)
- - copy_number_gain Familial Paternal Multiplex 27569545 Leppa VM , et al. (2016)
- - copy_number_loss Familial Maternal Multiplex 27569545 Leppa VM , et al. (2016)
c.183C>A p.Tyr61Ter stop_gained Unknown - Unknown 29286531 Tumien B , et al. (2017)
c.453-1G>C p.? splice_site_variant Familial Paternal - 34145886 Zou D et al. (2021)
c.-126C>T - stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.716T>G p.Leu239Arg missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.786C>A p.Ser262%3D stop_gained Familial Both parents - 34145886 Zou D et al. (2021)
c.173-1G>T - splice_site_variant Familial - Simplex 27848944 Trujillano D , et al. (2016)
c.378G>C p.Val126%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.889A>T p.Lys297Ter stop_gained Familial Maternal Simplex 25411445 Mignot C , et al. (2014)
c.1005G>A p.Trp335Ter stop_gained Familial Maternal Simplex 25411445 Mignot C , et al. (2014)
c.452+1G>C - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.-229_-226del - frameshift_variant Familial Paternal Multiplex 25411445 Mignot C , et al. (2014)
c.1063G>C p.Gly355Arg missense_variant Familial Paternal Multiplex 35266334 Wang Q et al. (2022)
c.579del p.Glu193AspfsTer21 frameshift_variant Unknown - Unknown 29286531 Tumien B , et al. (2017)
c.-167-1286G>A - splice_site_variant Familial Both parents - 38374498 Purvi Majethia et al. (2024)
c.140C>G p.Pro47Arg missense_variant Familial Maternal Multiplex 25411445 Mignot C , et al. (2014)
c.70+1G>T - splice_site_variant Familial Both parents Simplex 27848944 Trujillano D , et al. (2016)
c.918del p.Glu306AspfsTer21 frameshift_variant Familial - Simplex 27848944 Trujillano D , et al. (2016)
c.160G>T p.Arg54Ter stop_gained Familial Both parents Multiplex 24456803 Abdel-Salam G , et al. (2014)
c.139C>A p.Pro47Thr missense_variant Familial Both parents Multiplex 24369382 Mallaret M , et al. (2013)
c.515del p.Asn172ThrfsTer42 frameshift_variant Familial Maternal Multiplex 35266334 Wang Q et al. (2022)
c.1043del p.Phe348SerfsTer57 frameshift_variant Familial Both parents - 38256219 Luigi Vetri et al. (2024)
c.1114G>C p.Gly372Arg missense_variant Familial Both parents Multiplex 24369382 Mallaret M , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6). Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6). Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6). Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2016
icon
3

Increased from to 3

Description

Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6). Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).

Krishnan Probability Score

Score 0.4917591389809

Ranking 5122/25841 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 1.9385527361546E-8

Ranking 16063/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.95065155319044

Ranking 18576/18665 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
Zhang D Score

Score -0.31377519844172

Ranking 17404/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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