Human Gene Module / Chromosome 16 / WWOX

WWOXWW domain containing oxidoreductase

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 8
Rare Variants / Common Variants
18 / 0
Aliases
WWOX, D16S432E,  EIEE28,  FOR,  FRA16D,  HHCMA56,  PRO0128,  SCAR12,  SDR41C1,  WOX1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
16
Associated Disorders
ID, EPS, DD/NDD
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).

Reports related to WWOX (8 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 degenerat... 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
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
T>C - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_gain Unknown - - 27569545 Leppa VM , et al. (2016)
- - copy_number_loss Familial Maternal - 27569545 Leppa VM , et al. (2016)
- - 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];[c.918delG] p.[Tyr61Ter];[Glu306fs] stop_gained;frameshift_variant Familial - - 29286531 Tumien B , et al. (2017)
c.[409+1G>T];[409+1G>T] p.? splice_site_variant;splice_site_variant Familial Both parents Simplex 27848944 Trujillano D , et al. (2016)
c.[160G>T];[160G>T] p.[Arg54Ter];[p.Arg54Ter] stop_gained;stop_gained Familial Both parents Multiplex 24456803 Abdel-Salam G , et al. (2014)
c.[173-1G>T];[918del] p.[?];[Glu306AspfsTer21] splice_site_variant;frameshift_variant Familial - Simplex 27848944 Trujillano D , et al. (2016)
c.[139C>A];[139C>A] p.[Pro47Thr];[Pro47Thr] missense_variant;missense_variant Familial Both parents Multiplex 24369382 Mallaret M , et al. (2013)
c.[-366-?_*871+?del];[889A>T] p.[0];[Lys297Ter] copy_number_loss;stop_gained Familial Paternal and maternal Simplex 25411445 Mignot C , et al. (2014)
c.[1114G>C];[1114G>C] p.[Gly372Arg];[Gly372Arg] missense_variant;missense_variant Familial Both parents Multiplex 24369382 Mallaret M , et al. (2013)
c.[517-?_605+?del];[1005G>A] p.[His173AlafsTer67];[Trp335Ter] copy_number_loss;stop_gained Familial Paternal and maternal Simplex 25411445 Mignot C , et al. (2014)
c.[45_48delGGAC];[140C>G] p.[Asp16SerfsTer63];[Pro47Arg] frameshift_variant;missense_variant Familial Paternal and maternal Multiplex 25411445 Mignot C , et al. (2014)
c.[-366-?_516+?del];[517-?_1056+?del] p.[0];[His173_Met352del] copy_number_loss;copy_number_loss Familial Paternal and maternal Simplex 25411445 Mignot C , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Decreased from 3 to

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018
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.
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
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).
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.
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