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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

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.
ASD
Support
WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation.
Early infantile epileptic encephalopathy-28
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism
ASD
Support
The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degenerat...
Early infantile epileptic encephalopathy-28
Support
Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study
DD, epilepsy/seizures
Support
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
DD
Support
The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation.
Autosomal recessive spinocerebellar ataxia-12
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications
Epilepsy/seizures
Support
A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy.
Support
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
Epilepsy/seizures
Hypotonia
Support
Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies
ID, epilepsy/seizures
Support
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Early infantile epileptic encephalopathy-28
DD, ID, epilepsy/seizures
Support
Integrating de novo and inherited variants in 42
ASD
Support
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
ASD
Support
Deep phenotyping and whole-exome sequencing improved the diagnostic yield for nuclear pedigrees with neurodevelopmental disorders
DD, ID, epilepsy/seizures
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN851R001 
 copy_number_gain 
  
  
 Unknown 
  
  
 GEN851R002 
 copy_number_gain 
  
  
 Unknown 
  
  
 GEN851R003 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN851R004 
 copy_number_gain 
  
  
 Unknown 
  
  
 GEN851R005 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN851R006 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN851R007 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN851R008 
 copy_number_loss 
  
  
 Familial 
 Maternal 
  
 GEN851R009 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN851R010 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN851R011 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN851R012 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN851R013a 
 missense_variant 
 c.139C>A 
 p.Pro47Thr 
 Familial 
 Both parents 
 Multiplex 
 GEN851R014a 
 missense_variant 
 c.1114G>C 
 p.Gly372Arg 
 Familial 
 Both parents 
 Multiplex 
 GEN851R015a 
 stop_gained 
 c.160G>T 
 p.Arg54Ter 
 Familial 
 Both parents 
 Multiplex 
 GEN851R016a 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN851R016b 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN851R017a 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN851R017b 
 stop_gained 
 c.1005G>A 
 p.Trp335Ter 
 Familial 
 Maternal 
 Simplex 
 GEN851R018a 
 frameshift_variant 
 c.-229_-226del 
  
 Familial 
 Paternal 
 Multiplex 
 GEN851R018b 
 missense_variant 
 c.140C>G 
 p.Pro47Arg 
 Familial 
 Maternal 
 Multiplex 
 GEN851R019a 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN851R019b 
 stop_gained 
 c.889A>T 
 p.Lys297Ter 
 Familial 
 Maternal 
 Simplex 
 GEN851R020 
 intron_variant 
 c.178-61369T>C 
  
  
  
 Unknown 
 GEN851R021 
 intron_variant 
 c.718-253123T>C 
  
  
  
 Unknown 
 GEN851R022a 
 splice_site_variant 
 c.173-1G>T 
  
 Familial 
  
 Simplex 
 GEN851R022b 
 frameshift_variant 
 c.918del 
 p.Glu306AspfsTer21 
 Familial 
  
 Simplex 
 GEN851R023a 
 splice_site_variant 
 c.70+1G>T 
  
 Familial 
 Both parents 
 Simplex 
 GEN851R024a 
 stop_gained 
 c.183C>A 
 p.Tyr61Ter 
 Unknown 
  
 Unknown 
 GEN851R024b 
 frameshift_variant 
 c.579del 
 p.Glu193AspfsTer21 
 Unknown 
  
 Unknown 
 GEN851R025 
 stop_gained 
 c.-126C>T 
  
 Familial 
 Paternal 
 Multiplex 
 GEN851R026 
 splice_site_variant 
 c.452+1G>C 
  
 Familial 
 Paternal 
 Multiplex 
 GEN851R027a 
 stop_gained 
 c.786C>A 
 p.Ser262%3D 
 Familial 
 Both parents 
  
 GEN851R028a 
 splice_site_variant 
 c.453-1G>C 
 p.? 
 Familial 
 Paternal 
  
 GEN851R028b 
 copy_number_gain 
  
  
 Unknown 
  
  
 GEN851R029 
 synonymous_variant 
 c.378G>C 
 p.Val126%3D 
 Unknown 
  
  
 GEN851R030a 
 missense_variant 
 c.1063G>C 
 p.Gly355Arg 
 Familial 
 Paternal 
 Multiplex 
 GEN851R030b 
 frameshift_variant 
 c.515del 
 p.Asn172ThrfsTer42 
 Familial 
 Maternal 
 Multiplex 
 GEN851R031 
 missense_variant 
 c.754G>A 
 p.Val252Ile 
 De novo 
  
  
 GEN851R032 
 3_prime_UTR_variant 
 c.*110T>G 
  
 De novo 
  
  
 GEN851R033a 
 frameshift_variant 
 c.1043del 
 p.Phe348SerfsTer57 
 Familial 
 Both parents 
  
 GEN851R034a 
 splice_site_variant 
 c.-167-1286G>A 
  
 Familial 
 Both parents 
  
 GEN851R035a 
 missense_variant 
 c.716T>G 
 p.Leu239Arg 
 Unknown 
  
  
 GEN851R036 
 missense_variant 
 c.1208C>T 
 p.Pro403Leu 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Duplication
 1
 
16
Duplication
 2
 
16
Duplication
 1
 
16
Deletion
 1
 
16
Deletion-Duplication
 49
 
16
Deletion
 3
 
16
Deletion
 1
 
16
Duplication
 6
 

Model Summary

The LDE strain (lethal dwarfism with epilepsy) was inbred using heterozygous rats, derived from inbreeding of a closed colony of Wistar Imamichi rats. Mutant rats showed severe dwarfism, short lifespan (early postnatal lethality), and high incidence of epileptic seizures. The lde locus was mapped to a 1.5-Mbp region on rat chromosome 19 that included the latter half of the Wwox gene. The lde/lde rat is unique model for studying the physiological function of Wwox in CNS.

References

Type
Title
Author, Year
Primary
Phenotypic characterization of spontaneously mutated rats showing lethal dwarfism and epilepsy.
Additional
Retarded differentiation of Leydig cells and increased apoptosis of germ cells in the initial round of spermatogenesis of rats with lethal dwarf an...
Additional
A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: LDE strain (lethal dwarfism with epilepsy) was inbred using heterozygous rats, derived from inbreeding of a closed colony of Wistar Imamichi rats.
Allele Type: Spontaneous mutation
Strain of Origin: Wistar Imamichi LDE
Genetic Background: Wistar Imamichi
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ataxia1
Increased
 General observations
 3 weeks
Brain size1
Increased
 Measurement of tissue weight
 4 weeks
Hippocampal morphology3
Abnormal
 Histology
 Unreported
Hippocampal morphology1
Abnormal
 Histology
 4 weeks
Seizures1
Increased
 Observation of seizures
 2-9 weeks
Seizure threshold3
Increased
 Observation of sensory-evoked seizures
 Unreported
Electroencephalogram (eeg): signature of seizure/epilepsy3
Increased
 Electroencephalogram (eeg)
 Unreported
Apoptosis1
Increased
 Histology
 4 weeks
Reproductive function2
Decreased
 Histology
 3-8 weeks
Apoptosis2
Increased
 Tunel assay
 4-8 weeks
Hormone levels2
Decreased
 Immunostaining
 4 weeks
Hormone levels2
Decreased
 Enzyme assay
 4 weeks
Reproductive function1
Decreased
 Histology
 4 weeks
Size/growth1
Decreased
 Body length measurement
 3 weeks
Tissue weight1
Increased
 Measurement of tissue weight
 4 weeks
Reproductive system development2
Decreased
 Histology
 3-8 weeks
Tissue weight1
Decreased
 Measurement of tissue weight
 4 weeks
Mortality/lethality1
Increased
 Survival analysis
 3-7 weeks
Size/growth1
Decreased
 Body weight measurement
 3 weeks
Targeted expression3
Decreased
 Western blot
 2 weeks
Metabolite level quantification1
Increased
 In vitro diagnostic tests
 4 weeks
Renal morphology1
 No change
 Histology
 4 weeks
Skeletal development1
 No change
 Skeletal x-rays
 3 weeks
Hormone levels1
 No change
 Enzyme assay
 4 weeks
Hormone levels1
 No change
 Immunostaining
 4 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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