A Novel Whole Exon Deletion in WWOX Gene Causes Early Epilepsy, Intellectual Disability and Optic Atrophy
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Recent studies have implicated the WW domain-containing oxidoreductase encoding gene (WWOX) in a severe form of autosomal recessive neurological disorder. This condition showed an overlapping spectrum of clinical features including spinocerebellar ataxia associated with generalized seizures and delayed psychomotor development to growth retardation, spasticity, and microcephaly. We evaluated a child from a consanguineous Emirati family that presented at birth with growth retardation, microcephaly, epileptic seizures, and later developed spasticity and delayed psychomotor development. Screening for deletions and duplications using whole-chromosomal microarray analysis identified a novel homozygous microdeletion encompassing exon 5 of the WWOX gene. Analysis of parental DNA indicated that this deletion was inherited from both parents and lies within a large region of homozygosity. Sanger sequencing of the cDNA showed that the deletion resulted in exon 5 skipping leading to a frame-shift and creating a premature stop codon at amino acid position 212. Quantification of mRNA revealed striking low level of WWOX expression in the child and moderate level of expression in the mother compared to a healthy control. To the best of our knowledge, this is the first homozygous germline structural variation in WWOX gene resulting in truncated transcripts that were presumably subject to NMD pathway. Our findings extend the clinical and genetic spectrum of WWOX mutations and support a crucial role of this gene in neurological development.
KeywordsWhole-chromosomal microarray WWOX Microdeletion Microcephaly ID
Complementary deoxyribonucleic acid
Copy number variation
Dishevelled segment polarity protein 2
Erythroblastic leukemia viral oncogene homolog 4
Hypoxanthine phosphoribosyltransferase 1
messenger ribonucleic acid
Non-sense mediated decay
Polymerase chain reaction
Tumor suppressor p73
Runt-related transcription factor 2
Lipopolysaccharide-induced tumor necrosis factor-alpha factor
United Arab Emirates
United States of America
The rsp5-domain or WWP repeating motif
WW domain-containing oxidoreductase
We are indebted to the family for their participation in this study. We are grateful to Ms. Saniya Hamad for blood collection. We are thankful to Mayo Clinic that carried out the CMA analysis. We also thank UAEU for their financial support (grant number NP/13/45).
Conflict of Interest
All authors have declared that no competing interests exist.
SBS and BA designed the experimental plan, analyzed the data and wrote the manuscript. SBS performed mutation screening and expression analysis. AJ performed Sanger sequencing. AA helped in the clinical evaluation and blood sample collections. LA identified family and performed the clinical evaluation. All authors read and approved the final manuscript.
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