Journal of Molecular Neuroscience

, Volume 56, Issue 1, pp 17–23 | Cite as

A Novel Whole Exon Deletion in WWOX Gene Causes Early Epilepsy, Intellectual Disability and Optic Atrophy

  • Salma Ben-Salem
  • Aisha M. Al-Shamsi
  • Anne John
  • Bassam R. Ali
  • Lihadh Al-GazaliEmail author


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.


Whole-chromosomal microarray WWOX Microdeletion Microcephaly ID 



Base pair


Complementary deoxyribonucleic acid


Cerebrospinal fluid


Cycle threshold


Chromosomal micro-array


Copy number variation


Deoxyribonucleic acid


Deoxyribonucleotide triphosphates


Dishevelled segment polarity protein 2


Ethylenediaminetetraacetic acid




Erythroblastic leukemia viral oncogene homolog 4


High definition


Hypoxanthine phosphoribosyltransferase 1




messenger ribonucleic acid


Non-sense mediated decay


Polymerase chain reaction


Tumor suppressor p73


Relative quantification


Ribonucleic acid


Reverse transcriptase


Runt-related transcription factor 2


Standard deviation


Lipopolysaccharide-induced tumor necrosis factor-alpha factor


United Arab Emirates


United States of America


Wild Type


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.

Author’s Contribution

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Salma Ben-Salem
    • 1
  • Aisha M. Al-Shamsi
    • 2
  • Anne John
    • 1
  • Bassam R. Ali
    • 1
  • Lihadh Al-Gazali
    • 3
    Email author
  1. 1.Department of Pathology, College of Medicine and Heath SciencesUnited Arab Emirates UniversityAl-AinUnited Arab Emirates
  2. 2.Department of PaediatricsTawam HospitalAl-AinUnited Arab Emirates
  3. 3.Department of Paediatrics, College of Medicine and Heath SciencesUnited Arab Emirates UniversityAl-AinUnited Arab Emirates

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