Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Abstract Background WWOX biallelic and loss-of-function pathogenic variants cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 patients to date. In this study, we report on a WOREE syndrome patient who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the patient, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exon sequencing, quantitative real-time polymerase chain reaction (PCR), and whole-genome sequencing, to identify the genetic defects. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exon sequencing revealed homozygous exon 6 deletions in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the deletions were inherited from each parent. However, using whole-genome sequencing, we identified three larger deletions (intron 5, exon 6, and exon 6-8) involving the WWOX gene in the proband, with deletion sizes of 13,261, 53,904, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6-8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.