Frontiers in Pediatrics (Apr 2022)

A Phenotypic-Driven Approach for the Diagnosis of WOREE Syndrome

  • Antonella Riva,
  • Antonella Riva,
  • Giulia Nobile,
  • Thea Giacomini,
  • Thea Giacomini,
  • Marzia Ognibene,
  • Marcello Scala,
  • Marcello Scala,
  • Ganna Balagura,
  • Francesca Madia,
  • Andrea Accogli,
  • Andrea Accogli,
  • Ferruccio Romano,
  • Domenico Tortora,
  • Mariasavina Severino,
  • Paolo Scudieri,
  • Paolo Scudieri,
  • Simona Baldassari,
  • Ilaria Musante,
  • Paolo Uva,
  • Vincenzo Salpietro,
  • Vincenzo Salpietro,
  • Annalaura Torella,
  • Annalaura Torella,
  • Vincenzo Nigro,
  • Vincenzo Nigro,
  • Valeria Capra,
  • Lino Nobili,
  • Lino Nobili,
  • Pasquale Striano,
  • Pasquale Striano,
  • Maria Margherita Mancardi,
  • Maria Margherita Mancardi,
  • Federico Zara,
  • Federico Zara,
  • Michele Iacomino,
  • Michele Iacomino

DOI
https://doi.org/10.3389/fped.2022.847549
Journal volume & issue
Vol. 10

Abstract

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BackgroundWOREE syndrome is a rare neurodevelopmental disorder featuring drug-resistant epilepsy and global developmental delay. The disease, caused by biallelic pathogenic variants in the WWOX gene, usually leads to severe disability or death within the first years of life. Clinicians have become more confident with the phenotypic picture of WOREE syndrome, allowing earlier clinical diagnosis. We report a boy with a peculiar clinic-radiological pattern supporting the diagnosis of WOREE syndrome.MethodsDNA was extracted from blood samples of the proband and his parents and subjected to Exome Sequencing (ES). Agarose gel electrophoresis, real-time quantitative PCR (Q-PCR), and array-CGH 180K were also performed.ResultsES detected a pathogenic stop variant (c.790C > T, p.Arg264*) in one allele of WWOX in the proband and his unaffected mother. A 180K array-CGH analysis revealed a 84,828-bp (g.chr16:78,360,803–78,445,630) deletion encompassing exon 6. The Q-PCR product showed that the proband and his father harbored the same deleted fragment, fusing exons 5 and 7 of WWOX.ConclusionsGenetic testing remains crucial in establishing the definitive diagnosis of WOREE syndrome and allows prenatal interventions/parental counseling. However, our findings suggest that targeted Next Generation Sequencing-based testing may occasionally show technical pitfalls, prompting further genetic investigation in selected cases with high clinical suspicion.

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