AUTHOR=Riva Antonella , Nobile Giulia , Giacomini Thea , Ognibene Marzia , Scala Marcello , Balagura Ganna , Madia Francesca , Accogli Andrea , Romano Ferruccio , Tortora Domenico , Severino Mariasavina , Scudieri Paolo , Baldassari Simona , Musante Ilaria , Uva Paolo , Salpietro Vincenzo , Torella Annalaura , Nigro Vincenzo , Capra Valeria , Nobili Lino , Striano Pasquale , Mancardi Maria Margherita , Zara Federico , Iacomino Michele TITLE=A Phenotypic-Driven Approach for the Diagnosis of WOREE Syndrome JOURNAL=Frontiers in Pediatrics VOLUME=10 YEAR=2022 URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.847549 DOI=10.3389/fped.2022.847549 ISSN=2296-2360 ABSTRACT=Background

WOREE 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.

Methods

DNA 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.

Results

ES 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.

Conclusions

Genetic 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.