AUTHOR=Mellone Simona , Puricelli Chiara , Vurchio Denise , Ronzani Sara , Favini Simone , Maruzzi Arianna , Peruzzi Cinzia , Papa Amanda , Spano Alice , Sirchia Fabio , Mandrile Giorgia , Pelle Alessandra , Rasmini Paolo , Vercellino Fabiana , Zonta Andrea , Rabbone Ivana , Dianzani Umberto , Viri Maurizio , Giordano Mara 

TITLE=The Usefulness of a Targeted Next Generation Sequencing Gene Panel in Providing Molecular Diagnosis to Patients With a Broad Spectrum of Neurodevelopmental Disorders

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.875182

DOI=10.3389/fgene.2022.875182

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Neurodevelopmental disorders comprise a clinically and genetically heterogeneous group of conditions that affect 2%–5% of children and represents a public health challenge due to complexity of the etiology. Only few patients with unexplained syndromic and non-syndromic NDDs receive a diagnosis through first-tier genetic tests as array-CGH and the search for <italic>FMR1</italic> CGG expansion. The aim of this study was to evaluate the clinical performance of a targeted next-generation sequencing (NGS) gene panel as a second-tier test in a group of undiagnosed patients with NDDs.</p><p><bold>Method:</bold> A 221-gene next-generation sequencing custom panel was designed and used to analyze a cohort of 338 patients with a broad spectrum of NDDs (202 males and 136 females) including Intellectual Disability (ID), Autism Spectrum Disorders (ASD), Epilepsy, language and motor disorders.</p><p><bold>Results:</bold> A molecular diagnosis was established in 71 patients (21%) and a <italic>de novo</italic> origin was present in 38 (64.4%) of the available trios. The diagnostic yield was significantly higher in females than in males (29.4% vs. 15.3%; <italic>p</italic> = 0.0019) in particular in ASD (36.8% vs. 7.6%; <italic>p</italic> = 0.0026) and Epilepsy (38.9% vs. 14.4% <italic>p</italic> = 0.001). The most involved genes were <italic>SLC2A1</italic>, <italic>SCN1A, ANKRD11</italic>, <italic>ATP1A2</italic>, <italic>CACNA1A</italic>, <italic>FOXP1</italic>, and <italic>GNAS</italic> altered in more than two patients and accounting for the 19.7% of the diagnosis.</p><p><bold>Conclusion:</bold> Our findings showed that this NGS panel represents a powerful and affordable clinical tool, significantly increasing the diagnostic yield in patients with different form of NDDs in a cost- and time-effective manner without the need of large investments in data storage and bioinformatic analysis.</p>