De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes

Marcello Scala*, Nathalie Drouot, Suzanna C. MacLennan, Marja W. Wessels, Magdalena Krygier, Lisa Pavinato, Aida Telegrafi, Stella A. de Man, Marjon van Slegtenhorst, Michele Iacomino, Francesca Madia, Paolo Scudieri, Paolo Uva, Thea Giacomini, Giulia Nobile, Maria Margherita Mancardi, Ganna Balagura, Giovanni Battista Galloni, Alberto Verrotti, Muhammad UmairAmjad Khan, Jan Liebelt, Miriam Schmidts, Thorsten Langer, Alfredo Brusco, Beata S. Lipska-Ziętkiewicz, Jasper J. Saris, Nicolas Charlet-Berguerand, Federico Zara, Pasquale Striano, Amélie Piton

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Alternative splicing (AS) is crucial for cell-type-specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron-specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit-hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2-related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

Original languageEnglish
Pages (from-to)1299-1313
Number of pages15
JournalHuman Mutation
Issue number9
Publication statusPublished - Sept 2022

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© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.


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