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De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes
Author(s) -
Scala Marcello,
Drouot Nathalie,
MacLennan Suzanna C.,
Wessels Marja W.,
Krygier Magdalena,
Pavinato Lisa,
Telegrafi Aida,
Man Stella A.,
Slegtenhorst Marjon,
Iacomino Michele,
Madia Francesca,
Scudieri Paolo,
Uva Paolo,
Giacomini Thea,
Nobile Giulia,
Mancardi Maria Margherita,
Balagura Ganna,
Galloni Giovanni Battista,
Verrotti Alberto,
Umair Muhammad,
Khan Amjad,
Liebelt Jan,
Schmidts Miriam,
Langer Thorsten,
Brusco Alfredo,
LipskaZiętkiewicz Beata S.,
Saris Jasper J.,
CharletBerguerand Nicolas,
Zara Federico,
Striano Pasquale,
Piton Amélie
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24414
Subject(s) - biology , frameshift mutation , phenotype , genetics , alternative splicing , neurodevelopmental disorder , rna splicing , hypotonia , gene , exon , rna
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.