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

Autor: Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Drouot N; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, Illkirch, France., MacLennan SC; Department of Paediatric Neurology, Women's and Children's Hospital, Adelaide, South Australia, Australia., Wessels MW; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands., Krygier M; Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland., Pavinato L; Department of Medical Sciences, University of Turin, Turin, Italy.; Center for Molecular Medicine Cologne, Institute of Human Genetics, University of Cologne, Cologne, Germany., Telegrafi A; Clinical Genomics Program, GeneDx, Gaithersburg, Maryland, USA., de Man SA; Department of Pediatrics, Amphia Hospital, Breda, The Netherlands., van Slegtenhorst M; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands., Iacomino M; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy., Madia F; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy., Scudieri P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy., Uva P; Clinical Bioinformatics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Giacomini T; Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Nobile G; Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Mancardi MM; Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Balagura G; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Galloni GB; Struttura Complessa Neuropsichiatria Infantile Sud, Azienda Sanitaria Locale Città di Torino, Torino, Italy., Verrotti A; Department of Pediatrics, University of Perugia, Perugia, Italy., Umair M; Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan., Khan A; Faculty of Biological Science, Department of Zoology, University of Lakki Marwat, Lakki Marwat, Pakistan., Liebelt J; South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia., Schmidts M; Department of General Pediatrics and Adolescent Medicine, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany., Langer T; Department of Neuropediatrics and Muscle Disorders, Center for Pediatrics, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Brusco A; Department of Medical Sciences, University of Turin, Turin, Italy.; Unit of Medical Genetics, 'Città della Salute e della Scienza' University Hospital, Turin, Italy., Lipska-Ziętkiewicz BS; Clinical Genetics Unit, Department of Biology and Medical Genetics, Medical University of Gdańsk, Gdańsk, Poland.; Centre for Rare Diseases, Medical University of Gdańsk, Gdańsk, Poland., Saris JJ; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands., Charlet-Berguerand N; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, Illkirch, France., Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy., Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Piton A; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, Illkirch, France.; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.; Institut Universitaire de France, Paris, Île-de-France, France.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2022 Sep; Vol. 43 (9), pp. 1299-1313. Date of Electronic Publication: 2022 Jun 08.
DOI: 10.1002/humu.24414
Abstrakt: 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.
(© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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