2. Academic Validation
  3. De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder

De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder

  • Am J Hum Genet. 2020 Apr 2;106(4):438-452. doi: 10.1016/j.ajhg.2020.02.013.
Francesca Mattioli 1,  Gaelle Hayot 1,  Nathalie Drouot 1,  Bertrand Isidor 2,  Jérémie Courraud 1,  Maria-Victoria Hinckelmann 1,  Frederic Tran Mau-Them 3,  Chantal Sellier 1,  Alica Goldman 4,  Aida Telegrafi 5,  Alicia Boughton 6,  Candace Gamble 6,  Sebastien Moutton 7,  Angélique Quartier 1,  Nolwenn Jean 7,  Paul Van Ness 4,  Sarah Grotto 8,  Sophie Nambot 7,  Ganka Douglas 5,  Yue Cindy Si 5,  Jamel Chelly 9,  Zohra Shad 10,  Elisabeth Kaplan 10,  Richard Dineen 10,  Christelle Golzio 1,  Nicolas Charlet-Berguerand 1,  Jean-Louis Mandel 11,  Amélie Piton 12
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France.
  • 2 Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France.
  • 3 Laboratoire de Génétique Moléculaire, UF Innovation en diagnostic génomique des maladies rares, Plateau Technique de Biologie, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France.
  • 4 Department of Neurology, Neurophysiology Section, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 GeneDx, Gaithersburg, MD 20877, USA.
  • 6 Cook Children's Genetics Fort Worth, TX 76104, USA.
  • 7 INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France; Centre de Génétique et Centre de référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France.
  • 8 Service de Génétique Médicale, AP-HP Robert-Debré, Paris 75019, France.
  • 9 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France.
  • 10 Department of Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA.
  • 11 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; University of Strasbourg Institute of Advanced Studies, Strasbourg 67000, France.
  • 12 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France. Electronic address: piton@igbmc.fr.
PMID: 32197073 DOI: 10.1016/j.ajhg.2020.02.013
Abstract

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.

Keywords

C-terminal part; KH domains; NOVA2; alternative splicing; autism; de novo mutations; intellectual disability.

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