TY - JOUR T1 - Highly clustered <em>de novo</em> frameshift variants in the neuronal splicing factor <em>NOVA2</em> result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features JF - bioRxiv DO - 10.1101/858696 SP - 858696 AU - Francesca Mattioli AU - Gaelle Hayot AU - Nathalie Drouot AU - Bertrand Isidor AU - Jérémie Courraud AU - Frederic Tran Mau-Them AU - Chantal Sellier AU - Maria-Victoria Hinckelmann AU - Alica Goldman AU - Aida Telegrafi AU - Alicia Boughton AU - Candace Gamble AU - Sebastien Moutton AU - Angélique Quartier AU - Nolwenn Jean AU - Paul Van Ness AU - Sarah Grotto AU - Sophie Nambot AU - Ganka Douglas AU - Yue Cindy Si AU - Jamel Chelly AU - Zohra Shad AU - Elisabeth Kaplan AU - Richard Dineen AU - Christelle Golzio AU - Nicolas Charlet AU - Mandel Jean-Louis AU - Piton Amélie Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/12/04/858696.abstract N2 - The Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene 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 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered 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 on the basis of the genetic findings. ER -