De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders
Abstract
Abstract SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function ( n = 9) and missense variants ( n = 17), the latter being associated with a more severe and syndromic phenotype, including heart and gastrointestinal anomalies. We focused on de novo SF3B1 missense variants, which were largely distinct from those reported in cancer. Functional complementation assays show that de novo SF3B1 missense variants did not cause a loss of function of the protein. Targeted and genome-wide analysis of RNA splicing reveal that they affect canonical and alternative splicing more moderately than somatic variants, and subtly modify the splicing of many transcripts. These findings place SF3B1 among the rare U2 snRNP components implicated in both cancer and neurodevelopmental disorders, highlighting its critical and multifaceted role in human disease.
Article Details
Authors (67)
Kevin Uguen
Tiffany Bergot
Marie-Pier Scott-Boyer
Solène Chapalain
Camille Desdouets
Séverine Commet
Changlian Zhu
Yiran Xu
Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Yangong Wang
Tony Roscioli
New South Wales Health Pathology Randwick Genomics, Sydney
Frederic Tran-Mau-Them
Laboratoire de Génomique médicale, Centre Hospitalier Universitaire Dijon-Bourgogne
Laurence Faivre
Julien Maraval
Julian Delanne
Anne-Sophie Denommé-Pichon
Antonio Vitobello
Céline Jost
Marc Planes
Susan Hiatt
Patricia Wheeler
Claudia Gonzaga-Jauregui
Regeneron Genetics Center
Heng Wang
Baozhong Xin
Valerie Sency
Michael C. Kruer
Somayeh Bakhtiari
Patrick Sulem
Cynthia Curry
Trine Prescott
Gertrud Strobl-Wildemann
Theresa Brunet
Martine Doco Fenzy
Thomas Courtin
Céline Poirsier
Department of Genetics, Reims University Hospital
Trine Bjørg Hammer
Christina D. Fenger
Melissa MacPherson
Kosuke Izumi
Jacqueline Leonard
Dong Li
Elaine H. Zackai
Ian A. Glass
Scott Ward
Department of Mathematics, Imperial College London
Philippe M. Campeau
Maria Carla Hermida Borroto
Laurence Le Moigno
Hilde Van Esch
Liesbeth De Waele
Daniel G. Calame
James R. Lupski
Giulia Barcia
Cristina Peduto
Pauline Planté-Bordeneuve
Lucie Dupuis
Roberto Mendoza-Londono
Dimitri J. Stavropoulos
Jennifer Gillibert-Duplantier
Thomas Besnard
Laura Do Souto Ferreira
Benjamin Cogné
Stéphane Bézieau
Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Centre National de la Recherche Scientifique (CNRS), INSERM, l’Institut du Thorax, Nantes, France
Arnaud Droit
Laurent Corcos
Eric Lippert
Claude Férec
Sébastien Küry
Delphine G. Bernard