Bou-Rouphael J, Cospain A, Courtin T, Keren B, Marie C, Lesieur-Sebellin M, Heron D, de Sainte Agathe JM, Heide S, Lejeune E, Quelin C, Lecoquierre F, Nizon M, Isidor B, Besnard T, Cogne B, Latypova X, Levy J, Joset P, Steindl K, Palomares-Bralo M, Santos-Simarro F, Thomas MA, Abubakar A, Lynch SA, Müller AJ, Haack TB, Zenker M, Parker M, Clossick E, Spiller M, Crookes R, Holder-Espinasse M, Bayat A, Møller RS, Mieszczanek TS, de la Grange P, Buratti J, Marijon P, Ataf S, Gavin R, Parras C, Hassan BA, Mignot C, El Khattabi L
Am J Hum Genet. 2025;
Alternative splicing is highly prevalent in the brain where it orchestrates key processes such as neurogenesis and synaptogenesis, both essential for the nervous system's complexity and plasticity. Dysregulation of splicing has increasingly been linked to neurodevelopmental disorders. Here, we describe unrelated individuals carrying de novo, likely deleterious heterozygous variants in Splicing Factor 1 (SF1), all presenting with neurodevelopmental disorders of variable severity, frequently accompanied by autistic traits and other non-specific features. SF1 is a core component of pre-mRNA processing, facilitating early spliceosome assembly at the 3' splice site and regulating alternative splicing. We conducted functional studies in neural progenitor cells, which showed that SF1 downregulation alters gene expression and alternative splicing programs, particularly in genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. Together, these findings establish SF1 dysfunction as an additional spliceosomopathy contributing to neurodevelopmental disorders and underscore its essential role in human neurodevelopment and disease.
