Pathogenic variants in the splicing factor SF1 lead to a new neurodevelopmental disorder.

Alternative splicing is highly prevalent in the brain, orchestrating key processes like neurogenesis and synaptogenesis, which are critical for generating the nervous system's complexity and plasticity. Dysregulation of splicing mechanisms has been increasingly implicated in neurodevelopmental disorders. Splicing factor 1 (SF1) is integral to pre-mRNA processing, facilitating early spliceosome assembly at the 3' splice site and contributing to the regulation of alternative splicing. Here, we report a newly identified neurodevelopmental disorder associated with de novo heterozygous variants in SF1, characterized by intellectual disability, dysmorphic features, and structural brain anomalies in 15 affected individuals. Functional studies in neural progenitor cells demonstrate that SF1 inhibition alters alternative splicing programs, with pronounced effects on genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. These findings establish SF1-related dysfunction as a novel spliceosomopathy and highlight its critical importance in neurodevelopment and human disease. Overall design: High-depth RNAseq capturing splicing events in Neural Progenitor Cells (NPCs) transfected with siSF1 or siCTRL, originating from two iPSC backgrounds (WTSli21-B (NPC 1) and WTSli008-A (NPC 2)).