Alternative splicing categorizes organ development by stage and reveals unique human splicing variants linked to neuromuscular disorders

Alternative splicing (AS) diversifies protein expression and contributes to species-specific differences in organ development. Here, we focused on stage-specific splicing variants and their correlation with disease in humans compared to mice during brain and heart development. Temporal transcriptomic analysis revealed that splicing factors (SFs) can accurately classify organ developmental stages, and 5 SFs were identified specifically upregulated in humans during organogenesis. Additionally, inter-stage splicing variations were identified across analogous human and mouse developmental stages. Developmentally dynamic alternative splicing genes (devASGs) were enriched in various neurodevelopmental disorders in both species, with the most significant changes observed in human newborn brain and 16 weeks post-conception heart. Intriguingly, diseases specifically enriched in humans were primarily associated with neuro-muscular dysfunction, and human-specific neuromuscular devASGs were linked to mannose glycosylation and ciliary motility. These findings highlight the significance of SFs and AS events in organogenesis and inform the selection of appropriate models for translational research.