Jones, E. F.; Howton, T. C.; Soelter, T. M.; Crumley, A. B.; Lasseigne, B. N.

Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in the SETBP1 gene. While previous studies determined multiple roles for how SETBP1 and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We used STARsolo to quantify gene and splice junction (SJ) expression for 51,465 nuclei previously generated from the cerebral cortex of atypical Setbp1 S858R SGS patient variant mice (n = 3) and wild-type control mice (n = 3). After cell type annotation, we performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 34 genes with statistically significant alterations in SJU. Oligodendrocytes had the most genes with changes in SJU, followed by astrocytes, excitatory, and inhibitory neurons. One gene, Son, a splicing cofactor known to cause the neurodevelopmental disorder ZTTK Syndrome, had SJU changes in all six non-vascular cell types we measured in Setbp1 S858R compared to controls. This is the first research to report AS changes in the cerebral cortex of an SGS model and the first study to link SGS to perturbations in Son.