ABSTRACT Schinzel–Giedion syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function variants in the SETBP1 gene. Although previous studies determined multiple roles for SETBP1 and its associated pathways in disease manifestation, they did not assess whether cell-type-specific alternative splicing (AS) plays a role in SGS. We quantified gene and splice junction expression from single-nuclei RNA-sequencing data from the cerebral cortex and kidney of atypical Setbp1S858R SGS patient variant and wild-type mice. We identified 33 and 62 genes with statistically significant alterations in splice junction usage in the brain and kidney, respectively. We identified significant splice junction usage in a member of the heterogeneous nuclear ribonucleoprotein family, Hnrnpa2b1. These findings were cell-type specific in the cerebral cortex and cell-type agnostic in the kidney, suggesting tissue specificity of AS in Setbp1S858R mice. To broaden the impact of our results for the rare disease community, we developed a point-and-click web application that enables users to explore single-cell-resolution changes at the gene and splice junction levels. Overall, our findings implicate AS in a tissue- and cell-type-specific manner in the cerebral cortex and kidney of Setbp1S858R mice.
Jones et al. (Sun,) studied this question.