Project description:Genes encoding RNA splicing factors are frequently mutated in clonal hematopoesis and diverse cancers. Most spliceosomal mutations affect specific hotspot residues, causing changes in exon and splice site recognition that promote disease. However, a subset of patients carry splicesomal mutations in non-hotspot residues, and their contribution to disease are unknown. Here we systematically characterized the function of several rare and private spliceosomal mutations in order to determine their potential disease relevance. We discovered that several rare and private spliceosomal mutations phenocopy the mechanistic splicing alterations induced by their "hotspot" counterparts. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis.
