VP.02 Comprehensive characterization of early-onset skeletal muscle disease gene exon usage and splicing patterns across different developmental ages

Abstract

Alternative splicing is a normal post-transcriptional regulation process that facilitates the generation of multiple different protein isoforms from the one gene. This results in the production of a family protein isoforms uniquely suited to the needs of each tissue subtype and developmental stage. There is an increasing body of evidence to suggest that disease-causing variants that impact exons that are not "used" by highly abundant isoform transcripts might have less clinical impact. However, it is also increasingly clear that some exons encode regions of isoforms that perform important functional roles during critical developmental windows. They might not be highly used by all isoforms, but their inclusion within some transcripts is hugely important. Our overall understanding of normal skeletal and cardiac muscle exon usage and splicing patterns is extremely limited. This is adversely impacting our ability to understand how exon usage impacts clinical variability. In addition, due to recent bioinformatic advances, our ability to identify variants that might be adversely impacting normal exons usage and splicing patterns (potential splice-impacting variants) is rapidly improving. However, our limited understanding of "what is normal" is hampering our ability functionally validate these variants. In this study, we characterized the normal exon usage and splicing patterns of a range of important congenital and early onset skeletal muscle disease genes in different healthy skeletal and cardiac muscle subtypes across different developmental ages (fetal to adult). For some genes, exon usage and splicing patterns within specific regions of the transcript varied greatly across different tissues and/or developmental ages. Our study significantly expands our understanding of healthy striated muscle isoform biology and the relationship between alternative splicing patterns and skeletal muscle disease.