Pre-mRNA splicing defects underlie rare diseases. Briefings in Bioinformatics, 2023.

Identifying causative genes and variants underlying disease phenotypes is critical for improving patient outcomes. Despite diagnostic advances, only 25-40% of patients across cohorts receive a molecular diagnosis after whole-exome/whole-genome sequencing. Genomic variants affecting pre-mRNA splicing and its regulation underlie many genetic diseases. Despite this, most clinical laboratories do not offer RNA-seq as an additional assay for molecular diagnosis of diseases.

We are developing promising RNA-targeted technologies for disease diagnostics and therapeutics, particularly in cases where prior clinical genetic testing has been unrevealing. Potential approaches include the application of currently developed long-read transcriptomic technologies, such as TEQUILA-seq, as well as machine-learning approaches. Successful development of these approaches can have enormous clinical implications for patients with genetic diseases, many of whom have had long diagnostic odysseys.