Primary Annotated Resources to Advance Discovery In Genomic Medicine (PARADIGM) (360G-Wellcome-226083_Z_22_Z)

Rare diseases affect around 6% of the population and are mostly caused by rare genetic changes. However, despite enormous investment in genomics, whole genome sequencing does not yield a diagnosis for the majority of patients. Lack of clinically-relevant genome annotation frequently prevents robust variant classification and identification of new disease-causing loci. Our proposal seeks to fulfil the bold vision of coupling functional genomics data with clinical and bioinformatics expertise to empower diagnosis and discovery in genomic medicine. We will apply machine learning and expert curation to provide new literature-derived disease models and tissue-specific gene expression maps. Focusing on two contrasting monogenic disease areas (paediatric developmental disorders and adult cardiomyopathies) we will generate long-read RNA sequencing data from fetal brain and adult heart samples to detect full-length transcript isoforms. We will then use these alongside other emerging datasets to find new causes of disease in existing patient cohorts through a combination of computational phenomics, novel pathogenic variant identification, and isoform-informed burden testing. Finally, we will provide a suite of Primary Annotated Resources to Advance Discovery In Genomic Medicine (PARADIGM), by integrating our novel high- resolution datasets into existing tools and databases that are widely used by the genomic medicine community.