Driving therapeutic impact by comprehensively mapping variant effects

Year of award: 2024

Grantholders

  • Dr Elizabeth Radford

    University of Cambridge, United Kingdom

Project summary

Receiving a definitive diagnosis and improving access to treatment are priorities for individuals affected by rare diseases (UK Rare Disease Framework). Genomic sequencing is used to diagnose, quantify family members’ risk, enable preventative screening and, where possible, guide precision therapies. However, we cannot currently conclusively interpret most genetic variants. Interpretation of genetic variants is particularly challenging in individuals of non-European ancestries, and single parent families. This results in substantial inequity in access to and quality of care. Saturation mutagenesis techniques empirically test variant-effect at scale, providing functional evidence for variant classification. This approach is agnostic to genetic ancestry and has the potential to democratise access to a genetic diagnosis and personalised medicine. My first aim is to accelerate the diagnosis of clinically actionable genes by generating large-scale nucleotide-resolution maps of variant function. By including non-coding regions such as the promoter and 5’UTR I will also advance the mechanistic understanding of non-coding regions in disease and increase diagnostic yield. This may also identify novel therapeutic strategies by upregulating haploinsufficient genes by targeting the 5’UTR and promoter. Finally, I will conduct large-scale cellular screens to prospectively inform the development of exon-skipping treatments as novel therapies for rare developmental disorders.