Poster Presentation GENEMAPPERS 2024

Determining the pathogenicity of deep-intronic genetic variants (#61)

Joshua M Reid 1 2 , Ingrid E Scheffer 1 3 4 5 , Samuel F Berkovic 1 , Melanie Bahlo 2 6 , Michael S Hildebrand 1 3 , Mark F Bennett 1 2 6
  1. Epilepsy Research Centre, Depeartment of Medicine, The University of Melbourne, Melbourne, VIC, Australia
  2. Population Health & Immunity Division, Walter & Eliza Hall Institute, Parkville, VIC, Australia
  3. Neuroscience Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  4. Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
  5. Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
  6. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

Despite advances in sequencing technologies, many patients with genetic epilepsies still face diagnostic challenges. To uncover a genetic cause in these patients, screening will need to extend to regions not covered by conventional analyses. Variants identified in introns, the non-coding sequences in genes, are often disregarded as they are frequently occurring and difficult to interpret. However, recent studies have identified deep-intronic variants that cause disease by disrupting the process of gene splicing. An increasing number of computational tools that classify the impact of deep-intronic variants have been developed, but they are not yet utilised in mainstream analysis pipelines as their performance is not well characterised. To address this, we have compiled a truth dataset of known pathogenic and benign deep-intronic variants to evaluate the performance of several variant prediction tools. Our results indicate that the machine-learning tool Pangolin has the highest sensitivity in these regions as it correctly classified 84% of known pathogenic variants. We then applied a selection of in-silico tools to the sequencing data of unsolved epilepsy patients to identify and prioritise candidate variants. We are evaluating the contribution of deep-intronic splice variants to genetic epilepsies as it is believed that they are an underappreciated disease mechanism.