Project 459624

The Silent Genomes Project aims to increase access to state-of-the-art whole genome sequencing for Indigenous families with undiagnosed genetic conditions, in a culturally safe way. Currently, only ~30% of Indigenous families are receiving a genetic diagnosis. This may be due to: (1) lack of knowledge on normal/common variation in Indigenous people and/or (2) difficulty in detecting more complex variants using available clinical methods. As part of the Precision Diagnosis study, a sub-activity of the Silent Genomes Project, we work on the development of new approaches to detect hidden causes of genetic disease in these patients. Recently, we used the worm, Caenorhabditis elegans, as a model to test sequencing methods usually used and develop our own on genomes known to have complex variations (e.g. inversion of a part of a chromosome or two chromosomes exchanging a segment of DNA). We showed that using usual genome sequencing, we could reliably detect complicated variations. Importantly, we successfully applied these methods to undiagnosed rare disease patients and were able to identify previously missed variants of interest. However, interpreting the effect of such genomic changes and confirming its implication in the disease is challenging. While we continue applying our methods to genomes of undiagnosed patients, we propose to integrate knowledge on normal genetic variation in Indigenous people with gene expression (process by which the instructions in our DNA are converted into a functional product) analyses to facilitate the interpretation of complex genome disruptions. The Indigenous Background Variant Library (built as part of the Silent Genomes Project) will help eliminate common and prioritize rare/novel variants. In addition, analyzing gene expression will inform about the complex variant effect on gene function. Overall, our research has the potential to increase diagnostic success in rare disease patients, with a particular focus on Indigenous patients.