Grant: Project Grant

Rare diseases collectively affect millions of people worldwide. The majority of rare diseases are caused by harmful genetic changes that are inherited from a parent or arise during development by chance. Unfortunately, the cause of disease in many individuals is not found. Families affected by rare disease experience long diagnostic journeys that may span several years, involve multiple tests and procedures, and end in uncertainty about their health. Genome sequencing has the potential to discover disease-related genetic changes across the entire genome and change the current approach to genetic diagnosis. Clinical implementation of genome sequencing has been limited both by costs and our ability to interpret the vast landscape of genetic variation in individual genomes. Long-read sequencing is a recent technology that has improved the detection of complex genetic variants and variants in hidden regions of the genome. This technology is uniquely able to detect epigenetic changes, chemical modifications made to DNA, as part of the same test. Certain rare diseases show disorder-specific epigenetic signatures that could lead to a diagnosis if found in a patient. Therefore, long-read sequencing has the potential to improve rates of diagnosis and reduce testing burden. Extending our earlier findings, we will use long-read genome sequencing to study individuals with undiagnosed rare diseases and disorders related to disruption of the epigenome. The findings from this study will help us to better understand how genetic and epigenetic changes lead to disease. Multidisciplinary collaboration between the clinic and laboratory will help establish efficient approaches for identifying and interpreting genetic and epigenetic variation. As advances in technology lead to decreasing costs for genome sequencing, we anticipate that this work will provide valuable information about the feasibility of integrating genome sequencing into clinical genetics practice in Canada.