Grant: Canada Postdoctoral Research Award (CPRA) program

Rare diseases affect about one in twelve Canadians, yet many families remain undiagnosed even after extensive genetic testing. This "diagnostic odyssey" delays care, increases costs, and leaves patients without clear guidance. A timely and accurate diagnosis is the gateway to precision management, targeted treatment, genetic counselling, and access to supports. In this project, I will analyze long-read genome data from unsolved patients and their families in the pan-Canadian Care4Rare EXPAND network. Long-read sequencing generates much longer stretches of DNA sequence compared to standard short-read technologies. This makes it possible to detect types of genetic changes that are often missed, including large rearrangements, repeat expansions, and difficult-to-sequence regions. Importantly, long-read technologies can also measure DNA methylation, a chemical signal on DNA that regulates how genes are used. These methylation patterns can provide new clues to disease by uncovering parent-of-origin effects, supporting the role of uncertain variants, and revealing episignatures, which are characteristic methylation profiles that serve as biomarkers for specific rare disorders. By integrating long-read sequencing with methylation, this project will identify a diagnosis for a significant portion of patients who remain unsolved after current clinical tests. We will further validate and study these findings to understand how the underlying genetic and epigenetic mechanisms cause disease. The results will demonstrate the clinical utility of long-read sequencing combined with methylation profiling and establish a practical path for bringing these technologies into routine patient care.