Grant: Travel Awards - Institute Community Support

Rare genetic diseases affect one in 12 and together affect the lives of approximately 500, 000 Canadians. While individually rare, such diseases collectively account for up to 10% of hospitalizations. Their disproportionate prevalence, primarily the result of years of geographical, cultural or religious isolation, which leads to low genetic variation, allows us to infer the disease-causing variant is within a highly homozygous region and transmitted through carriers. Identifying disease genes is important for several reasons. First, it can help us understand the dynamic function and mechanism of the gene product in the normal state. Second, we can implement presymptomatic testing and carrier screening for high risk populations. Thirdly, depending on the biochemical pathway, the gene may be an attractive pharmacological target for treating individuals affected with the rare disease and those affected with a more common and complex deficiency in the same pathway. Herein, we describe nine rare paediatric diseases in unique and isolated Canadian communities. As there is known consanguinity within these communities, we used a genetic mapping method called autozygosity mapping, which uses hundreds of thousands of DNA markers spanning the entire genome to identify stretches of chromosomes shared only in affected children. Next, through exome sequencing, which is a new genetic technique that sequences only protein-coding regions of the genome, we generated a list of genetic variants within the autozygous region. We applied a filtering strategy using computational biology, population studies and functional tests to determine the biological significance of the mutations. This research demonstrates the stages involved in characterizing a new disorder, which is the first step towards novel diagnostic and therapeutic methods. We hope to implement our findings in genetic counselling, prenatal and newborn screening programs in vulnerable communities.