Grant: Project Grant

Intracranial aneurysm (IA) is a common cerebrovascular disorder that can lead to sudden and unpredictable severe complications with devastating consequences for the patients and their families, and implicate huge costs for the health system of Canada. Genetic predisposition has been considered as one of the most significant risk factors for IA based several independent studies. Previous epidemiological studies have shown that certain isolated populations, such as Inuits, are particularly at high risk to develop IA. Over the past 10 years, we have identified 50 individuals with definite brain aneurysm belonging to 25 families from 8 different villages in Nunavik. We have also collected a second cohort of French Canadian people diagnosed with IA, originating from Québec City. Within this cohort, we have identified and collected 80 families with IA (total of 144 affected individuals and 180 unaffected first-degree relatives). A cohort of 500 sex- and age-matched control individuals has been collected as well. Genetic studies using next generation sequencing was undertaken in order to characterize the specific genetic vulnerability to IA in both Inuits and French Canadians. These two populations, in which founder effect has been well documented, offer advantages for gene mapping of heritable disorders by reducing both the genetic and the environmental heterogeneity. The pathogenecity of genetic DNA variations, identified through next generation sequencing analyses, will be biologically validated using our unique in vitro tissue-engineered patient-derived vascular and microvascular models. We expect to identify and validate a number of genes conferring susceptibility to IA, and to gain insight into the mutational mechanisms and pathogenic pathways of this disease. Also, this approach could provide unique tools to identify "at risk" patients, which would be able to be followed in a timely fashion, allowing the prevention of the devastating outcome of aneurysm rupture.