Grant: Project Grant

In the Gitxsan First Nation of Northern British Columbia, we recently identified a change in a gene called ANK2 linking a variety of heart conditions in families affected with long QT syndrome (LQTS). We are long-standing research partners (15 years) with the Gitxsan community and have enrolled >800 participants in studies addressing a high rate of LQTS. Although most people in the community with LQTS have a common genetic change causing LQTS type 1 (KCNQ1 p.V205M), not all families with LQTS have that change. Importantly, the discovery of the new gene change (AnkB p.S646F) identifies the underlying cause of LQTS type 4 in several people without the p.V205M change. We have also found that this gene may have effects beyond LQTS, such as on heart structure. Notably, in these families the gene change may contribute to infants with heart disease (congenital heart malformations) and heart muscle disease in adults (cardiomyopathy). Our study proposes to explore further the presence of the p.S646F variant in the population, and the role in heart disease throughout the life course. Clinical management strategies will be based on evidence learned from the clinical and population studies. We will also carry out laboratory studies in heart cells from mice to determine the effects of the gene change at the level of the cell, and how they may lead to heart development and heart muscle disease. Our team combines strong expertise in the local Indigenous context, clinical genetics, cardiology, and cell biology and builds from our preliminary results to provide a full understanding of the range of heart disease caused by this gene change. This study will contribute to a broader understanding of how the ANK2 gene contributes not only to LQTS in some people, but also other types of common heart disease.