Grant: Project Grant

Inherited Long QT syndrome (LQTS) is a heart rhythm disorder that can lead to cardiac arrest at any age. Usually rare, LQTS is more common (>15 times) in the First Nations of Northern BC. We have partnered with the Gitxsan for more than 10 years to understand the causes of LQTS and have previously identified a genetic mutation causing LQTS type 1. Importantly our community based studies revealed that the LQTS1 mutation was not present in some of our LQTS-affected patients. Critically, we have now identified another genetic mutation, which not only leads to LQTS but also other significant heart structure and rhythm problems. The gene (ANK2) codes for the AnkB protein, which is responsible for LQTS type 4. The position of the mutation in in the ANK2 gene is unique, and baseline studies in the laboratory reveal an abnormal protein product. Because the protein, AnkB, serves as an 'anchor' for key heart membrane proteins and is essential for heart cells to beat properly, the range of abnormalities can be broad, and might be different from one person to another, consistent with our clinical findings. We expect this newly identified mutation will account for the majority of the remainder of LQTS in this community and for a range of other types of heart disease affecting all age groups. In continued partnership with the Gitxsan Health Society, we have developed a strong team including cardiology, medical genetics, and cell biology to identify the population, individual and cellular effects of this mutation. In this study, we will expand genetic screening in the community, and identify the spectrum of heart disease. In parallel, cell biology studies conducted in the Swayne lab will determine how the mutation in ANK2 causes electrical and other heart disease. This information will be used to put in place treatment for those affected and provide critical insights into causes of inherited heart disease.