| The ideals of precision medicine hold the potential to alter medicine from a reactionary discipline to a preventative approach. By utilizing the genetic information encoded at birth, physicians could identify those at risk of disease prior to any disease manifestation allowing for early intervention or even prevention of disease. This initiative holds no greater promise than in the sudden cardiac death associated disorders. While these disorders are highly manageable with current therapeutic strategies, sudden death is often the sentinel event in these disorders. Therefore, the utilization of genetic biomarkers to identify those at risk, prior to any clinical presentation, could dramatically reduce the risk of death. While profound advances have been made in the genetics of sudden cardiac death-associated disorders, a larger than anticipated background rate of benign variation confounds the interpretation of rare variants in susceptibility genes. Furthermore, the identification of a pathogenic mutation does not dictate a person will have a cardiac event due to the issues of reduced penetrance and variable expressivity inherent to most of the SCD-susceptibility genes.;Collectively, this thesis addresses these major issues limiting precision medicine by focusing on KCNQ1-mediated LQTS. First, the potential for in silico predictive algorithms to enhance variant interpretation is severely limited by high false positive and false negative issues. While the synergist use of multiple tools holds greater potential than individual tools, the use of conservation guided topology estimates may hold the greatest promise for providing physicians with enhanced variant interpretation to guide clinical decisions making. Despite the identification of a clearly pathogenic variant, clinician still are unable to provide clear probabilities for the risk of sudden death in carriers, thus severely limiting these genetic biomarkers for clinical decision making. Towards this end, the identification that synonymous variants hold the potential to impact KCNQ1 splicing, leading to alterations in the stoichiometric balance of mutant to wildtype transcripts, can provide clinicians with greater clues into who is at the highest risk of expressing the disease.;While precision medicine holds great potential to reduce the impact of the sudden cardiac death associated disorders, the limitations of variant interpretation, reduced penetrance, and variable expressivity limit the clinical utility of the genetic biomarkers in the susceptibility genes. The work in this thesis provides steps to limit these issues and provide physicians with tools to overcome these limitations allowing for improved clinical decisions. |
