Sudden unexplained death (SUD) is a tragic event and genetic disorders of heart rhythm and function have been demonstrated in approximately 30% of SUD cases. Any SUD event is a dramatic signal that first-degree relatives require risk stratification. Evaluation of first-degree relatives of a SUD victim is limited by several important gaps in knowledge. First, studies have not prospectively evaluated the rate of transmitted versus de novo mutations in SUD cases when data from molecular autopsy are available. The implications of molecular autopsy for surviving family members depends on the probability of transmitted pathogenic variants. Second, when molecular autopsy is not performed, the value of genetic testing remains unknown for first-degree relatives. Better genetic risk stratification in this population will improve family diagnosis rates and improve counseling. Finally, genetic risk stratification of pathogenic and likely pathogenic variants in families with SUD depends on expanding the list of genes that may harbor pathogenic variants. The project has three specific aims: 1) Determine the frequency of transmitted versus de novo pathogenic and likely pathogenic variants in SUD; 2) Establish the yield of whole genome evaluation in phenotype-positive relatives of a SUD victim; and 3) Use whole genome sequencing (WGS) to identify novel candidate genes associated with SUD. The proposed research is innovative because it uses a close partnership between a multi-state consortium of medical examiner's offices and a nationally-recognized clinical and genetics center to produce a detailed genotype and phenotype evaluation of both SUD victims and their first-degree relatives using WGS. The proposed research is significant because the data generated from this project will improve the evaluation and management of first-degree relatives of SUD victims. Phenotype-genotype correlations will improve counseling. Finally, targeting treatment to those relatives at highest risk for events should decrease further sudden death in the population. This project will advance the candidate's overall training goal, which is to become an independent patient-oriented researcher, with expertise in the genetic diseases that impact SUD. This grant supplements the candidate's background in clinical research and public health by providing an opportunity for focused training in genetics and bioinformatics. Through coursework and practical training in WGS, the candidate will achieve relevant expertise and create a genotype-phenotype database that can be expanded to test additional hypotheses. The candidate's exceptionally strong mentoring team at Northwestern University and the robust resources for translational genetic research dedicated to Dr. Webster's training create a tremendous opportunity for career development and will contribute to the long-term goal of decreasing mortality in first-degree relatives after a sudden unexpected death event.
In some young people who have suffered sudden unexplained death (SUD), testing reveals gene variants associated with congenital disorders of heart rhythm or heart function. First-degree relatives may have an elevated risk for sudden death. The proposed research is relevant to public health because it uses whole genome sequencing and detailed clinical information to improve risk stratification in first-degree relatives of SUD victims. This research may prevent additional sudden death events and it will contribute to the NIH mission of helping individuals live longer, more fulfilling lives.