The Discovery of Novel Genes in Inherited Sudden Arrhythmic Death Syndromes

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PROJECT SUMMARY / ABSTRACT Dr. Christina Miyake is a pediatric electrophysiologist with clinical expertise in heritable arrhythmia disorders, a Master’s degree in biophysics and molecular physiology, and training in basic science. She practices at Texas Children’s Hospital, the largest pediatric hospital in the U.S., and Baylor College of Medicine a leader in human genome research. She also collaborates with the Harris County Medical Examiner’s Office which oversees the 3rd largest county in the U.S. Her long-term goal is to be an independent translational researcher, focusing on the genetic etiologies of pediatric sudden arrhythmic death syndromes (SADS). Pediatric inherited SADS are caused by genetic alterations that result in life threatening arrhythmias and sudden cardiac death in otherwise healthy children, producing devastating consequences with significant societal impact. In 30-70% of SADS cases, the genetic alteration is unknown, suggesting that many genes are yet to be discovered. The search for new genes causing SADS has been limited by the rare and sporadic nature of these cases and the limited access of physicians and families to advanced sequencing techniques such as whole exome or genome sequencing. Dr. Miyake seeks to utilize her background and expertise to identify the genetic determinants responsible for SADS and ultimately to improve patient outcomes. Her short-term career development goals in this proposal are: to acquire the requisite skill set to independently analyze and interpret genetic sequencing data for novel gene discovery, to strengthen her biostatistical background, and to position herself for an independent research career in gene discovery and gene-based outcome studies. This study is highly innovative because novel gene-identification will be performed by an experienced clinician directly involved in care of the affected patient (i.e. Dr. Miyake). In this proposal, Dr. Miyake aims to: 1) create and establish a comprehensive database and biobank of pediatric SADS cases, 2) utilize advanced genomic sequencing techniques to identify novel genes associated with SADS and 3) combine database and WES findings to define genotype-phenotype associations in pediatric SADS. The database will be constructed from patients and families at Texas Children’s Hospital and from sudden death cases at the Medical Examiner’s office. This mentored grant includes coursework and hands-on lab training to develop a mastery of techniques from accomplished experts in novel gene discovery (Dr. Dianna Milewicz), human genome sequencing (Dr. James Lupski), statistical genetics (Dr. Suzanne Leal), clinical cardiology (Dr. Daniel Penny), and bioinformatics (Dr. Xiaoming Liu). Ultimately, the SADS database and biobank for this project will provide the infrastructure for future research into comprehensive SADS gene discovery. Long-term, these discoveries will help in patient management, the prevention of sudden death, and a better understanding of cellular physiologic function within the heart.