The Discovery of Novel Genes in Inherited Sudden Arrhythmic Death Syndromes

项目摘要/摘要 克里斯蒂娜·三宅一生博士是一位儿科电生理学家，在遗传性心律失常方面具有临床专长。 生物物理学和分子生理学硕士学位，以及基础科学培训。她在德克萨斯州练习 儿童医院是美国最大的儿科医院，贝勒医学院是人类健康的领先者 基因组研究。她还与哈里斯县法医办公室合作，该办公室负责监督 她的长期目标是成为一名独立的翻译研究员，专注于 儿童心律失常猝死综合征(SADS)的遗传病因儿童遗传性SADS是 由基因改变引起的，导致危及生命的心律失常和心脏性猝死 儿童健康，产生具有重大社会影响的破坏性后果。在30%-70%的SADS中 在一些病例中，这种基因改变是未知的，这表明许多基因尚未被发现。寻找 导致SADS的新基因受到这些病例的罕见和零星性质的限制，以及 医生和家庭获得先进的测序技术，如整个外显子组或基因组 测序。宫家博士试图利用她的背景和专业知识来识别基因决定因素 对SADS负责，并最终改善患者的预后。她的短期职业发展目标是 这项建议是：获得独立分析和解释基因测序所需的技能 数据用于新的基因发现，以加强她的生物统计学背景，并为自己定位 在基因发现和基于基因的结果研究方面的独立研究生涯。这项研究具有很高的 创新，因为新的基因鉴定将由经验丰富的临床医生直接参与 受影响的病人(即三宅一生医生)的护理。在这项提案中，宫家博士的目标是：1)创建和建立一个 全面的儿童SADS病例数据库和生物库，2)利用先进的基因组测序 识别与SADS相关的新基因的技术和3)结合数据库和WES的发现以确定 儿童SADS的基因-表型相关性。该数据库将从患者和 德克萨斯儿童医院的家庭和法医办公室的猝死病例。这 指导助学金包括课程作业和动手实验室培训，以培养对技术的掌握 在新基因发现(Dianna Milewicz博士)、人类基因组测序(James博士)方面有成就的专家 统计遗传学(Suzanne Leal博士)、临床心脏病学(Daniel Penny博士)和生物信息学(Dr. 刘晓明)。最终，该项目的SADS数据库和生物库将为 未来对全面发现SADS基因的研究。从长远来看，这些发现将有助于患者 管理，防止猝死，以及更好地了解细胞的生理功能 心脏。

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.