The Duke Center for Combinatorial Gene Regulation (CCGR), an NIH-funded Center of Excellence in Genome Science, awarded two Clinical Trainee Pilot Research Grants of $15,000 each to Duke clinical trainees. The goal of these grants is to offer multi-disciplinary/cohort-based training in genetics and genomics for clinical trainees, expand the cohorts available to the CCGR project and develop new clinical partnerships.
Genomics is inherently highly multidisciplinary, and expanding national genomics capacity will demand expanding multidisciplinary education and training. These pilot grants will provide exposure to interdisciplinary genomics research for the awardees and promote the adoption of newly developed CCGR technologies and methods.
Congratulations to the Awardees!
Ashley Dischinger, MD | Fellow in Pediatrics
Mentor: Andrew Landstrom, MD, PhD, Assistant Professor of Pediatrics
Project Title: Identification of disease-causing variants in genetically unexplained families with sudden cardiac-death predisposing arrhythmias
This project will identify genetic causes of heritable heart conditions, specifically those that cause sudden cardiac death. Dozens of genes have been identified as associated with the development of channelopathies (arrhythmia syndromes) and cardiomyopathies (cardiac muscle diseases); however, approximately two-thirds of sudden death cases will test negative for a known genetic variant. I will leverage two families with sudden cardiac death-predisposing arrhythmias to conduct genome sequencing in an attempt to identify what gene panels and exome sequencing have missed. If a novel variant is identified, this can have several short and long-term implications including 1) allowing for risk-predictive genetic testing in the identified family to determine individuals at-risk for sudden cardiac death based on presence/absence of the candidate variant; 2) identifying the first genetic variant, and possible gene locus, for a known genetic syndrome with no known gene described; 3) opening the door to therapeutic modulation of the identified mechanism, among others.
Navid Nafissi, MD | Fellow in Cardiology
Mentor: Svati Shah, MD, MHS, Professor of Medicine
Project Title: Whole Genome Sequencing in Patients with Arrhythmia Phenotypes and Negative Targeted Sequencing Results
Inherited cardiac arrhythmia syndromes can lead to unexpected death in otherwise healthy individuals. Genetic testing in these individuals is often unrevealing, even when the signs and symptoms are clearly expressed among multiple family members with the same disease. Typically, genetic testing involves DNA sequencing of the protein coding regions of arrhythmia-related genes that are associated with thedisease in question. However, recent evidence in inherited arrhythmia syndromes has shown that non-protein coding, regulatory elements can also cause these diseases by modulating the expression of arrhythmia-related genes.
Within Duke University Health System, we have identified 60 individuals with clinical evidence of inherited arrhythmic diseases who have negative genetic testing of arrhythmia-related genes. We will sequence the entire genome in these individuals to identify and prioritize putatively functional noncoding variants in regulatory elements in cardiac arrhythmia genes. The inherited arrhythmia syndromes we are interested in include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy, which can all lead to fatal arrhythmias. We are also investigating cases of sudden cardiac arrest, which are most often due to cardiac arrhythmias. Genetic testing is an important component of guideline-directed care of patients with these conditions. A positive result can confirm the suspected clinical diagnosis, offer cascade screening to family members, and sometimes provide prognostic information to the patient. After identifying and prioritizing potentially pathogenic noncoding variants in these patients, we plan to pursue additional grant funding to perform validation studies to determine which variants may be causative. Identifying a causative variant in these patients would allow us to tailor their genetic counseling. Moreover, we would also improve our understanding of the genetics of these under-recognized and often fatal diseases.