Presenting Author:

Megan Puckelwartz, Ph.D.

Principal Investigator:

Elizabeth McNally, M.D.

Department:

Medicine

Keywords:

Whole genome sequencing, molecular autopsy, sudden cardiac death, sudden death in the young, arrhythmia, cardiomyopathy

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C31 - Clinical

Molecular Autopsy for Sudden Death using Whole Genome Sequencing

Sudden and unexpected death (SUD) in young individuals is often attributed to abnormal cardiac conduction system disease or arrhythmic death. Estimates of sudden death (SD) in the young, not including infants, vary from 0.6 to 6.2 per 100,000 people. The most common causes of SD include hypertrophic cardiomyopathy (HCM), coronary artery abnormalities, myocarditis, arrhythmogenic right ventricular cardiomyopathy (ARVC), and ion channelopathies that include long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia and Brugada Syndrome. For some of these diseases, structural defects are evident at autopsy. However, between 3% and 30% of sudden death in previously healthy children and young adults have no morphologic abnormalities identified at autopsy. A negative autopsy does not exclude cardiomyopathy since structural changes can be subtle or arrhythmias may precede the development of morphologically evident cardiomyopathy. The occurrence of SUD in a family indicates the victim’s first-degree relatives may also have elevated risk for sudden death. For these reasons, in collaboration with the Cook County Medical Examiners Office, we are conducting molecular autopsies on young (average age 31.2 ± 10.2 years) individuals with SUD. Whole genome sequencing was performed on each subject and rare, potentially deleterious variants were identified. Variants in genes associated with epilepsy, cardiomyopathy and irregular heart rhythms were given highest priority. To date, we have evaluated 12 subjects and identified pathogenic, likely pathogenic or variants of unknown significance that warrant further follow up in 10/12 (83%) genomes. Variants associated with epilepsy were deemed potentially pathogenic in 1 subject. Cardiac or arrhythmogenic variants were identified in the other 9 genomes with potentially pathogenic variants. In 5 of the genomes examined, more than 1 potentially pathogenic variant was identified, indicating that multiple hits may increase the likelihood of SUD. Overall, these data indicate that molecular autopsy may serve as a useful tool to understand the genetic underpinnings of sudden death.