The role of molecular autopsy in unexplained sudden cardiac death

Sudden cardiac death (SCD) is one of the most common causes of death, with many attributable to cardiac/coronary abnormalities evident at autopsy. A significant number of SCDs, however, particularly in young people, remain unexplained following a medico-legal investigation, including autopsy, and are referred to as autopsy-negative sudden unexplained death (SUD). Due to molecular advances, however, a cardiac channel molecular autopsy may potentially provide a pathogenic basis for SUD and establish cause and manner of death.

Over the past decade, five population-based investigations of sudden death in young people elucidated the frequency of and causes responsible for these tragic events. The most inclusive epidemiologic study concluded that nearly 30% of SCDs in young people are autopsy-negative (i.e. SUD) and most likely secondary to cardiac channelopathies. Case reports on the post-mortem molecular diagnosis of cardiac channelopathies through the use of a molecular autopsy have been presented. Recently, a molecular autopsy series of SUD identified pathogenic mutations in long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-associated genes in over one-third of cases. Similar post-mortem cardiac channel genetic testing in a large population-based cohort of sudden infant death syndrome has elucidated mutations in 5-10% of cases.

With autopsy-negative SUD accounting for a significant number of sudden deaths in young people, a new role for the medical examiner is emerging. An accurate diagnosis, derived from a molecular autopsy, will guide the appropriate initiation of pre-emptive strategies in hopes of preventing future tragedies among those left behind.