Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young

Postmortem genetic testing (molecular autopsy) for the common long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) genes reveals a pathogenic mutation in up to 30% of sudden unexplained death (SUD). The role of additional cardiac arrhythmia and cardiomyopathy genes in SUD is largely unknown.

The purpose of this study was to investigate the feasibility and outcomes of performing exome sequencing-based molecular autopsies in a cohort of consecutive SUD cases.

Autopsies performed from 2005 to 2009 were reviewed for SUD. Postmortem blood was collected, DNA was isolated, and whole exome sequencing was performed. Rare sequence variants in cardiac arrhythmia and cardiomyopathy genes were sought.

There were 50 SUD cases aged 1 to 40 years (mean 21.7 ± 12 years) in the 5-year period, with a male predominance of 1.9:1. The most common event at death was "sleep" (48%). Exome sequencing in a subgroup of 28 SUD cases revealed 3 rare variations in 3 SUD cases (10%; 2 from exome sequencing and 1 from previous Sanger sequencing) in the common LQTS genes: a splice site variation and a single base deletion in KCNH2, and a missense variation in KCNQ1. Six rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies were identified in 6 SUD (21%).

Exome sequencing-based molecular autopsy is a useful strategy as part of the investigation of SUD cases. The findings further expand the role of the molecular autopsy in both identifying a cause of death in the decedent and evaluating at-risk family relatives.