Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths

Area of Science:

• Forensic Genetics
• Cardiology
• Molecular Diagnostics

Background:

• Sudden unexplained deaths (SUD) pose challenges for medical examiners when autopsy findings are inconclusive.
• Inheritable cardiac channelopathies are implicated as a potential cause of SUD by affecting heart rhythm.
• Molecular diagnostics are increasingly recommended for SUD investigations to identify genetic predispositions.

Purpose of the Study:

• To assess the utility of cardiac channelopathy gene testing in a large cohort of autopsy-negative SUD cases.
• To identify the prevalence of known and novel channelopathy variants in diverse SUD populations.
• To evaluate the contribution of molecular testing to medicolegal death investigations.

Main Methods:

• Analysis of 274 autopsy-negative SUD cases (infants and non-infants) investigated by the NYC Office of Chief Medical Examiner (2008-2012).
• Routine molecular genetic testing for six major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RyR2).
• Characterization of detected variants, including previously classified and novel putative channelopathy-associated variants.

Main Results:

• Cardiac channelopathy-associated variants were identified in 13.5% of infants and 19.5% of non-infants.
• The SCN5A gene was most frequently implicated, accounting for 68.4% of infant and 50% of non-infant variants.
• African American infants showed the highest SUD risk, and African American non-infants had a significantly younger mean age-at-death.

Conclusions:

• Molecular testing for cardiac channelopathies is a valuable tool in SUD investigations.
• Genetic findings provide crucial information for medical examiners/coroners in determining cause of death.
• This testing can offer potentially life-saving information to surviving family members regarding inherited risks.