Next generation sequencing : a possible answer to sudden unexplained deaths in a young South African cohort?

Abstract

Sudden cardiac death (SCD) is a major public health concern. In sub-Saharan Africa (SSA), including South Africa, there is a lack of reliable statistics on the incidence of SCD, even though there has been a fourfold increase in noncommunicable diseases (NCD), particularly cardiovascular diseases (CVD). Sudden cardiac death contributes to an estimated 50% of all cardiovascular deaths, which highlights South Africa’s need for research into better detection, treatment and prevention. This study aimed to identify an inherited cardiac arrhythmogenic disorder, linked to variants in cardiomyopathy- and arrhythmia-related genes, as a potential contributing factor to sudden cardiac deaths. DNA was extracted from blood samples collected at autopsy of 51 sudden unexpected death (SUD) cases, and subjected to next-generation sequencing (NGS) of 49 genes linked to inherited cardiac arrhythmogenic disorders. Variants were annotated and interpretated for clinical significance using the Galaxy bioinformatic platform. In total, 175 different missense variants were identified in the study population (n = 51). Of these, 92.5% (162/175) were known, documented variants, and the remaining 7.4% (13/175) were considered novel. Of the known variants, 78.4% (127/162) were of benign/likely benign significance, 20.4% (33/162) were variants of unknown significance (VUS), and 1.2% (2/162) was pathogenic. The 13 novel variants were analysed using online prediction software, with 92.3% (12/13) predicted to be likely benign and 7.7% (1/13) grouped into the VUS category. Post-mortem genetic testing provided evidence of a genetic arrhythmic/cardiac conduction disorder as the probable pathogenic basis for approximately 4% (2/51) of sudden unexpected death (SUD) cases.