Genetics and genomics of sudden unexplained cardiac death

Abstract

The aetiology of sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) is not fully explored. Expert cardiac pathology and detailed familial clinical evaluation can identify an inherited cardiac disease in up to 50% of the cases and subsequently guide the genetic investigation in the living family members. Post-mortem genetic testing, known as the "molecular autopsy", has been increasingly used in the last 15 years as a complementary diagnostic tool. Advances in next-generation sequencing technologies, allowing the use of whole exome sequencing of expanding panels of genes, provide further insight into the pathogenesis of SCD and SADS. However, identification of numerous variants of unknown significance, emphasises the importance of cautious genetic interpretation. In this review, we present the diagnostic process followed in characteristic young SCD and SADS cases. We describe current evidence regarding cardiac pathology, appropriate familial clinical evaluation, and genetic analysis performed in relatives or in the proband's DNA.