The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics.

Abstract

Cardiomyopathies, arrhythmic syndromes, aortopathies, and other cardiovascular diseases with Mendelian inheritance are relatively frequent conditions for which genetic testing is recommended in various guidelines.1,2 The most widely recognized indication for genetic testing in patients with these conditions is to identify a causative mutation and subsequently provide pre-symptomatic or predictive testing of relatives who are at risk of developing the same disease at a later stage. This process of cascade screening of family members ensures adequate clinical surveillance of mutation carriers and allows non-carriers to be discharged from clinical follow-up. A number of studies have reported a greater cost-effectiveness combining molecular screening with clinical screening compared with isolated clinical investigations.3 Previously, genetic testing was based on conventional techniques like Sanger sequencing analysing genes one by one, but recent advances in DNA sequencing technologies have made it possible to investigate large numbers of disease genes simultaneously, making mutation analysis much faster and cheaper. These new methods are known as next-generation sequencing (NGS) and represent a major advance in the ability to identify causative mutations in families affected by genetic diseases (see Supplementary material online, Figure S1 ).4,5 However, analysis of large numbers of genes may identify a number of sequence variants of uncertain clinical significance (VUS). As a result, cardiologists and clinical geneticists who counsel and manage families with inherited cardiovascular disorders are facing a major challenge in determining the clinical relevance of NGS results.6,7 This paper gives a brief overview of the principles of NGS, discusses the general strategies for the interpretation of sequencing results, and reviews the implications of NGS for cardio-genetic services. In addition, …