Next-generation sequencing represents a major advance in identifying causative mutations for hereditary cardiovascular conditions, though interpreting variants of uncertain significance remains a challenge.
This viewpoint paper provides guidance on the clinical application, interpretation, and ethical considerations of next-generation sequencing in patients with inherited cardiovascular diseases.
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, 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 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, issues related to genetic counselling and ethical considerations are discussed. A summary of viewpoints is given in Table 1.
Mogensen et al. (Sun,) conducted a review in Hereditary cardiovascular conditions. Next-generation DNA sequencing (NGS) vs. Conventional techniques (Sanger sequencing) was evaluated. Next-generation sequencing represents a major advance in identifying causative mutations for hereditary cardiovascular conditions, though interpreting variants of uncertain significance remains a challenge.