Challenges in Molecular Diagnostics of Channelopathies in the Next-Generation Sequencing Era: Less Is More?

Inherited arrhythmogenic diseases (IADs – also called cardiac channelopathies) are defined as a group of genetic diseases characterized by electrically unstable substrate in a structurally normal heart (1). Genetic testing in cardiac channelopathies has completed its transition from a research-based activity to that of a clinical genetic service. In parallel, the advancements of the sequencing technologies are providing ways to sequence several genes at a relatively low cost. This is progressively changing the approach to the genetic diagnosis of IADs. Indeed, while Sanger-based genetic testing was traditionally limited to the well characterized, most prevalent genes, next-generation sequencing (NGS) allows screening even the “minor” disease genes with very short turnaround time. This approach to genetic testing is highly efficient, but it is also generating remarkable interpretative problems mostly related to the high prevalence of variants of unknown significance (VUS), i.e., not clearly related to disease pathophysiology. This issue is relevant to several genetic diseases of the heart but is particularly evident in IADs, where the familial co-segregation analysis is hampered by the incomplete penetrance and the variable expressivity. How to design the most appropriate screening approach is challenging and it requires in-depth knowledge of the specific diseases of interest. In this Opinion article, we will review the available NGS approaches and try to outline the available strategies to optimize the performance of this genetic testing methodology.