Increasing sensitivity—a common-sense approach?

Excerpt

In this issue of the Netherlands Heart Journal, two manuscripts and an editorial emphasise the challenges of genetic counselling in cardiomyopathies. Advances in genetic screening have increased the number of genes that can be screened to trace disease-causing variants and enable the identification of a large group of people at risk of developing cardiac arrhythmias and heart failure. The downside, as emphasised in this issue, is that the ability of screening a large panel of genes also uncovers many gene variants of unknown clinical significance (VUS). After the initial enthusiasm about expanded gene panels, scientists became more and more aware that not all known variants are pathogenic and are, in fact, quite common in the general population. The use of the term gene mutation is under debate as mutation implies pathogenicity, while most newly detected gene variants are not pathogenic. Thus, gene variant would be a better term than mutation, and ‘gene variant carrier’ may be used for persons who are at risk of cardiomyopathy. Yet, at the same time, this is where the clinical problem lies. The study by van Lint and colleagues shows that many gene variant carriers may not be at risk of developing a cardiac arrhythmia or cardiac disease [1]. The actual pathogenicity of gene variants appears to vary from disease-causing to being a disease modifier. From a clinical perspective, a new discussion about the clinical utility of large gene panels is warranted, and Dooijes, Siemelink and Baas propose in their editorial that a national consensus about smaller diagnostic gene panels with optimal sensitivity and specificity would aid to optimise genetic screening and counselling, and improve the identification of persons with an actual pathogenic gene variant [2]. …