Growing Pains in Cardiovascular Genetics.

Over half a century ago, heart specialists – there were no board certified cardiologists yet – began to report unusual phenotypes like very long QT intervals or extraordinary left ventricular hypertrophy that ran in families and caused sudden death in the young. In the 1980s and 90s, linkage analysis in large families identified the first disease genes, landmark discoveries that have been critical for understanding basic physiologic and pathophysiologic processes in the heart, counselling families, defining penetrance that is so often incomplete, and identifying phenotype positive patients in whom coding region variants in these first disease genes were absent. In those patients, disease pathways defined by early rigorous linkage-based studies implicated new candidate genes for mediating these cardiovascular genetic phenotypes. So, for example, once beta-myosin heavy chain mutations were identified in hypertrophic cardiomyopathy (HCM), genes encoding other contractile proteins became logical candidates; similarly, ion channel genes or modifiers were candidates in channelopathies and desmosomal proteins in arrhythmogenic right ventricular cardiomyopathy (ARVC). As a result, we now have long lists of disease genes for major cardiovascular genetic diseases, and dramatic improvements in sequencing costs and efficiencies have enabled widespread application of panel-based sequencing. While these advances have improved care of affected patients and their families, two papers in the current issue of Circulation highlight potential flaws in the logic that underlies increasing use of these panels across large patient populations.,