There are 20 to 25 000 genes in the human genome. About 40% have no known function, but cardiac electrophysiologists probably think that they know their slice of the genome well. After all, there have been decades of research on the cardiac action potential and the ion channels that propagate it. A small, but growing number of reports, however, reveal noncanonical functions of ion channels that have nothing to do with the heartbeat. For example, congenital heart defects have been associated with long QT syndrome in rare cases. To investigate the relationship, Duff and colleagues generated a mouse mutant that carried the N629D mutation in the endogenous Kcnh2 gene, ie, targeted knock-in. Mutations of KCNH2 , also referred to as hERG or mERG in the human or mouse, cause long QT syndrome. The homozygous N629D/N629D mutation is lethal by day 11.5 of gestation (analogous to 7 weeks in humans). On day 9.5, the embryos have an irregular rhythm with pauses and no detectable I Kr current. If the overall phenotype were simply explained by the arrhythmia, the result would be reassuringly consistent with what we know about cardiac electrophysiology. The homozygous N629D mutation, however, also disrupted the development of the right ventricle, outflow tract, and vasculature from the aorta to …