Genetic Determinants of Hereditary Bradyarrhythmias: A Contemporary Review of a Diverse Group of Disorders

Abstract Bradyarrhythmia is a common clinical presentation. Although the majority of cases are acquired, genetic screening of families with bradyarrhythmia has led to the discovery of a growing number of causative hereditary mutations. These mutations can interfere with any of the steps required for the occurrence of each cardiac cycle, including generation of an action potential in the sinoatrial node, successful exit of the action potential from the node, propagation of the action potential throughout the atria until the depolarization waves reach the atrioventricular node, and finally transmission of the action potential to the ventricles through the His-Purkinje system. As expected, channelopathies are the predominant culprit for hereditary bradyarrhythmias, because they play a crucial role in action potential generation and propagation. Interestingly, there are an increasing number of genes that encode for various regulatory or structural cellular components that have been linked to hereditary bradyarrhythmias. Furthermore, population-based genetic screening has revealed that age-related conduction defects may in fact be caused by genetic predispositions rather than the simple process of aging. With recent advances in genetic testing and the creation of animal models, not only have we discovered new culprit genes but it has also has become evident that there are still significant gaps in our knowledge of cardiac pathophysiology. In this review, we discuss the clinical presentations of known hereditary bradyarrhythmias and their associated conditions in addition to detailing our current molecular understanding of the mechanisms by which they are manifested.