Defining the disconnect between in vitro models and human arrhythmogenic disease: context matters.

Understanding the pathogenetic chain of events between genotype and phenotype is critical to the appropriate diagnosis and treatment of heritable diseases. Although our knowledge of the molecular substrate of many diseases continues to increase, identifying the mechanistic links between a susceptibility variant and disease expression remains a major challenge. A minority of mendelian diseases display complete clinical penetrance in individuals harboring known disease-causing mutations, with rare examples such as achondroplasia and Huntington disease. Even in the most wellcharacterized hereditary arrhythmia syndrome, the long-QT syndrome (LQTS), in which genotype-phenotype relationships and gene-specific management strategies1 exist for the most common molecular subtypes (LQTS 1 to 3), the reasons for incomplete penetrance and variable expression in this disease remain largely unknown. In fact, LQTS has relatively low penetrance; however, in those LQTS genotype-positive individuals who do exhibit symptoms, the initial presentation can be catastrophic, and all too often, families come to clinical attention as a result of aborted cardiac arrest or sudden cardiac death. Therefore, identification of diseaseassociated mutations in individuals at risk for heritable arrhythmogenic disorders is imperative for subsequent risk reduction in their family members and them.