Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Much progress has been made in identifying genetic loci linked to hereditary arrhythmia syndromes over the past decade and a half. Linkage analyses for Mendelian diseases have been powerful in the discovery phases. Considerable challenges remain however, for the clinician faced with individual patients and families when the clinical symptoms are atypical or intermediate and when novel mutations or polymorphisms are reported in the course of genetic testing. To unambiguously define the deleterious nature of any given mutation, additional functional analyses are required. Such studies should not only detect the functional consequence of mutations but also the degree of severity and mechanisms that bring about the deleterious behavior. These principles apply not only to cardiac arrhythmia syndromes but also to any hereditary genetic disease. In practice, this is not always feasible or possible with current technology. This is particularly problematic when standard genetically manipulable animals (mouse) differ considerably from human, as they do in cardiac electrophysiology. An additional obstacle occurs when the target organ is not amenable to biopsy without considerable risk (e.g. heart, brain, etc.). For evaluation of genetic mutations in cardiac arrhythmia syndromes, heterologous expression of affected genes has helped tremendously. Hereditary arrhythmia syndromes include: the long QT syndrome, the Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, the short QT syndrome, and arrhythmogenic right ventricular dysplasia. We will restrict our discussion to the long QT syndrome; however, the basic principles of verifying functional consequences of mutations also applies to the other syndromes. In this chapter we will review the progress in characterizing arrhythmia-linked genetic mutations. Several areas of recent technical advancement have been achieved which we will discuss in detail. We will also highlight how biophysical, biochemical and cell-biological studies may be used to help inform clinicians in managing the more subtle and varied aspects of patients with specific mutations. Lastly, we will discuss how such studies may eventually point to therapeutic modalities that will lead to gene-specific, or personalized medicine.