Molecular Underpinning of “Good Luck”

Abstract

The concept that the phenotype observed in patients affected by inherited arrhythmogenic diseases is determined exclusively by the primary genetic defect, transmitted as a mendelian trait, has been questioned by a substantial body of clinical literature showing that incomplete penetrance and variable expressivity are common features of these diseases.1,2 Investigations demonstrating genotype–phenotype correlations have provided major advances in the understanding of arrhythmogenic disease.3–6 These studies defined the average behavior (symptoms, prognosis, and response to therapy) of a population of individuals who carry a mutation in a given disease-related gene. From these studies, we now know, for example, that long-QT syndrome (LQTS) patients with mutations on the HERG gene have greater QT interval prolongation and a more malignant clinical course than LQTS patients with mutations of the KCNQ1 gene and that they are less likely to respond to antiadrenergic therapy.5,6 Article p 368 These data are extremely helpful in guiding our therapeutic decisions but do not explain why some individuals belonging to a high-risk group remain asymptomatic for their entire lives or why other subjects with a benign clinical profile experience cardiac arrest. The issue of incomplete penetrance is particularly puzzling in Brugada syndrome,7,8 a disease in which the clinical manifestations can be highly variable within the same family and in which it is the rule, rather the exception, to find close relatives who share the same mutation in the SCN5A gene with different manifestations. While one family member with the mutation may show a completely normal ECG, another may have overt ECG manifestations of the syndrome and recurrent cardiac arrest. Therefore, the study by Poelzing et al9 in this issue of Circulation not only is a stimulating basic science report but more importantly provides clinicians with insight into the complexity of inherited arrhythmogenic syndromes. This …