Genotype-Phenotype Correlation in Congenital LQTS: Implications for Diagnosis and Risk Stratification

Abstract

The hereditary long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphic ventricular tachycardia (torsade de pointes), and sudden arrhythmic death. This inherited cardiac disorder constitutes an important cause of malignant ventricular arrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. Diagnosis relies on combined assessment of ECG and clinical factors related to the patient’s personal and family history and may be difficult in approximately one quarter of LQTS subjects who present with a normal range QTc. Genetic testing is important for both diagnosis and risk assessment. Accumulating data from the International LQTS Registry have facilitated a comprehensive analysis of risk factors for aborted cardiac arrest or sudden cardiac death in prespecified age-groups, including the childhood, adolescence, adulthood, and post-40 years periods. These analyses have consistently indicated that the phenotypic expression of LQTS is time-dependent and age-and sex-specific, warranting continuous risk assessment in affected patients. Furthermore, the biophysical function, type, and location of the ion-channel mutation are currently emerging as important determinants of outcome in genotyped patients. These new data may be utilized to improve risk stratification and for the development of gene-specific therapies that may reduce the risk of life-threatening cardiac events in patients with this inherited cardiac disorder.