Look beyond the hERG mutation: A neutral SCN5A variant may turn lidocaine into a threat

n f m t e p c t fi t p a n t R t i m d T h 1 p t m i o B t c p i s a f r t u P c B The long QT syndrome (LQTS) is an inherited cardiac isorder associated with susceptibility to life-threatening entricular arrhythmias and sudden cardiac death, affecting bout 1 in 1,000 to 2,000 people worldwide. More than 40 ears after the first clinical finding of a familial ECG trait ith unusually prolonged QT interval, more than 700 muations in 10 LQTS-associated genes have been identified Gene Connection for the Heart, Fondazione Maugeri Pavia, taly, www.fsm.it/cardmoc), mostly affecting the function f proteins that are directly involved in generation of the ardiac action potential (AP). The better understood forms f LQTS result from inherited monogenic mutations causng either a loss of function in a repolarizing ion channel e.g., hERG), or a gain of function in a depolarizing ion hannel (e.g. SCN5A), resulting in a prolonged cardiac AP. he phenotype of most symptomatic LQTS patients correates generally well with the underlying genotype, but here are noteworthy cases of carriers of the same mutation xhibiting a striking phenotypic variability. These interinividual differences in disease presentation may arise from bvious subjective factors (e.g., comorbidity with other ardiac diseases), but it is becoming clear that the genetic ackground plays a significant role in both the disease xpression and the effectiveness of the therapy (for review ee Saenen and Vrints). In fact, more severe disease varints have been associated with the expression of genetic odifiers, ranging from the coexistence of a second mutaion on the same LQTS gene to the presence of common olymorphisms either on the LQTS gene or on other enes. In this issue of Heart Rhythm, Lin et al describe the nusual in utero presentation of intermittent AV block and entricular tachycardia in a fetus and his sibling with long T syndrome. Two distinct mutations were found in the roband: an LQTS type 2 mutation in hERG, the gene oding for the rapidly activating delayed rectifier K chan-