De novo mutation in the SCN5A gene associated with early onset of sudden infant death

Background-Congenital long QT syndrome (LQTS), a cardiac ion channel diseas e, is an important cause of sudden cardiac death. Prolongation of the QT in terval has recently been associated with sudden infant death syndrome, whic h is the leading cause of death among infants between 1 week and 1 year of age. Available data suggest that early onset of congenital LQTS may contrib ute to premature sudden cardiac death in otherwise healthy infants. Methods and Results-In an infant who died suddenly at the age of 9 weeks, w e performed mutation screening in all known LQTS genes. In the surface ECG soon after birth, a prolonged QTc interval (600 ms(1/2)) and polymorphic ve ntricular tachyarrhythmias were documented. Mutational analysis identified a missense mutation (Ala1330Pro) in the cardiac sodium channel gene SCN5A, which was absent in both parents. Subsequent genetic testing confirmed pate rnity, thus suggesting a de novo origin. Voltage-clamp recordings of recomb inant A1330P mutant channel expressed in HEK-293 cells showed a positive sh ift in voltage dependence of inactivation, a slowing of the time course of inactivation, and a faster recovery from inactivation. Conclusions-In this study, we report a de novo mutation in the sodium chann el gene SCN5A, which is associated with sudden infant death. The altered fu nctional characteristics of the mutant channel was different from previousl y reported LQTS3 mutants and caused a delay in final repolarization. Even i n families without a history of LQTS, de novo mutations in cardiac ion chan nel genes may lead to sudden cardiac death in very young infants.