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 disease, is an important cause of sudden cardiac death. Prolongation of the QT interval has recently been associated with sudden infant death syndrome, which 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 contribute to premature sudden cardiac death in otherwise healthy infants. METHODS AND
RESULTS: In an infant who died suddenly at the age of 9 weeks, we 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 ventricular 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 paternity, thus suggesting a de novo origin. Voltage-clamp recordings of recombinant A1330P mutant channel expressed in HEK-293 cells showed a positive shift 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 channel gene SCN5A, which is associated with sudden infant death. The altered functional characteristics of the mutant channel was different from previously reported LQTS3 mutants and caused a delay in final repolarization. Even in families without a history of LQTS, de novo mutations in cardiac ion channel genes may lead to sudden cardiac death in very young infants.