De Novo Mutation in the SCN5A Gene Associated With Early Onset of Sudden Infant Death

Abstract

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.

Recurrent Third-Trimester Fetal Loss and Maternal Mosaicism for Long-QT Syndrome

“…The important role of de novo mutations in perinatal LQTS is supported by the fact that disease-causing mutations at the same SCN5A residue (1623) have arisen independently at least 3 times, 3,14,25 and a number of other spontaneous mutations in LQTS-associated genes have been linked to lethal arrhyth-mias in the fetus and neonate. 5,28,29 The poor prognosis of infants with neonatal LQTS undoubtedly also contributes to low heritability.…”

A Novel mutation L619F in the cardiac Na channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating

“…However, the L619F mutation also causes an increase in Na + channel window current, which enhances Na + channel activity in a different voltage range. Whereas an increase in the magnitude of window current has been previously reported for LQT3 mutations (Abriel et al, 2001;Wedekind et al, 2001), a combination phenotype of increased sustained current and enhanced window current is new. Increased Na + channel activity underlies prolongation of the ventricular action potential, which is manifested as lengthening of the QT interval on the electrocardiogram of the mutation carriers.…”

Sudden infant death syndrome and long QT syndrome: The zealots versus the naysayers

“…While recognized risk factors suggest that SIDS is a heterogeneous entity with multifactorial pathogenesis, the LQTS hypothesis [13,14] has continued to garner support in the cardiovascular field due to reports of prolongation of the QT interval in SIDS cases [15,16] and identification of mutations in the same ion channel genes that cause LQTS in SIDS postmortem genetic samples [17][18][19][20][21]. The epidemiologic significance of these findings is the subject of ongoing debate [22,23].…”