Sudden death during the first year of life is a leading cause of infant mortality in developed countries. Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy as well as to perinatal and neonatal morbidity and mortality, but the relationship to genetic disorders presenting later in life is unclear. For exampe, mutations in SCN5A encoding the cardiac sodium channel have been associated with a spectrum of increased sudden death risk extending from fetal life to adulthood. Carriers of certain SCN5A mutations present with earlier onset and more severe congenital arrhythmia syndromes, but the molecular basis for the unexpected severity and lethality of certain variants during early life is unknown. This is the first competing renewal for our research study that investigates links between sudden death in early life and cardiac ion channelopathies. The overarching goal of our new proposal is to understand the molecular genetic basis for arrhythmia susceptibility during early development and to determine the clinical value of this knowledge.
In Specific Aim 1, we will elucidate the contribution of developmentally regulated alternative splicing of SCN5A to arrhythmia susceptibility in early life. These experiments are based upon our preliminary evidence that a specific splice variant of SCN5A is expressed more prominently in fetal and infant heart than adult heart, which prompted our hypothesis that certain mutations and rare genetic variants cause greater functional disturbances in channels encoded by the alternatively spliced transcript.
In Specific Aim 2, we will determine correlations between a prolonged QTc observed during the neonatal period, LQTS gene mutations and persistent LQTS in later life. This work involves a strategic partnership between the Principal Investigator and investigators in Italy who will provide access to a large and unique cohort of infants and children incidentally found to have prolonged QTc intervals by systematic ECG screening. Finally in Specific Aim 3, we will determine the spectrum of genetic variation associated with malignant perinatal ventricular arrhythmia syndromes by performing exome sequencing of a cohort of subjects with unusually severe or malignant cardiac arrhythmias documented during early life. The unifying hypothesis underlying the proposed experiments is that sudden death during a period extending from mid- gestation through 1 year of life can be associated with mutations in arrhythmia susceptibility genes, and that factors such as developmentally regulated SCN5A alternative splicing or mutations with unusually severe functional consequences, possibly in novel genes, potentiate the risk of life-threatening events.
Sudden unexplained death during the first year of life is a major reason for infant mortality in the Western world. Congenital long-QT syndrome, a genetic condition associated with life-threatening disturbances in heart rhythm, can increase risk of sudden death during infancy, in newborns and even in the unborn. Our study seeks to determine the molecular basis for unusually severe forms of long-QT syndrome, to understand the long-term clinical significance of incidentally discovered long-QT syndrome in neonates, and to discover new genetic causes of life-threatening arrhythmia syndromes in babies.
|Pipilas, Daniel C; Johnson, Christopher N; Webster, Gregory et al. (2016) Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. Heart Rhythm 13:2012-9|
|Yu, Chih-Chieh; Ko, Jum-Suk; Ai, Tomohiko et al. (2016) Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. Heart Rhythm 13:1716-23|
|George Jr, Alfred L (2015) Calmodulinopathy: a genetic trilogy. Heart Rhythm 12:423-4|
|Potet, Franck; Beckermann, Thomas M; Kunic, Jennifer D et al. (2015) Intracellular calcium attenuates late current conducted by mutant human cardiac sodium channels. Circ Arrhythm Electrophysiol 8:933-41|
|Bari, Vlasta; Girardengo, Giulia; Marchi, Andrea et al. (2015) Time, frequency and information domain analysis of heart period and QT variability in asymptomatic long QT syndrome type 2 patients. Conf Proc IEEE Eng Med Biol Soc 2015:294-7|
|Beckermann, Thomas M; McLeod, Karen; Murday, Victoria et al. (2014) Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. Heart Rhythm 11:1446-53|
|Schwartz, Peter J; Volders, Paul G A (2014) Sudden death by stress: how far under the nerves should we dig to find out why LQT1 patients die? J Am Coll Cardiol 63:828-30|
|George Jr, Alfred L (2014) Use of contemporary genetics in cardiovascular diagnosis. Circulation 130:1971-80|
|Hwang, Hyun Seok; Nitu, Florentin R; Yang, Yi et al. (2014) Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants. Circ Res 114:1114-24|
|Limpitikul, Worawan B; Dick, Ivy E; Joshi-Mukherjee, Rosy et al. (2014) Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes. J Mol Cell Cardiol 74:115-24|
Showing the most recent 10 out of 32 publications