Neonatal Long QT Syndrome and Sudden Infant Death

Project: Research project

Project Details


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 example, 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 midgestation
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.
Effective start/end date8/1/147/31/18


  • National Heart, Lung, and Blood Institute (5R01HL083374-08)


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