| Dilated cardiomyopathy (DCM) is a leading cause of heart failure and sudden cardiac death worldwide. While DCM can occur as a secondary consequence of other disease processes, it is now well recognized that genetic factors underlie the pathogenesis of the intrinsic myocardial disease of DCM. Nevertheless, DCM remains an idiopathic disorder in a majority of patients who undergo clinical genetic testing. The advent of next generation sequencing now enables exome-wide mutation scanning to discover primary molecular genetic defects that cause sporadic DCM in children. Chapter I provides a clinical and genetic overview of DCM, and introduces next generation sequencing as a transformative technology for novel gene discovery. Chapter II details the application of whole exome sequencing as a strategy to uncover the genetic underpinnings of DCM in a pediatric cohort. Chapter III documents the identification of de novo mutations in known DCM genes as a cause for sporadic pediatric DCM. Chapter IV demonstrates the utility of whole exome sequencing to solve a diagnostic dilemma in a patient presenting with nonsyndromic DCM. Chapter V offers an explanation for early-onset heart failure through discovery of a novel modifier gene with correlative electron microscopic findings. Chapter VI describes a variably penetrant, functionally characterized susceptibility variant in pediatric DCM. Chapter VII highlights the synergy of whole exome sequencing, ultrastructural analysis of cardiac tissue, and zebrafish modeling for novel autosomal recessive DCM gene discovery and validation in a sibling pair with end-stage heart failure. Chapter VIII establishes a novel, functionally validated de novo mutation in syndromic fetal-onset DCM. Chapter IX summarizes and highlights the significance of our genetic findings in pediatric DCM, and concludes by outlining future directions for novel gene discovery and functional validation in pediatric DCM. |
