Pediatrics

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The Genetics of Left Ventricular Outflow Tract Obstruction

Congenital heart defects are the common congenital anomaly, occurring in approximately 3-6% of live births. Of the patients with CHD, 14-25% will have defects in the cardiac valves and associated structures. While these defects occur in the setting of other clinical syndromes, it is increasingly recognized that these defects occur in the absence of other syndromes and that there are familial aggregations in CHD, particularly in patients with left sided left ventricular outflow tract (LVOT) defects. In addition, with increasing success in treating patients with these defects there is an increasing adult population who may require additional interventions.  Indeed valvular heart disease remains a major cause of morbidity and mortality in adults in the United States. The LVOT obstruction (LVOTO) malformations consist of an anatomically varied set of defects across a wide spectrum of clinical severity, including bicuspid aortic valve (BAV), aortic valve stenosis (AVS), coarctation of the aorta (COA), interrupted aortic arch (IAA), hypoplastic left heart syndrome (HLHS), and Shone complex. Left-sided flow abnormalities account for about 14% of CHD and probands exhibiting one LVOTO trait can have affected relatives with different phenotypic presentations suggesting common pathways leading to these LVOTO malformations.

Our hypothesis is that defects in endocardial cushion endothelial to mesenchymal transdifferentiation pathways lead to LVOT malformations. To test this hypothesis we propose the following specific aims:

1)      Enroll patients with LVOT defects and screen them for mutations in pathways involved in endothelial proliferation and differentiation. Once patients are enrolled we will obtain DNA specimens to prepare DNA for genetic studies.  Candidate genes will be amplified by polymerase chain reaction (PCR) and the PCR products analyzed using a Lightscanner, a relatively new system for detecting genetic variants.  Any samples giving abnormal profiles will be analyzed by DNA sequencing.

2)      Inject zebrafish embryos with morpholinos to knockdown the expression of genes involved in EMT pathways and investigate the effect on cardiac development, focusing on valve formation and ventricular function. We have previously characterized the developing zebrafish myocardium both in terms of structure and function using histological and echocardiographic techniques.  We will perform similar studies in morpholino-treated fish to investigate the effect of knocking out gene function on cardiac development and function.

12/07