Hypoplastic left heart syndrome (HLHS) is one of the most lethal forms of congenital cardiovascular malformation. Genetic epidemiological studies have demonstrated an increased prevalence of left heart obstructive disease in first degree relatives of patients with HLHS, suggesting a genetic etiology. HLHS is the severe, neonatal presentation of the spectrum of left heart obstructive diseases, which includes first trimester spontaneous abortion, HLHS, aortic and mitral stenosis, coarctation and bicuspid aortic valve. With 2 percent of the general population having a bicuspid aortic valve, these lesions are extremely common. By investigating a more severe phenotype such as HLHS, we may gain insight into the pathogenesis of the more common forms of left heart obstructive disease such as first trimester spontaneous abortions and bicuspid aortic valve. Jacobsen syndrome (characterized by translocation or terminal deletion of 11q23.3) is frequently associated with left heart obstructive disease and supports a gene locus for left heart obstruction at 11q23.3. We have a fibroblast cell line containing a de novo balanced translocation t(10; 11) (q24.3; q23.3) from a non-syndromic female infant with HLHS. This translocation is likely to disrupt a gene(s) at 11q23.3 that causes HLHS. We have physically mapped the breakpoint by fluorescence in situ hybridization to a single 1.5 Mb YAC clone. Using markers from the spanning YAC, we identified proximal and distal BACs by FISH. We describe both physical mapping and gene based approaches to identifying the disrupted 11q23.3 gene. Mutational screening of the 11q23.3 gene will utilize single- stranded conformational polymorphism analysis. With the 11q23.3 gene, clinical correlation studies using the cardiovascular phenotype and these genetic findings may establish that left heart obstruction shares a common pathogenesis. My career goals are to investigate the cause of HLHS and congenital cardiovascular malformations. The K08 will provide the necessary training in molecular genetics to accomplish these goals. Dr. Lifton is a recognized leader in cardiovascular genetics and his. mentorship is a vital component to my career development. The Departments of Pediatrics and Genetics at Yale combined with the extensive resources of the Lifton laboratory provide an ideal environment for acquiring the investigative skills needed to launch my research career. This award provides all of the essential components to develop my career and will maximize my academic potential.
