Hypoplastic left heart syndrome is one of the most devastating congenital heart lesions, accounting for as much as 25% of all deaths of neonates with congenital heart disease. Although there is no known etiology, hypoplastic left heart syndrome does occur at an extremely high frequency in a rare chromosomal deletion disorder called Jacobsen syndrome. These patients have multiple medical problems and have been found to be hemizygous for the distal region of chromosome 11q. This project is designed to perform initial studies in humans with Jacobsen syndrome to identify the minimal critical region in 11q for cardiac defects, and to subsequently examine non-Jacobsen patients with hypoplastic left heart syndrome for microdeletions within the cardiac minimal region at 11q. Based on the identification of the human cardiac minimal region, a mouse model will be developed, utilizing CRE/LOX strategies to generate a deletion on the mouse syntenic region on chromosome 9 that corresponds to the critical cardiac region. Generation of the anticipated cardiac phenotype in the mouse will be followed by studies in human patients that should ultimately lead to the identification of a gene(s) that causes hypoplastic left heart syndrome (HLH-1), and allow a mechanistic dissection of the developmental pathways exploiting mouse model systems. Accordingly, the Specific Aims are as follows: 1) Clinical characterization of all patients with Jacobsen and other ``q defects; 2) Genetic mapping of Jacobsen syndrome patients; 3) Screening of non-Jacobsen syndrome patients with hypoplastic left heart syndrome; and 4) Deletion of the mouse syntenic cardiac minimal region and identification of the HLH-1 gene.
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