Eight out of every thousands infants in the United States are born with a congenital heart defect. The most common involve the conotruncus or outflow tract of the heart. Little is known concerning the etiology of these abnormalities. The purpose of this SCOR is to identify and characterize genes required for early conotruncal morphogenesis. The approach is based upon our observation that patients suffering from DiGeorge Syndrome (DGS), Velo-Cardio-Facial syndrome (VCFS) and 30% of children with congenital abnormalities of the outflow tract of the heart (excluding those with DGS and VCFS) all carry microdeletions within chromosomal region 22q11. The fact that all tissues affected in these patients are dependent upon the cranial neural crest during early development, along with the shared genetic abnormality suggest a common etiology of these congenital defects. Further, they suggest that within chromosome 22q11 lie a gene or set of genes programmed for expression during this critical period of heart morphogenesis. Guided by these observations, we have organized 4 projects and 4 cores with the goal of isolating and characterizing genes required for conotruncal development. Our program will utilize three model systems, the human newborn with nonsyndromic conotruncal defects, the mouse embryo and mouse strains presenting conotruncal defects, and the chick embryo. Project 1, the clinical project, provides the focus for the other three projects. Project 1, with the support of the Clinical Core (A) and the Cell and Molecular Biology Core (B) will identify and evaluate newborns with conotruncal heart defects to delineate the region of chromosome 22q11 deleted. Genes within this region will be isolated, sequenced and mapped within 22q11 by Project 2 with the support of Core B and the DNA Sequencing and Analysis Core (C). Project 3 will evaluate the role of these candidate genes in mouse development as well as provide cDNA unique to cardiac neural crest for molecular evaluation in project 2 and genetic evaluation in project 1. This project will utilize both normal and trisomy mouse embryos (all of which have conotruncal defects) to evaluate neural crest function and identify possible candidate genes for analysis within the other 3 projects. The evaluation of neural crest behavior will be in collaboration with project 4. Project 4 provides the experimental embryology required for detailed evaluation of the candidate genes in cardiac neural crest function using the avian embryo in which cardiac neural crest behavior and function is best described. Upon completion of the work proposed here, we will have identified and mapped genes critical to early heart development within human chromosome 22q11 as well as identified and characterized other genes critical to outflow tract morphogenesis.
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