Cardiovascular malformations (CVM) are a common class of birth defects that are major contributors to infant mortality and cost of neonatal care. A large body of epidemiological data has established that genetic factors play a large role in the causes of CVM. An important group of genetic abnormalities, called genomic disorders, involve imbalances in chromosomal copy number - usually deletions or duplications involving one or a few adjacent genes. Submicroscopic chromosomal imbalances have already been found to be important in several common complex or syndromic forms of CVM. These disorders are most likely to be observed in patients affected with CVM plus multiple congenital anomalies (MCA), but only approximately 10% of such cases have a known genomic disorder. Until recently, it has not been technically feasible to comprehensively survey the genome for such imbalances. In preliminary studies we have used several newly available microarray platforms to establish protocols for genome-wide survey of alterations in chromosomal copy number. In a feasibility study we found that about one third of CVM/MCA cases have relatively large submicroscopic chromosomal aberrations. In this research program, we propose to expand the copy number analysis of CVM/MCA cases. The results will allow more precise assessment of the frequency of pathological variants and to better characterize how they play a causal role in CVM. We propose to characterize the boundaries of the chromosomal imbalance events and to investigate the potential molecular mechanisms of gene dysfunction. We will prioritize individual genes that might play a direct role in the CVM phenotype and then examine whether more subtle mutations in those genes play a role in isolated or non-syndromic CVM. Identification of specific genes that underlie CVM would improve understanding of the origins of these common anomalies. Improved ability to screen for chromosomal imbalances and mutations in relevant genes will aid in diagnosis and early intervention for CVM.
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