Approximately 1 in 2000 newborns has an apparently balanced chromosome rearrangement, with 6.1% and 9.4% risks for a serious congenital anomaly from a de novo translocation and inversion, respectively. These anomalies include isolated defects ranging from cleft lip/palate, abdominal wall defects, limb defects, cardiac abnormalities or mental retardation, or they can occur as part of clinically recognizable syndromes. Consequently, these rare individuals offer a unique resource for functional annotation of the human genome and for revealing mechanisms operative in human development that would be difficult or impossible to identify with less complex systems. The goal of the Developmental Genome Anatomy Project (DGAP) is to pursue functional genomics in humans by capitalizing on balanced chromosomal rearrangements in subjects with developmental abnormalities to identify genes and conserved sequences critical to development that are disrupted or dysregulated. Following the observation that de novo structural abnormalities involving all chromosomes have been reported in association with congenital anomalies, it has been speculated that a significant number of such chromosomal breaks directly disrupt or dysregulate genes critical to specific molecular pathways. So far, we have identified over 150 such genes in DGAP subjects. In other cases, the mechanism of disruption does not directly break the gene but rather alters its regulation. In this renewal application of DGAP, we propose to continue our study of individuals with multiple congenital anomalies and apparently balanced chromosomal rearrangements with the aim of furthering gene discovery, delineation of regulatory elements and implication of conserved sequences of unknown function. Balanced chromosomal rearrangements will serve as the signposts to identify these critical genes. In addition we will extend our efforts in structural variation to explore the role of crypti rearrangements in human morbidities as well as annotating the genome for rearrangements without phenotypic consequences.
The Developmental Genome Anatomy Project (DGAP) is largely focused on studies of a group of subjects with structural variation underserved by the health care system: those with congenital abnormalities due to balanced chromosome rearrangements. Our mission is to discover genes of importance in human development that are disrupted by these chromosomal rearrangements--genes that are difficult to identify by more traditional human genetic strategies--thereby opening investigation of the disorders that they cause. In addition, an expanded scope of DGAP includes individuals with balanced chromosome rearrangements and no clinical phenotype for further annotation of the human genome for genes where a single copy is sufficient for normal development.
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