Approximately 1 in 2000 newborns has an apparently balanced rearrangement, with a 6.1% risk from a de novo translocation and a 9.4% risk from a de novo inversion for a serious congenital anomaly. These anomalies can 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 cfe 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. In the first period of funding we identified a number of such genes in DGAP research subjects. In others, the mechanism of disruption does not directly break the gene but rather alters its regulation. In this resubmission 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. Collaborations between cytogeneticists and clinical geneticists across the medical genetics community have been established to collect patient samples with a variety of developmental defects and balanced chromosomal rearrangements. Analysis of chromosomal breakpoints through FISH mapping studies is used to identify single genomic clones containing relevant candidate sequences, and an online DGAP database is available (Project 1). Molecular identification and analysis of candidate genes and other conserved sequence elements, as well as mutation studies in affected individuals is the focus of subsequent studies (Project 2). Development and characterization of model organisms for the candidate genes identified will establish pathogenicity in the human disorders (Project 3). Administrative and Clinical Genetics Cores support the research endeavor. DGAP constitutes multi-laboratory and multi-institutional research encompassing the disciplines of clinical genetics, cytogenetics, molecular biology and developmental genetics to illuminate genes involved in fundamental pathways during human development. RELEVANCE: The Developmental Genome Anatomy Project studies a group of patients underserved by the health care system: those with congenital abnormalities due to 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.