DESCRIPTION (Adapted from the Investigator's Abstract): Numerical chromosome anomalies account for a significant proportion of childhood diseases. Much remains to be learned about cellular mechanisms responsible for faithful chromosome segregation and maintenance of the normal genomic constitution. One approach to the elucidation of these basic cellular functions is through the characterization of heritable disorders exhibiting mutant cellular phenotypes. Given that chromosome segregation is essential for viability, few human disorders have been identified which exhibit faulty chromosome segregation. However, one such disorder is Roberts syndrome (RS). This rare autosomal recessive disease is clinically manifested by mental and growth retardation, tetraphocomelia, and variable craniofacial abnormalities. Cell lines derived from RS patients exhibit cytogenetic abnormalities which include random chromosome loss and the premature separation at metaphase of heterochromatic regions, a cytological phenomenon referred to as heterochromatic repulsion (HR). RS cells also exhibit subtle hypersensitivity to a broad spectrum of agents, including certain mutagens. Biochemical approaches have not provided insights into RS and the disorder is too rare for classic genetic linkage analysis. Somatic cell hybridizations have demonstrated complementation of both the HR and hypersensitivity phenotypes. The present application proposes to map the gene which complements these phenotypes. RS cells will be fused with microcells bearing few (1 to 4) chromosomes derived directly from normal human cells. Direct human-human transfer eliminates the need to establish the usual somatic cell hybrid intermediates used in microcell chromosome transfer and facilitates assessment of effects rendered by simultaneous transfer of several chromosomes. Automated genotyping will be used to correlate complementation with a newly introduced chromosome(s). Similarly, chromosomes transferred from cell lines bearing relevant deletions or derivatives will facilitate finer mapping of the complementing locus. Genes previously mapped to the area will be evaluated in a "candidate gene" approach or, beyond the scope of this proposal, mapping data will be used for positional cloning of the gene. Identification of a gene which corrects RS cellular phenotypes should provide new insights into mechanisms which influence numerical chromosome content and the avoidance of birth defects.