Down syndrome (DS) is a major cause of mental retardation and congenital heart disease (CHD). Little is known about the molecular events that cause the DS phenotype. The ultimate goal of the proposed research in the program is to define the genes and their functions responsible for the phenotypic features of DS. As a first step, the specific aims of the Clinical Molecular Core are designed to molecularly define the chromosomal regions deleted or duplicated in patients with partial aneuploidy 21 and specific phenotypic features. Three panels including more than 100 cell lines have been assembled. New cases are added at a rate of 10 per year. Each panel now includes a series of overlapping duplications or deletions that span the length of chromosome 21. This panel includes 53 individuals with partial trisomy 21 or partial monosomy 21. The analysis of this panel will combine definition of phenotype with high resolution cytogenetics, fluorescence in situ hybridization, and quantitative Southern blot dosage analysis.
The specific aim i s delineation of a DS (trisomy 21) phenotypic map. Molecular definition of the duplicated regions and the breakpoints will be determined by quantitative Southern blot analysis suing chromosome 21 unique DNA sequences. Phenotypic features will be established according to the NICHD DS conference (4/90). The panel is informative for holoprosencephaly, mental retardation, skeletal dysplasia, immune deficits, DS CHD, duodenal stenosis, and leukemia in addition to the physical, radiological, cognitive, neurologic and laboratory features of DS. A database will be used to record clinical, cytogenetic and molecular data. Chromosomal constitution will be determined using high resolution cytogenetic analysis and in situ hybridization. The core will provide a basic resource of partially aneuploid individuals and their cell lines with which to study the expression of chromosome 21 and the role of specific genes in determining organismal phenotype.
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