The Down syndrome critical region.

Since the early 1970's numerous attempts have been made to learn whether specific segments of chromosome 21, when triplicated, are responsible for the clinical condition Down syndrome (DS). Studies were reported in which positive or negative clinical diagnoses of DS were made in the presence of partial trisomy of one or another segment of the chromosome. The distal half of the long arm of 21 (21q22) possesses most of the gene transcribing sites of the chromosome. It was this region that was thought to contain loci essential to production of the clinical syndrome. Subsequent studies identified subregions of this band as "minimal" or "critical" sites necessary and sufficient to produce the clinical condition. A major problem with these assignments was that different investigators defined different critical/minimal regions. In 1994 evidence was presented in which regions of most of the long arm of chromosome 21 were said to contribute to the DS phenotype. Soon after, a report described a child with DS and partial tetrasomy of the short arm and proximal long arm of 21, segments clearly distinct from the previously identified critical areas. Thus the clinical diagnosis of DS can be made in the presence of partial aneuploidy of nearly all segments of chromosome 21. It must be concluded that no evidence exists that individual loci on 21 are singularly responsible for specific phenotypic abnormalities in DS. Without exception, each of the clinical findings associated with DS is a multifactorial trait. The analysis of each trait in DS should thus be similar to analyses of the same traits in the general population with a focus on the way aneuploidy affects expression of multifactorial characteristics.