DOWN-SYNDROME PHENOTYPES - THE CONSEQUENCES OF CHROMOSOMAL IMBALANCE

Down syndrome (DS) is a major cause of mental retardation and congenit al heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointe stinal tract, an increased risk of leukemia, immune system defects, an d an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical m ap of chromosome 21 allows the molecular definition of the regions dup licated in these rare cases of partial trisomy. As a first step in ide ntifying the genes responsible for individual DS features and their pa thophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determin ed using fluorescence in situ hybridization and Southern blot dosage a nalysis of 32 markers unique to human chromosome 21. Combining this in formation with detailed clinical evaluations of these patients, we hav e now constructed a ''phenotypic map'' that includes 25 features and a ssigns regions of 2-20 megabases as likely to contain the genes respon sible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the fa cies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics , and mental retardation. This strongly suggests DS is a contiguous ge ne syndrome and augurs against a single DS chromosomal region responsi ble for most of the DS phenotypic features.