Down syndrome phenotypes: the consequences of chromosomal imbalance.

TLDR

Down syndrome, caused by trisomy 21, is a leading cause of intellectual disability and congenital heart disease and is associated with characteristic facial features, gastrointestinal anomalies, leukemia risk, immune defects, Alzheimer‑like dementia, and serves as a model for studying human aneuploidy. Using the chromosome‑21 physical map, the authors established a panel of cell lines from 16 individuals with partial trisomy and mapped their breakpoints by FISH and Southern blot of 32 chromosome‑21 markers. The study produced a phenotypic map linking 25 clinical features to 2–20 Mb chromosomal regions, demonstrating that genes beyond the D21S55 locus contribute to Down‑syndrome traits and supporting the view that DS is a contiguous‑gene syndrome rather than driven by a single region.

Abstract

Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and 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 map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, we have now constructed a "phenotypic map" that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.