Understanding the basis for Down syndrome phenotypes

Abstract

Down syndrome is a collection of features that are caused by trisomy for human Chromosome 21. While elevated transcript levels of the more than 350 genes on the chromosome are primarily responsible, it is likely that multiple genetic mechanisms underlie the numerous ways in which development and function diverge in individuals with trisomy 21 compared to euploid individuals. We consider genotype-phenotype interactions with the goal of producing working concepts that will be useful for approaches to ameliorate the effects of trisomy.

Figure 1. Possible Phenotypic Consequences of Gene Action in Down Syndrome

(A) A trisomic gene or genes might directly affect cellular function in a fully differentiated cell to cause a functional phenotype of DS or in an immature cell to produce a developmental phenotype. (B) Trisomic genes may alter expression of disomic genes, leading to a cellular manifestation and a DS phenotype. A trisomy-induced change in cellular function altering the relationship of that cell to surrounding cells leads to a secondary distortion of (C) disomic gene expression or (D) function in neighboring cells. Modifier genes or environment (yellow box) might interact at multiple points to initiate, ameliorate, or exacerbate phenotypes.

Figure 2. A Primary (1°) Effect of Trisomy Produces an Aberrant Phenotype as the Cells Proliferate

Trisomy causes a primary defect in (circular) cells as they proliferate. This primary defect results in a signaling error to neighboring (square and triangular) cells, resulting in their aberrant development as a secondary (2°) consequence of trisomy. Plain background indicates normal cells; striped background indicates an aberrant phenotype.