Genetic interactions and co-operating effects of non-HSA21 genes on the phenotypic variability in Down syndrome

Abstract

Trisomy 21 (T21) defines the complex characteristics of Down syndrome (DS). However, enormous variation has been documented in the multifarious features of the syndrome, regardless of full or partial T21 among individuals with DS. Individual variability exists in degree of manifestation for each subset of the DS-features, especially intellectual disability, characteristic facial/physical dysmorphology, a hypocellular brain, and Alzheimer's disease (AD), though constitutively present in all DS. A small segment in the chromosome 21 (HSA21) was designated as the Down Syndrome Critical Region (DSCR) responsible for defining DS characteristics; however, DSCR dogma has been challenged due to variability in penetrance and expressivity of DS-phenotypes. Characterization of genes identified in human DS and recombinant mouse models of DS have postulated that DS-features are not the sole contribution of DSCR genes but the possibility of interaction among non-contiguous genes might exist. Several studies suggested that DSCR region is necessary for some of the DS-phenotypes but not sufficient to produce most of the DS-specific features such as congenital heart defect (DS-CHD) and leukemia. Further, allelic variation, epigenetic and environmental impact and small effects of modifier genes might result in perturbation of genetic homeostasis in subjects with DS. Collectively, the solitary effect of a triplicated gene was demonstrated to be inconspicuous; however, its contribution to trisomic phenotypes was predicted likely in antagonistic or synergistic association with other specific genes. Nevertheless, gene-phenotype association has remained unanswered for complex expression of the DS-phenotypes at the backdrop of trisomic HSA21.