Chapter 6 - Gene-dosage imbalance due to trisomic HSA21 and genotype–phenotype association in Down syndrome

Abstract

Gene-dosage imbalance appears central causing phenotypic expression in individuals with Down syndrome (DS), their facial and cognitive differences, and early onset of Alzheimer disease (AD) and/or aging compared to the euploid population. Besides, the impact of the triplicated HSA21 genes and the cooperating effects of the disomic genes further complicate the genotype–phenotype basis of phenotypic variability in DS. Molecular understanding has tagged some of the HSA21 genes with DS phenotypes; however, disrupted genomic homeostasis is yet to be delineated with DS features aiming at therapeutic developments. Altogether, a cocktail of overexpressed, underexpressed, and compensated genic expression has indicated interaction of genic and nongenic complements, including epigenetic and environmental components. The situation is more complex for mosaic or translocated DS. Nonetheless, research on DS pathomechanism is primarily concentrated on primates and/or cell lines developed from DS patients. Specific link of triplicated DSCR1, DYRK1A, APP, SOD, RCAN1, RUNX1, ETS2, ERG, etc. with DS phenotypes, AD, cardiac defects, leukemia, and others has often been contradicted in studies involving reduction of trisomy to disomy through cross-breeding of DS mouse models. Thus, collective effects of gene-dosage imbalance, allelic variations, and contribution of modifier genes of the global genome and coincidental small effects confer phenotypes in DS individuals. Moreover, gene expression in different trisomic tissues at different developmental stages and also altered transcription to proteomic translation render variable clinical phenotypes in individuals with DS. This chapter has summarized the gene-dosage imbalance, interaction of genes, transcriptomes, and proteomics in trisomic condition, with a view to understanding the factors of phenotypic variability in DS patients.