Down syndrome

Abstract

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. This endeavour is challenging, as there are >200 protein-coding genes on chromosome 21 and they can have direct and indirect effects on homeostasis in cells, tissues, organs and systems. Although this complexity poses formidable challenges to understanding the underlying molecular basis for each of the many clinical features of DS, it also provides opportunities for improving understanding of genetic mechanisms underlying the development and function of many cell types, tissues, organs and systems. Since the first description of trisomy 21, we have learned much about intellectual

Consequences of aneuploidy in human fibroblasts with trisomy 21

“…This fact is consistent with a correlation between the number of genes on the triplicated chromosome and the degree by which aneuploidy disrupts cellular physiology. In the context of Down syndrome, a genecentric view poses that increased expression of the triplicated genes encoded on chromosome 21 causes cellular defects (Antonarakis et al, 2004;Antonarakis et al, 2020). Our studies show that trisomy 21 cells shared several phenotypes with other mammalian aneuploid cells, including trisomic MEFs, human trisomies 13 and 18, and even with aneuploid yeast cells (Hwang et al, 2019;Pfau and Amon, 2012;Stingele et al, 2012;Torres et al, 2007;.…”

“…The phenotypes associated with trisomy 21 at the organismal level are complex as individuals with Down syndrome are born with varying severities of and higher risks for several human diseases (Antonarakis et al, 2020). There are two main gene-centric hypotheses proposed to explain the biological consequences of trisomy 21.…”

“…Examples include genes that regulate splicing (U2AF1L5, RBM1, U2AF1), chromatin regulators (HMGN1, BRWD1), secretory-endosomal functions (DOPEY2, CSTB, and SYNJ1), protein turnover (USP25), or metabolism (SOD1). Nonetheless, it has been challenging to prove that a third wild type copy of a given gene encoded on chromosome 21 is solely the main driver for a particular disease (Antonarakis et al, 2004;Antonarakis et al, 2020).…”

An Approach to the Airway Management in Children with Craniofacial Anomalies

“…Genetics: Down's syndrome is a congenital autosomal disorder caused by the existence of a third copy, full or partial, of the chromosome 21 (HSA21), usually by nondisjunction [8].…”

Behavioral Phenotyping for Down Syndrome in Mice

“…Down syndrome (DS) is the most common genetic form of intellectual disability, caused by trisomy of Homo sapiens autosome 21 (Hsa21) (Antonarakis et al, 2020). Individuals with DS present with a distinct collection of symptoms and manifestations that affect multiple organs and systems, although notable variation exists among individuals.…”