Why is the third chromosome in Down syndrome causing such severe damage?

It is more pertinent to ask why trisomy on chromosome 21 leads to such a relatively harmless disorder like Down's syndrome? And does not kill before childbirth. Actually, the third chromosome is not only the 21st, but any other. And if the third sex chromosome does not lead to special excesses (except for sterility, and even then not in all cases), then the third autosome in all other cases leads to incomparably more severe disorders than Down's syndrome. Usually, everything ends in miscarriage, and if a child is born, he lives very poorly and for a short time.

About the mortality of trisomy for other autosomes (except for the 21st)

The only viable autosomal trisomy in humans is chromosome 21 trisomy, which causes Down's syndrome. Trisomics on chromosomes 13 (Patau syndrome) and 18 (Edwards syndrome) can survive to birth, but are characterized by significant developmental disabilities and early postnatal mortality. Trisomies in other autosomes lead to early embryonic mortality. Characteristically, chromosomes 13, 18 and 21 are chromosomes, occupying the last three places in the number of genes among autosomes

https://ru.wikipedia.org/wiki/Aneuploidy

With sex chromosomes, the question is only about trisomy XXX : why is it so harmless and almost does not affect fertility? And variants of trisomy XXY and XYY, for example, do not differ that much from normal XX or XY (there are relatively few extra duplicating or "third" genes), since Y is incomparably smaller than X, and has little effect on what it actually has few genes). Therefore, the viability of their bearers, in principle, does not raise questions.

About trisomy on the X chromosome

Trisomy on the X chromosome leads to a slight increase in intrauterine mortality [2]. Development can occur with some disabilities, problems with coordination, motor skills and speech development may occur. In some cases, a smaller head size is noted (without a noticeable decrease in mental abilities) [3]. Trisomy on the X chromosome does not lead to significant impairment of fertility, in most cases it manifests itself only in slightly earlier menstruation.

All manifestations of Down syndrome are associated with overexpression of dose-dependent genes contained in 21 chromosomes, of which there are three in Down syndrome patients. The more such genes, the brighter the trait is. Among them there is a gene encoding a protein that inhibits the division of nerve cells and causes their early differentiation, which leads to disorders of the nervous system. Alzheimer's disease develops faster in patients with Down syndrome. the precursor protein of beta-amyloid (the main component of the plaques that cause disease) is encoded on chromosome 21. Cardiovascular, bone and soft tissue disorders in the structure of the body are all encoded on chromosome 21, just somewhere the genes are not yet fully defined. You can read about all here.

However, it's not all bad. Such trisomy due to dose-dependent genes causes the production of a large number of antitumor factors and a reduced ability to form new vessels, which sharply reduces the incidence of cancer pathology in patients with Down syndrome.