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According to the National Down Syndrome Society, Down Syndrome is the most common chromosomal condition, with roughly one in 700 children born in the United States affected. The genetic disease results specifically from a partial or complete extra copy of chromosome 21.

What I'd like to know is why this is, when there are 22 other chromosomes that in theory are just as susceptible to nondisjunction (the most common process resulting in the extra copy of chromosome 21, accounting for 95% of cases). Why is chromosome 21 uniquely affected?

My personal thoughts, not necessary for understanding the question:

It seems to me that there are two likely options here.

Option 1 is that there is some property of chromosome 21 that causes it to be treated slightly differently from other chromosomes making such nondisjunction more likely. Perhaps it is the largest, or smallest, or the most guanine-cytosine base pair rich, or poor, and so on, in which case I'd love to hear what it is that differentiates chromosome 21.

Option 2 is survivorship bias, namely that chromosome 21 is the only chromosome where trisomy tends not to result in the death of the fetus. If true, this would indicate that trisomy occurs at roughly equal rates in the other chromosomes, but that typically this results in miscarriage.

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    This is a great question. I’m going to get researching. My gut feeling is option 2, as the only other (much rarer) triaomies I am aware of are 13 (Patau) and 18 (Edwards), both of which tend to result in death shortly after birth if not before.
    – Chris
    Sep 11 '19 at 22:27
  • Quick side note: There are 23 different (or 24 different) chromosomes [46, XX and 46, XY]. Triple X Syndrome also exists, but usually the autosomes (all but the gonosomal (sex) chromosomes) are focussed.
    – Narusan
    Sep 12 '19 at 14:20
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    Another side note: Down Syndrome can be either due to Trisomy 21 or a translocation of/on chromosome 21 (5% of the cases). I'm assuming you are interested in the copy number variant, that is to say Trisomy 21, not the clinical presentation of the phenotype Down Syndrome. I'll might get to write an answer later on.
    – Narusan
    Sep 12 '19 at 15:36
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I found the answers in a fascinating, and easy to read paper in Nature, called "Chromosomal Abnormalities: Aneuploidies"

Here are some key insigths from there:

With few exceptions, trisomies do not appear to be compatible with life. In fact, trisomies represent about 35% of spontaneous abortions (Figure 1; Hassold & Hunt, 2001).

As far as why trisomy 21 is more survivable than other trisomies of non-sex chromosomes (autosomes), the answer may be in the length of the chromosome -- except for the Y chromosome, #21 has the lowest number of genes, so an excess may be more survivable:

In humans, the overexpression of X-linked genes is prevented by X inactivation, but no similar mechanism has been identified for autosomes. It is therefore interesting that trisomy 21 is the only viable autosomal trisomy, because the number of protein-coding sequences predicted for chromosome 21 is the smallest of any human chromosome, with the exception of the Y chromosome. Thus, an additional copy of chromosome 21 would be predicted to perturb the normal equilibrium in cells less than an extra copy of any other autosome.

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