What causes Down syndrome?

Down syndrome, also known as trisomy 21, is a condition characterized by a delay in growth, a distinct set of facial characteristics, and intellectual disability[1]. This is caused by imbalances in gene expression resulting from having three copies of chromosome 21, instead of the normal two copies (Figure 1). Figure 1. Down syndrome human karyotype indicating the presence of three copies of chromosome 21 in a male patient (XY). Image source: Wessex Regional Genetics Centre/ Wellcome Images.

X-inactivation: preventing Down syndrome using stem cells

A recent study by Lawrence and colleagues published in the journal Nature reported the ability to turn off the extra copy of chromosome 21 associated with Down syndrome. They utilized a mechanism called X-inactivation, a cellular process that results in the shutting off of one of the X chromosomes in females (XX), that prevents females from having double the X chromosome gene products compared to males (XY). Researchers co-opted this mechanism to turn off one of the copies of chromosome 21 in stem cells derived from a patient with Down syndrome[2].

How is Down syndrome diagnosed?

It is typically diagnosed through various prenatal testing methods including ultrasound, blood tests, amniocentesis and chorionic villus sampling (CVS). Presently there is no way to reverse the affects associated with Down syndrome and while researchers emphasize that there is still a long way to go, the advances made in this study could potentially lead to the correcting of Down syndrome by gene therapy. Down syndrome is believed to affect approximately 1 in 700 individuals in the US, making it the most common chromosomal abnormality in humans. The risk of having a child with Down syndrome increases with maternal age although 80% of children with Down syndrome are born to women under the age of 35 (Figure 2)[3]. Figure 2. Graph showing the increased incidence of Down syndrome with increasing maternal age. Adapted from Dayal et al. Preimplantation Genetic Diagnosis. Medscape References (2011).

How does X-inactivation work?

X-inactivation is achieved through the expression of an RNA called Xist (X-inactive specific transcript). Xist is expressed only on one of the X chromosomes and is required to recruit specific proteins that modify the chromosome, and essentially shut it off. Thus, genes are expressed only from the X chromosome that has not been inactivated by Xist (Figure 3). Figure 3. Expression of Xist on one of the X chromosomes leads to recruitment of protein to that chromosome that are required to inactivate the chromosome. This ensures that there is only one active X chromosome in females. Image source: the National Institute of Genetics. The scientists generated nerve stem cells from a patient with Down syndrome and postulated that if they put the gene for Xist onto one of the copies of chromosome 21, that they could switch it off. The Xist gene was inserted into chromosome 21 using zinc finger nucleases (ZFN). ZFN are proteins that recognize specific DNA sequences and subsequently cut the DNA at specific cut sites. The cell typically repairs these cuts using a process called homologous recombination (HR). Researchers found that if they supplied the cells with DNA encoding the Xist gene fused to sequences matching the cut site on chromosome 21, that the Xist gene would get incorporated into chromosomal DNA during HR (Figure 4a). Expressing Xist on one of the copies of chromosome 21 was found to silence it (Figure 4b), and nerve cells with two copies of chromosome 21 were found to grow faster than those with three copies. This is not surprising since an extra copy of chromosome 21 is believed to slow down brain development and cause cognitive problems associated with Down syndrome[2]. Figure 4. Techniques used to inactivate one copy of chromosome 21 in stem cells from a patient with Down syndrome. (a) Zinc finger nucleases are used to recognize specific DNA sequences on chromosome 21 and they induce DNA cutting. Supplying DNA sequences containing the Xist gene during the repair process result in the insertion of the Xist gene into chromosome 21. (b) Figure from Jiang et al. (2013) showing the presence of three copies of chromosome 21 (green dots) and the incorporation of Xist into one of the copies of chromosome 21 (red dots).

Gene Silencing: The Future of Down syndrome and X-inactivation

Since these studies were done in stem cells, it will be interesting to see whether the same promising results will hold true in animal models. If they do, it may pave the way for gene therapy approaches where Xist may be used to prevent gene dosage defects in Down syndrome. However, in order for gene therapy to switch off the extra chromosome in the majority of cells in the body, it would have to be initiated at a very early stage of pregnancy, which would require noninvasive prenatal genetic screening. Nonetheless, this may be a tremendous step forward since currently the only option for some is to have a child with Down syndrome or to terminate the pregnancy, and perhaps gene silencing can change that.


If you would like to learn more about the role of genetics in fertility, continue reading this related blog post: “Three-Person IVF Can Reduce Risk Of Mitochondrial Diseases”. If you enjoyed this post and want to read more, please follow us on Twitter or become a fan on Facebook. Author: Antonia Borovina


    1. Leshkin, L. Trisomy 21: The Story of Down Syndrome. (2003)
    2. Jiang, J. et al. Translating Dosage Compensation to Trisomy 21. Nature (2013)
    3. Dayal, M. et al. Preimplantation Genetic Diagnosis. Medscape References (2011)
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