Tetrasomy 18p Research Updates
The Chromosome 18 Clinical Research Center would like to share a new article from Dr. Cody covering updates on Tetrasomy 18p research. Please enjoy the article below:
What Research is Happening with Tetrasomy 18p?

To some it may look like not much is happening, but it actually is; it is just foundational work that proceeds at a pace that the available funding allows. Beyond funding, what are the challenges? What is happening, and what do we need to do next?

Main unaddressed medical issues:
Many of the issues such as seizures, constipation, and feeding difficulties that are common in individuals with Tetrasomy 18p have treatments or management strategies. However, the single biggest problem for which there needs to be more aggressive treatment development involves cognitive disability. This translates into very poor adaptive behaviors like the ability to care for oneself, as well as planning and conducting the activities of daily living. Investigating ways to improve these types of abilities is a challenge and not something for which there is significant precedent for other conditions exhibiting these same challenges. But that is not a reason to fail to try. We have the advantage that we have a window into the underlying cause: too many copies of the perfectly normal genes on chromosome 18p. If we can learn how to downregulate just those genes that underly the cognitive challenges, then maybe we can improve the ability to learn adaptive skills. At the same time, we are not ignoring the issues that are treatable using today’s medical knowledge. All of this is not without its challenges, but within every challenge lies opportunity.

Genetic challenges:
  1. Everyone with Tetrasomy 18p has the same duplication, except for a couple of people with small 18q arm duplications. Because there are no individuals with smaller duplications, it makes it impossible to do comparison studies between people with large and small duplications in order to correlate specific characteristics with specific 18p identify regions (and potentially genes). This means we are unable to do genotype phenotype mapping, which is the approach that has yielded so much information for the deletion syndromes.
  2. It is also harder with duplications than deletions to know when a duplicated gene is actually generating too much gene product, and hence potentially causing a problem. In comparison to deletions, if someone is missing a portion of a gene and not even the whole gene, you can be pretty confident that the gene is nonfunctional. This means that in population studies of people who think they are normal yet have a gene deletion, we can be confident that the gene does not cause overt disability when deleted. But if one of these so-called “normal” people has a single gene duplication, even of an entire gene, you can’t be sure the gene is acting in the same way it would if it were within three copies of the entire 18p arm. This is because there are yet to be determined control elements for each gene, some of which are close to the start of the gene and others are far away – somewhere on the same chromosome. This makes it impossible to know when a single gene duplication is functioning as it would in a whole 18p arm duplication. So, this straightforward strategy that has worked so well for eliminating genes from the potential key gene list as done for deletions will not work for duplications.
  3. This challenge of defining just what it takes for a gene to act as it does when duplicated as part of an entire chromosome arm also applies to creating mouse models of the condition. Inserting an extra copy of a gene into a mouse raises the question of unintended effects due to the placement of the inserted gene, in addition to the uncertainly as to the inserted gene being fully functional.

In spite of these challenges, there are approaches that can be useful in determining the underlying causes of these issues and then identifying ways to remediate them.

How we are working on it:
  1. We are using data from the scientific literature and databases to determine which genes on 18p are dosage sensitive. In other words, those that are dysregulated when there are too many copies of the gene. This sparse information is from studies of gene function when the genes are overactive and is monitored daily in updates from the PubMed. These data are collected in our Duplication Gene Dosage Map (https://www.chromosome18.org/genesandcriticalregionsduplications/)
  2. Although data from typical people with very small duplications is challenging to interpret, there are individuals with larger duplications of sections of chromosome 18. We recently combined funding from several sources to perform whole genome sequencing for the 22 such individuals enrolled in our research study who have partial duplications of chromosome 18. By comparing the location of the region of the chromosome that is duplicated with their medical and developmental information, we will be able to identify chromosome 18 regions correlating with specific consequences. These data will contribute to, and expand our Duplication Gene Dosage map. The theory is that the genes important in T18 will be equally if not more important in Tet18p.

What we need to do:
Enough with the negative! Now we need to move forward.
  1. We will continue monitoring medical and developmental progress and issues in people with Tetrasomy 18p. For example, this is how we learned about the low bone density problem.
  2. We need to determine which genes are the key genes. We believe that similar to the deletions, there will be only few key genes: likely about 10%, or 6 to 7 of the 67 genes on 18p whose function we need to focus on. As pointed out in the genetic challenges section, the overall approach of determining key genes for Tetrasomy 18p will need to be different than for the deletions. But this is where the Trisomy 18 research mentioned above will be helpful. The Trisomy 18 data will help to determine which are the few key genes that are important to investigate further. If we were to take a blind approach and try to understand the duplication consequences of every single one of the 67 genes using cell lines and mouse models, it would be exceedingly expensive, time consuming (as in years or decades), and 90% unproductive. Instead, we are taking this approach to narrow down the potential number of key genes on which to focus our attention.
  3. Another way that could provide insight into identifying the key genes is to determine the level of expression or activity for each of the 67 genes from different people with 1, 2, 3 and 4 copies of 18p. By determining which genes have the same or nearly the same activity level – regardless of the number of copies of the gene – this will allow us to eliminate those genes as key genes. Likewise, identifying the genes whose activity is greatly changed due to the number of copies will help identify the most likely candidates for being key genes. We did experiments to address this question years ago but found the results to be too noisy to get definitive results. Since that time, the technologies to measure gene activity have improved, and we have a new approach that should greatly increase the data quality. However, this project is currently unfunded.
  4. Once we have a short list of potential key genes and determine from the literature if they are reasonable candidates (such as the fact that they are normally expressed in the brain), then we can proceed with creating mouse models. But as mentioned above, we would not be trying to add an extra gene, instead we would attempt to up-regulate the existing 2 copy genes in the mouse to determine their effects behaviorally and anatomically. The ability to do this is a new methodology that will likely be even more well described by the time we are ready to employ it. We can use the mouse models to learn more about the cellular abnormalities in order to develop the cell-based assays necessary for the screening of thousands of potential compounds, eventually leading us to find one that can normalize and down-regulate the key genes.

This may be a long road, but one that is feasible. These last two steps in particular need to be aggressively pursued. If we don’t make it happen no one else will. 
To view any of Dr. Cody's previous FAQ videos, please click the link below:
Do you have questions about anything in this email? Contact Annice Hill for more information.
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