Most people realize that we at the Chromosome 18 Clinical Research Center focus on a specific group of genetic changes: large deletions and duplications of chromosome 18. However, there are a lot of different kinds of genetic changes. These other types of genetic changes sometimes give us clues about the role of genes on chromosome 18.

Before going any further, it will be useful to review some genetic concepts. Chromosomes are the basic units of heredity that are passed from parent to child. We have two copies of each chromosome: one from each parent. The genes are lined up along the chromosomes like beads on string. Each of these genes is responsible for telling the body how to make a protein. Proteins carry out many functions within the body. Sometimes, there can be a genetic change that affects how a gene functions. When this happens, the protein is not able to do its job correctly. This may lead to health and developmental concerns.

There are a number of different types of genetic changes. Our work is focused on what happens when there are large deletions or duplications of chromosome 18. This usually means that a number of genes are either deleted or duplicated. However, other types of genetic changes affect only one gene. These include tiny deletions or duplications within a gene or even just a change in one “letter” in the gene. Sometimes, these types of changes are called “mutations”.

Mutations that affect a single gene can provide a great deal of information to us. By understanding what happens when a single gene on chromosome 18 is not working, we can begin to understand how that one gene contributes to the health of someone with a large deletion or duplication. For example, we have long known that some individuals with 18q- have more significant cognitive delays. They are not able to speak and some do not walk. However, we did not know why this was. We believed that it was due to a single gene, but we had not figured out which one was responsible. In 2007, a team of scientists reported that small mutations in TCF4 , a gene on chromosome 18, cause Pitt-Hopkins syndrome. Pitt Hopkins syndrome is associated with unique facial features, abnormal breathing patterns, and, importantly, significant cognitive disabilities. When we looked at our own study population of 18q-, it became apparent that individuals with deletions that included the TCF4 gene did indeed have more significant cognitive disabilities. We had found the explanation for why some people with 18q- have more significant cognitive challenges than others.

However, we have to be careful when drawing conclusions from single gene disorders. Just because a small change in a single gene causes a specific issue, this does not mean that a deletion of the entire gene will cause the same issue. An example of this is a condition called Bainbridge-Ropers syndrome (BRPS). This condition is associated with very significant developmental disability. Most children do not develop speech. Mutations in ASXL3 , which is located in chromosome band 18q12.1, cause BRPS. Does that mean that people with complete deletions of ASXL3 have BRPS? Interestingly, the answer is no . Why not? It turns out that only some ASXL3 mutations actually cause BRPS. We believe that the mutations associated with BRPS cause the protein to interfere with the appropriate functioning of the second normal copy of this gene. People with a deletion of the entire copy of the gene, as is the case for most people with 18q-, do not make that abnormal protein. Therefore, the second copy of the ASXL3 gene is able to function normally. Having one functional copy of ASZL3 is enough.

In conclusion, we can learn a great deal from other variations on chromosome 18. However, we also have to be careful in looking at the data from single gene conditions, as they may not be relevant to a deletion or duplication of an entire gene.