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It should come as no surprise to most chromosome 18 families that no two individuals with chromosome 18 conditions are alike. Even if they have the exact same chromosome change, as is the case for those with tetrasomy 18p and half of those with 18p-, individuals may have very different health and developmental concerns. Many families understandably wonder why this is so. After all, they have the same underlying genetic finding, so why would they be so different when it comes to clinical presentation? The answer lies in two separate but related genetic concepts: incomplete penetrance and variable expression.
The term "penetrance" describes the likelihood that, when a certain gene is deleted or duplicated, a certain outcome occurs. For example, 100% of people who are missing the delayed myelination critical region have delayed myelination. This means that delayed myelination has 100%. In other words, it has complete penetrance. In contrast, only 25% of people who are missing the kidney malformation region will actually have kidney malformation. This is why, when discussing what to expect, genetics professionals often use percentages to describe the likelihood of different things happening.
Variable expressivity is another explanation for the variation that we see among our chromosome 18 families. This phrase means that different individuals missing the same gene might have somewhat different presentations.
TSHZ1, a gene on 18q, is a good example of variable expressivity. This is the gene associated with aural atresia and stenosis (absent or small ear canals). However, this gene has also been linked with cleft palate and vertical talus (rocker bottom feet). Both of these are other features frequently seen in people with 18q-. Thus, it is clear that deletions of this gene can lead to different outcomes in different people.
Some genes show both reduced penetrance as well as variable expressivity.
TGIF1 on the short arm of 18p is a good example of this. Deletions of this gene are linked with a very specific brain malformation called holoprosencephaly. Only about 10% of people that are missing this gene actually have holoprosencephaly. Therefore, it exhibits incomplete penetrance. However, people missing this gene may have a holoprosencephaly microform rather than "true" holoprosencephaly. For example, they may have a cleft lip or a single central incisor (a tooth in the middle of the upper jaw, rather that two symmetric upper teeth on either side of the midline). This gene also shows variable expressivity.
Now that we know what these terms mean, we can discuss
why these variations occur. We at the Chromosome 18 Clinical Research Center focus on the deletions and duplications of one specific chromosome. However, we must keep in mind that there are 21 other chromosomes that men and women have in common, plus an X and a Y chromosome. These other chromosomes contain the remaining genes in the genome-over 19,000 of them! We have very little understanding of how variations in the other genes on other chromosomes impact the expression of the genes on chromosome 18. In addition, we also must consider environmental influences. This may mean prenatal exposures. It may also include other postnatal experiences, such as therapy or treatment for medical issues. These factors certainly influence the health and development of someone with a chromosome 18 change.
Incomplete penetrance and variable expressivity present some challenges to researchers. Both of these phenomena complicate our ability to link specific genes with specific findings. Moreover, it makes it more difficult to tell families exactly what to expect based on the underlying genetic change. However, our research continues and the scientific community continues to uncover more secrets of the genome. We anticipate that we will someday understand all of the various factors influencing how deletions and duplications affect individuals.
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