In our last post, Dr. Jannine Cody talked about the importance of using the right words when talking about chromosome changes. Specifically, the word "syndrome" is not an accurate description of conditions involving deletions or duplications of chromosome 18. But, the question, then arises, what should we use in its place? In today's post, Dr. Cody talks about this dilemma!
Saying adios to the “s” word is the easy part. I have tried to stop using it for the past 10 years or so. But what do we replace it with? That’s the larger challenge. We may have to take different approaches with the different chromosome 18 conditions as we learn enough to differentiate subtypes of each condition. We embarked on this route last year when we divided 18q- up into proximal 18q- and distal 18q-. This was possible because, while everyone with an 18q deletion has different breakpoints, there is one very small region in the middle of the long arm that has never (so far anyway) been found to be deleted in anyone. This essentially cuts the chromosome arm in half and makes two groups; those with deletions closer to the centromere (proximal deletions) and those with deletions closer to the end of the long arm (distal 18q-). So, now we have broken up the term 18q- into “proximal 18q-“ and “distal 18q-“. The information on our website has been organized in this way.
This issue was really brought to a head with the recent identification of TCF4 as the first gene on chromosome 18 to be definitively defined as dosage sensitive. In other words, one copy of this particular gene is responsible for specific outcomes. Of all the genes on chromosome 18, we only expect that about 5-10% of genes will cause problems when present in one copy instead of two. So TCF4 is one of the key genes we have been trying to identify. To make this all the more important, those with one copy of this gene have a very different developmental progression and medical characteristics than most others with 18q deletions. So it is not only important to distinguish between proximal and distal 18q-, but also between those with and without TCF4 deletions.
Truly, these refinements in the nomenclature of 18q- are ground-breaking, and since we are treading where no geneticist has gone before, we need a new naming convention. Using the nomenclature proposed for single gene disorders as a starting point, I came up with a new naming convention:
Proximal 18q- for someone with a deletion of a region between the centromere 44 Mb.
Distal 18q- (TCF4 +/+) for someone with a deletion somewhere between 45 Mb and the 18q teleomere that does not include the TCF4 gene.
Distal 18q- (TCF4 +/-) for someone with a deletion somewhere between 45 Mb and the 18q teleomere that does include the TCF4 gene.
The +/+ symbol indicates that there are two copies of the TCF4 gene, and the +/- symbol indicates that there is only one copy of the gene.
We have now replaced the single term (18q-) with 3 new terms. And this is just the beginning. As we figure out which other genes are responsible for the features of 18q-, the list within the parentheses will get longer. But, at the same time, this means that our understanding of these conditions is growing as well. I don’t envision one day having a list of 30 genes as a part of someone’s formal genotype, but maybe only 5 or so key genes that will be informative about the prognosis.
I know some of the families whose children have 1 copy of the TCF4 gene as a result of a larger deletion refer to their child as having Pitt Hopkins, which they sort of do. But they may also have additional issues that are not related to the absence of the TCF4 genesuch as delayed myelination or hearing impairment based on the other genes they are missing. So between us, when people use the term Pitt Hopkins, we know what that means and does not mean, and that is just kind of a shorthand term. But just remember that your medical team is not as “in the know” about the nuances of this terminology and you may mislead them by using the term Pitt Hopkins when they actually have distal 18q- (TCF4 +/-). You may also mislead them by using the word syndrome. Without them even realizing it, they are programmed to expect that all kids with the same syndrome are pretty much alike. They may have expectations and biases regarding prognoses or treatments that are inaccurate. So, be knowledgeable and accurate about the terms you use.
The same issues will apply to 18p- and Ring 18 as we learn more about these conditions as well. Right now we are appreciating that about half of the people with 18p deletions have breakpoints very near the centromere. So this makes for two major groups 18p- (cen) and 18p-. Stay tuned for more information about how these are different. With regard to Tetrasomy 18p and full Trisomy 18, the majority of individuals have the same genetic abnormality, but they are still not syndromes because there are many different genes involved. For example, the features associated with trisomy 18 are caused not by the extra chromosome itself, but by the extra copy of the genes ON chromosome 18. So, in this way, there are actually 300 different causes for the features associated with trisomy 18!
When I was defending my PhD dissertation, John Opitz (a towering figure in human genetics – figuratively and literally) asked me if 18q- was a syndrome. As I explained my answer, I realized that I had better stop using that word. I asked him what term he would suggest and he said, “the phenotype associated with a deletion of 18q.” That is kind of a mouthful. So when forced I use the term “condition” when talking about the outward presentation (phenotype) and the word “abnormality” when talking about the genetic component (genotype). But I still find it hard after all these years to completely jettison the “s word”.
