|
This is likely a question that arises in every parent’s mind at some point. Their child may be more or less developmentally advanced in some areas than others with the same chromosome 18 condition, or their child may have a specific problem when others do not. There are several possible explanations for these differences, some of which we are just now learning to appreciate.
Of course, the first reason is that no two children--not even siblings, or especially siblings--are just alike in their development of skills, temperament, and health problems. While this is an important basis to remember, this is not a very satisfying answer because we already expect siblings to be completely different individuals.
The other reason people with the same chromosome 18 condition are different from each other relates to their actual chromosome 18 condition. Most of the chromosome 18 conditions involve different regions of the chromosome that are deleted or duplicated. In fact, there are no two unrelated people with an 18q deletion or Ring 18 who have exactly the same region of the chromosome missing. In addition, about half of the people with 18p- have a unique region of the short am missing. The other half of those with 18p- have the entire short arm present in only one copy instead of two copies. Tetrasomy 18p and full Trisomy 18 are unique in that almost everyone in each of those two groups has the same chromosome change. Thus, for most people with a chromosome 18 conditions, they have a one-of-a-kind unique condition and will not be like anyone else.
We have found that it is not the size or the number of genes within the deletion or duplication that has the most significant impact on outcome, but rather the specific gene content of that chromosome change that counts. For example, individuals with terminal deletions of 18q whose deletion includes the last (distal) 70 genes of 18q have an average IQ of 61. Conversely, those whose terminal deletions also included just one additional gene had an IQ that was unmeasurably low and exhibited the characteristics of Pitt Hopkins syndrome. Individuals with only one gene deletion of TCF4 are equally as challenged, making this gene a very significant driver of development.
On the other end of the spectrum is the finding that there are people without health issues who think they are perfectly normal but have deletions of a region of 18q that includes seven genes. These are extreme examples of a one-gene deletion resulting in profound developmental limitations, and a seven-gene deletion having no ill consequences at all, but they stand to illustrate the point that some genes have a more significant impact than others when present in a number of copies other than the normal two copies.
Determining which genes have an impact, and what that impact is, is a major area of focus for the Chromosome 18 Clinical Research Center. The progress on this work can be viewed on our website (https://wp.uthscsa.edu/chromosome-18/research/). By viewing our “Clinical Dosage Maps,” individuals can learn what we have discovered about certain genes that have an impact when deleted or duplicated. The majority of these genes are able to be classified as to their effect due to a chromosome change. One of our research goals is that a family could look up a specific molecularly defined region and learn about the genes and their impact for creation of an individual treatment and management plan. But….
There is one major finding that significantly moderates such an effort. The term geneticists use is called “penetrance.” This concept brings us back to the question posed in the title of this article, “why is my child so different from the other children with the same condition?” Penetrance is defined as the percent of time that a genetic disease diagnosis actually results in a clinical presentation of the disease.
For example, you have probably heard of cases in which several members of the same family have a genetic diagnosis, but not everyone presents with the disease. This is due to reduced penetrance and is one reason why you often hear about genetics as risk factors for different diseases.
One of the significant findings we have made regarding the chromosome 18 conditions involves the issue of penetrance. So far, we have found only one gene on chromosome 18 that is 100% penetrant when there is one copy instead of the normal two copies. That gene is the TCF4 gene, mentioned above. No other gene comes close to that level of penetrance, or significance for that matter.
Discovering that reduced penetrance is such a common feature of conditions caused by genes present in the wrong number of copies, we decided to classify the genes in the “Gene Dosage Maps” as low penetrance (causing disease less than 50% of the time) and causal (more than 50% of the time). From our research, we have determined that just over 10% of all the genes on chromosome 18 fall into one of these two classifications. The other 90% of chromosome 18 genes appear to have no effect due to a change in the number of copies.
The appreciation that reduced penetrance is such a common feature of gene copy number changes in chromosomal conditions has two different implications: The first is that the information from the Gene Dosage Map is not predicative, but rather anticipatory. Thirty years ago, we thought that if you just knew which genes were within a deletion or duplication then you would be able to predict the outcome for the person. The understanding that reduced penetrance is so common means that if you know which genes are in the region of deletion or duplication, then you know what the possible outcomes might be, or should be monitored.
The second implication from the discovery of reduced penetrance as the norm for the chromosome 18 conditions means that even if two people had the same deletion or duplication, they are unlikely to have the same outcome. Combined with the fact that each person also has about 20,000 other genes that all interact to shape who they are, there is no reason to expect two people with the same chromosome 18 condition to be just alike. Nevertheless, it is always amazing how alike they are given all the reasons for them to be different!
| 
