A New Chromosome 18 Project
The Chromosome 18 Clinical Research Center has been selected by the National Institutes of Health (NIH) to participate in the Gabriella Miller Kids First Pediatric Research Program.
The Chromosome 18 Clinical Research Center has been selected by the National Institutes of Health (NIH) to participate in the Gabriella Miller Kids First Pediatric Research Program. This program seeks to define the genetic determinants of structural birth defects and pediatric cancers. The Kids First Program will fund the Broad Institute of MIT and Harvard to sequence the entire genomes of 150 of the chromosome 18 deletion participants who have structural birth defects.
Being selected by the NIH for participation in this effort is important for several reasons. First, we have learned that even when we know which of the chromosome 18 genes causes a specific issue there is still incredible variability between individuals. This makes it difficult to anticipate which issues a specific person with a deletion of a specific gene might experience. For example a deletion of the TSHZ1 gene causes closed ear canals. But not everyone with a deletion of this gene has closed or even narrow ear canals. Only just over ¾ of the individuals with a deletion of the TSHZ1 gene are affected. Even within the affected group very few have both ears with closed canals, some have one affected ear, while others have merely narrow ear canals which can include one or both ears. There is a wide spectrum in how someone might be affected by a deletion of this gene; if they are even affected at all.
This phenomenon in which only a portion of the people with the genetic change actually manifest the trait is called penetrance. We would say in this example that the TSHZ1 gene is 75% penetrant because only about ¾ of those with a deletion of this gene are affected. Penetrance describes what percent of the time a change in the gene (deletion, duplication or mutation) causes the associated problem.
In one way this example is a good one because it describes a physical, anatomical change making it easy to visualize. But in another way it is a bad example because deletions of this gene have a much higher penetrance than most of the chromosome 18 genes known to be causative of a problem when deleted or duplicated. In fact many of the causative genes on chromosome 18 have a penetrance of under 50% when deleted. This makes it very hard to anticipate who will have which issues. When it comes to treatment, knowing which issues are most likely to occur in a specific individual can greatly improve treatment outcomes when caught early or even prevented.
One way to learn about what other factors affect penetrance is to study variations in the DNA sequence of all the other genes in the genome. This is what participation in the Kids First program will do. The genome sequence data generated by the Kids First Program will be exclusively available to our team of collaborators to analyze for 6 months. After 6 months, the data will be available to other NIH approved investigators to analyze as well. Our expectation is that these data will help us to clarify the answers to these questions. But also and more importantly, our hope is that the more scientists scouring these data the more we will learn and the more the scientific community will see the importance of studying chromosome abnormalities; especially those involving chromosome 18.
This is the second reason being selected into this program is important. It allows outside investigators to become interested in the chromosome 18 conditions. These investigators will not have access to any of the participants’ personal information such as name or contact information. Should outside investigators need additional participant information such as more specific medical information they will not be able to contact participants directly but instead they will be able to collaborate with the Chromosome 18 Clinical Research Center.
While recruitment for participants in this particular project was limited to those with structural birth defects, the participants selected for participation also have the range of other issues common in people with chromosome 18 deletions. We anticipate that a byproduct of participating in this program will also help us to tease apart the factors impacting the behavioral, developmental and cognitive issues associated with the chromosome 18 conditions. These are the issues that we find to be much more impactful in the lives of those with the chromosome 18 conditions.
While the NIH Kids First Program funds the genome sequencing done by the Broad Institute it does not provide any finding to the Chromosome 18 Clinical Research Center. The ability to be selected to participate in this program and prepare the samples and data to be sent to the NIH is thanks to the funding from the Chromosome 18 Registry and Research Society.
