Step 6: Gene Function Studies

Happy Thanksgiving, everyone! In celebration, I'm finally getting around to posting the next step in our "Path to Treatment" for chromosome 18 conditions.

So far, we've talked about:

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description
Step 4: Gene Identification
Step 5: Syndrome Management Plan

Even after we have linked specific genes with specific features of the conditions involving chromosome 18, we still don’t necessarily have a good idea of HOW those genes cause medical and developmental problems. For example, we might wonder why it is that missing a specific gene causes severe language delays. Is it because the gene plays a role in how the way the brain develops? Or is it because it causes some problems with the way that the brain communicates with the muscles that control the muscles necessary for speech?

It is at this point that we really start relying on the experiences and knowledge of scientists in other disciplines. Many genes on chromosome 18 already have already had extensive information published in the scientific literature. Scientific papers might give us information about what happens when a single base pair in a gene is changed. Or it might tell us a little bit about the protein product that the gene is responsible for creating. Or perhaps where in the body those proteins are localized.

Unfortunately, there are also many genes on chromosome 18 that have very little information available. In this case, we can turn to an increasingly large variety of technologies that have been developed to understand gene function.

Once we understand how gene deletions and duplications lead to the various health and developmental concerns, we can start working to fix those problems at the molecular level. Basically, we want to find a treatment that can address the underlying changes in the genes and therefore the proteins that they code for.

Step 5: Syndrome Management Plan

We're continuing the "Path to Treatment" series today! As you may already know, the ultimate goal of the Chromosome 18 Clinical Research Center is to not to "manage" the chromosome 18 conditions, but to find treatments specifically designed for the chromosome changes. This is a long process, with many steps along the way. On this page, we have already discussed the first four steps towards meeting our goal...

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description
Step 4: Gene Identification

I also just realized that I have not posted a link that may help with the visualization of the whole process! Here's a diagram that shows the steps, in order, as well as where we are with the various chromosome 18 conditions. I'll also post a copy of the image below.

You might want to click on the image to enlarge. Or, visit this link, which will take you to a PDF that has brief descriptions of each step.

And with that introduction, I will start discussing the next step in the process: a "Syndrome Management Plan"!

Once we have identified the genes that are responsible for different features, we can start to create a management plan that is tailored to an individual’s specific chromosome change.

Right now, most chromosome 18 changes are diagnosed by a routine chromosome analysis. You can read more about how chromosome 18 changes are diagnosed here. The chromosome analysis can identify the chromosome change and the general location of that change, but it cannot determine exactly which genes were involved. So, even though we know that different genes are involved in different people’s deletions or duplications, the chromosome analysis does not give us enough information to know exactly which genes are different. Therefore, we cannot give people specific information about what to expect based on the results of the chromosome analysis. Instead, we must rely on a general description of the chromosome change to give families an idea of what types of things to expect.

However, microarray analysis has changed all this. Microarray analysis is a new technology that can give us precise information about the location of a breakpoint, as well as the specific genes that are involved in a chromosome change. It can also detect much smaller chromosome changes. Now, when the diagnosis of a chromosome 18 change is made on a chromosome analysis, clinicians can perform a microarray analysis and learn which of genes are involved in the deletion or duplication. That information, combined with our knowledge of the roles that various genes play in causing medical and developmental concerns, will one day allow us to create personalized medical management guides for individuals with a chromosome 18 change.

This is probably best explained with an example. In the future, we will be able to say something like this: “Gene A is responsible for foot abnormalities, Gene B causes growth hormone deficiency, and Gene C leads to kidney problems.” Then, when a routine chromosome analysis identifies a deletion of the tip of chromosome 18, we will perform microarray analysis to get additional information about exactly which genes are involved in the deletion. Microarray results for this newly diagnosed individual may tell us that Gene A and Gene B are deleted, but Gene C is not deleted. Using this information, we can be sure that the family has a thorough orthopedic evaluation to detect any problems and start necessary treatments as soon as possible. We will also be able to tell the family that there is a high probability the child will develop growth hormone deficiency. We therefore will need to closely monitor growth and refer to endocrinology at the first sign of a problem. We can also tell them that a renal ultrasound is not necessary, because the gene for kidney abnormalities is not deleted, and therefore they are at no greater risk for kidney problems than any other children.

In this way, we can create individualized management guides that are specifically tailored to a person’s chromosome change.

While this is a step in the right direction, an individualized management guide is not the same thing as a treatment. From this point onwards, our efforts will be focused on identifying treatments that are specific to each chromosome change.

Step 4: Gene Identification

Today, we're continuing the "Path to Treatment" series here on this blog! The aim of these posts is to talk about the various steps that researchers go through in the question for treatments of the chromosome 18 conditions. You can read the previous installments here:

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description

The fourth step, gene identification, pulls together information from the clinical and molecular assessments. In essence, this step involves trying to link different features of the condition with specific genes on chromosome 18. We take a group of people with distal 18q- (or other chromosome 18 condition) that have the same feature, for example, growth hormone deficiency. We look at the data that we gathered during the clinical assessments and identify all individuals that did not respond to the growth hormone stimulation test, and are therefore growth hormone deficient. Because there is no common breakpoint on 18q, everyone has a different deletion involving different genes. We compare the deletions of the patients with growth hormone failure and determine which area of chromosome 18 is deleted in all those particular patients. This area is called the “critical region”. We would assume that the gene responsible for growth hormone failure is located within this region.

Usually, the critical region will contain several different genes. The trick is to determine which one is most likely to cause a problem when deleted or duplicated! We expect that only 5-10% of the genes on chromosome 18 will actually be responsible for the features of the chromosome 18 conditions. Considering that there are just over 300 genes on chromosome 18, we expect to identify about 15-30 genes that actually play a role in causing the medical and developmental concerns associated with the chromosome 18 conditions.

We have a number of different ways to determine whether a gene is in fact the one that we are searching for.

(1) We research the genes in the critical region. This usually involves several visits to the medical school library! We look at what has been reported in the scientific literature to determine where the gene is usually expressed, what its function is, and whether it makes sense that a deletion or duplication of the gene could lead to the feature we’re examining.

(2) We look at animal models. These are animals (usually mice) that have been bred to be missing a particular gene. We then look at the animal to see what problems it has. If it has the same issue that we are examining, such as growth hormone deficiency or a heart defect, then this is evidence that we have the right gene!

(3) We search for people with gene deletions of or single base pair changes in the gene of interest. For example, if we think that a particular gene is the cause for growth hormone deficiency, we might look at that gene in people with isolated growth hormone deficiency. If we can find changes in the gene in any of those people, that is even more evidence that we’ve found the right gene!

Once we have found the genes that cause the features of the chromosome 18 conditions, we can progress to the next step: the creation of an individualized management plan!

Blog Maintenance

Hi, everyone!

Just a note that I've added a few more chromosome 18 blogs to the list on the right of this page. When you have a few minutes, I hope that you will make a quick visit to their pages! They are some very talented and honest writers. And, of course, the photos they post on their blogs are simply fantastic.

Step 3: Syndrome Description

So far, we have gathered information about the effects of chromosome changes through (a) a literature review, and (b) a thorough series of clinical assessments. Now, it is time to pull together a syndrome description. This description is a comprehensive collection of all the different things that we’ve found in a group of people with a particular chromosome change. Some things might be quite common, such as strabismus in people with tetrasomy 18p. Other things might be seen in a minority of individuals, such as holoprosencephaly in people with 18p-. Other things might only be reported once, and it is unclear whether it is a consequence of the chromosome change, or perhaps it is completely unrelated to the chromosome change.

Once we’ve got the syndrome description, what do we do with it? Well, the first thing we want to do is share our description with others. We can do this in a couple of different ways. We write scientific papers for publication in medical journals to share information. We make presentations at various scientific conferences. We also share information with patient advocacy groups. In our case, this is mainly through the Chromosome 18 Registry’s website as well as at the annual Registry meeting.

The syndrome description gives families and providers an idea of what kinds of issues and concerns may arise in someone with a particular chromosome change. This gives them an opportunity to screen for problems, prepare for various possible outcomes, and just have a better idea of what kinds of things might pop up as a person ages. However, as most parents will tell you, a syndrome description is useful, but it most certainly is not the end-all, be-all. Although we are able to describe the different features that have been seen in people with chromosome changes, we cannot predict precisely who will get which features. There are still several steps that must be completed before we are able to provide personalized information based on a person’s specific genetic change.

Once we are able to fully describe the range of features that are associated with a condition, we can then start to figure out which ones are associated with different breakpoints. For example, we can ask questions such as, “What is different between people who have a breakpoint in 18q23.1 versus those with a breakpoint in 18q12.3?” In fact, this question leads us directly into the next step on the path to treatment: gene identification.

Step 2: Clinical and Molecular Assessments

Once we have completed the literature review, we can move on to the next step in the process: the clinical and molecular assessments.

Clinical Assessments. Using the information from the literature review, we can design a series of evaluations aimed at clarifying and expanding our understanding of the condition. The ultimate goal of this step is to understand how, precisely, the chromosome change affects a person. How does it affect development? What about bone structure? Does the chromosome change lead to any hormonal issues? How about vision? And hearing?

The information gathered in the literature review is critical in helping us with this step. Because we have been able to identify gaps in knowledge about the conditions, we can design assessments to fill in those gaps! Thanks to the literature review, we also know which features have already been described but still require additional investigations. For example, thanks to the literature review, we recognized that many people with distal 18q- have short stature. This led us to question WHY they have short stature. Is it because of a change in their bones? Is it because they are missing certain growth factors? We developed assessments that would help us answer these questions. We included bone surveys and growth hormone testing. We learned that many people with distal 18q- often have growth hormone deficiency! With that knowledge, we were able to start treating people, which, in many cases, led not only to an improvement in growth, but also an improvement in cognitive ability!

As you might have guessed from the example above, the phrase “clinical assessments” may refer to a pretty wide range of possible evaluations. It might involve an examination by a medical professional, such as a geneticist or an ophthalmologist. It might involve imagine studies, such as x-rays or an MRI. It could involve some blood work to look at different hormones and other substances in the blood. Surveys might be used to determine whether behavior and intelligence are affected by the chromosome change.

In addition to deciding which assessments to complete, it is also important to determine who will perform those assessments. Obviously, we want only highly-qualified professionals performing these evaluations. They should have advanced training in their area of expertise, and they should also have experience in working with people with intellectual or physical challenges. This is where our team of clinical investigators comes in. We have assembled a team of professionals who help us design informative evaluations.

In addition to designing the evaluations, our team of clinical investigators is also responsible for performing those evaluations. It is very important that every person we see is evaluated using the same protocols; ideally, the same professional would perform the evaluation as well! This is important because we want to make sure that any differences that we identify between study patients are not due to different procedures. In other words, by ensuring that every study patient goes through the same evaluation process completed by the same clinical investigator, we ensure that we are collecting the most reliable data!

One last word about our team of clinical investigators. All of our clinical investigators collaborators have one very important quality: the ability to think outside of the box. In addition to performing evaluations and making treatment recommendations, our clinical investigators must also be able to take their findings and move them to the next level. In other words, they need to understand underlying biological and molecular mechanisms and use that knowledge to identify novel treatments. This requires them to keep abreast of all the latest developments and technologies in addition to seeing patients, interpreting complex data, and writing manuscripts! No small feat!

Molecular Assessments.

While our clinical investigators are busy evaluating patients and interpreting clinical data, our laboratory technicians are busy examining the molecular basis of the chromosome 18 conditions. The molecular assessments we complete in the laboratory are focused on chromosome 18 and provide us with more data than tests run in clinical laboratories. This is important for two reasons.

First, we must confirm that everyone in a particular study group has the same chromosome change. We have to make sure, for example, that individuals in the 18p- study group do not also have a duplication or deletion on another chromosome. If there are other non-18 chromosomes involved, it is more difficult to determine the effects of a chromosome 18 change. For example, if a child with a heart defect has both a deletion on chromosome 18 as well as a duplication on chromosome 6, we would not be able to determine whether the heart defect is due to the missing genes on chromosome 18, the extra genes on chromosome 6, or a combination of the two!

The second reason that a molecular assessment is so important is that it allows us to determine which genes are involved in the chromosome 18 change. We use the latest technology to identify the precise locations of the breakpoints involved in a deletion or duplication. This is a critical step in understanding which genes lead to a medical or developmental problem. This in turn will tell us about the underlying biology of those problems, which will hopefully lead us to treatment and prevention options.

Once we have thoroughly assessed and evaluated many people with the same condition, it is time to pull all of our data together to create a syndrome description. This is the next step along the pathway to treatment.

Step 1: Literature Review

In order to plot out our research course for the future, we have to know where we’ve already been. What has already been studied? What questions have already been answered? What remains unknown? We answer these questions by completing a review of the medical literature.

Sounds easy enough, doesn’t it? We just need to do a quick search on PubMed (which catalogs all the manuscripts published in most academic journals). Then, we just read them all and VOILA! Literature review complete!

Unfortunately, this is not the way it works.

The first step in performing a quality literature search is the search itself. We often have to use multiple different search terms and weed through the results to find the articles that are relevant to our research questions. This is often easier said than done. For example, let’s say we want to look for all the articles ever published about 18q-. We would have to use multiple search terms, including “18q-“, “deletion 18q”, “de Grouchy syndrome”, and several others in order to capture all the articles that have been written about this condition.

Once we’ve created the list of articles we wish to review, we actually have to track down those articles! This is pretty straightforward, but it can be time-consuming! Some articles are available online, but many (especially the ones published several years ago) have to be manually located and copied. Or, if the library does not subscribe to a particular journal, the article must be ordered from another institution.

Usually, the stack of articles is at least several inches thick, if not more. Now the REAL work can begin! We read each article carefully and thoroughly, looking for information that is relevant to our research questions. We’re looking not only for information about the clinical features of the condition, but also information about the molecular nature of the genetic change. It is important to read all manuscripts with a critical eye and ask the question, “Does this relate to the questions we’re asking? Did the authors use appropriate methods to get their data? What are the conclusions of this paper? What impact does this paper have for the direction of our research?”

Of course, the literature review is not something that is every truly completed. Hundreds of articles are published every month, so we must repeat our original searches every so often to make sure that we catch any new information that is out there.

Once we have a good idea of what is already out there, we can move on to the next step in the research process: the Clinical Assessments.

Path to Treatments

When a child is diagnosed with a chromosome change, families often go through many questions in a very short amount of time. “How did this happen?” “What does it mean?” “What is the treatment? What is the cure?”

Our goal at the Chromosome 18 Clinical Research Center is to answer these questions. We want to be able to tell families exactly what to expect and how to deal with complications if/when they happen. Eventually, we want to be able to prevent complications from ever happening in the first place!

However, research is a time-consuming process. If we want reliable data and solid, publishable conclusions, we have to go about it the right way. Since families are an integral part of this process, it is important that they understand how things progress. In a series of posts, we’re going to discuss the various steps on the path towards treatment.

Supporting Rick Guidotti

Many of us know Rick Guidotti, the man behind Positive Exposure. Rick takes photos of people with various genetic conditions. His photos capture the breathtaking beauty of his subjects. We have had the privilege of having him at our annual conference many times and many of our families have been photographed by him. In fact, the beautiful rotating images on the Registry's website are all Rick Guidotti's.

So, I am sure that many will be interested to know about the documentary about Rick, entitled "On Beauty"! Here is a trailer for the film, which features video footage taken from the 2009 conference in Las Vegas! (Rated PG13 for language!)



The producers of the documentary are looking for funding to finish up the film, so there is not a definite release date yet. But, you can follow the latest on their facebook page, visit their official page, or even make a donation to the film here.

Once again, thank you, Rick, for all you do!

New Year's Resolutions

Holy moly!! I did not realize that it had been so long since I have posted on this here blog! Goodness gracious! Apologies!

It is so hard to believe, but that time of year has come again. Time to make those New Year's resolutions. There are so many possible resolutions to choose from, and at some point in my life, I am pretty sure that I’ve made every resolution out there. I resolve to lost weight! I resolve to save money! I resolve to respond to emails in a timely fashion! I resolve to start a garden! I resolve to learn how to cook! I resolve to keep my resolutions!!

Well, most of the time, these resolutions are forgotten until, say, December, when I look back at the year and wonder what happened to all of my good intentions. Then the guilt sets in and I promise myself that, next year, I’ll do better.

This year, it finally dawned on me that, maybe my dedication is not the issue. Maybe I’m just setting the bar too high for myself! I spent the last week of 2010 wondering what kind of resolution I could make that would still be attainable. Then, this morning, I finally came up with my resolution!!

On the whole, I think I'm a fairly positive person. But I don’t always share my positive thoughts with people when I have them. So, here's my resolution: I am just going to be a more publicly positive person. That is to say, when I think something or someone is the bee’s knees, I’m going to be sure I tell them. Starting right here.

Today, I am grateful for the Chromosome 18 Clinical Research Center. I am thankful for the opportunity to work with a wonderful team of professionals. I am thankful for the recent developments in technology that are enabling us to move forward in the research. I love that so many families out there are willing to open up and share their lives and stories and information with us.

And while I’m on the topic, I am grateful for the Chromosome 18 Registry & Research Society. I think the administrative staff and coordinators do a great job of keeping the families up-to-speed and connected. I L-O-V-E when parents contact me with questions (even when I don’t have the answers!) I love seeing the conversations on the Facebook page. I particularly love seeing the photos there!!

As I re-read what I just wrote, it strikes me as kind of cheesy. But, I think I will post it anyway. Because, after all, who doesn’t love a little cheese now and then?!

Happy New Year, everyone! May you have a fantastic 2011!!!