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Advances in health and medicine.
Marjorie Bekaert Thomas
Advances in health and medicine.
Children's Health Channel
Reported July 4, 2011

Decoding Genetics: Sequencing Genomes -- In Depth Doctor's Interview

David Dimmock, MD, from Children’s Hospital of Wisconsin/Medical College of Wisconsin, discusses how analyzing data from genetic tests led him towards determining the proper diagnose of a pediatric patient.

What was your role in regards to Nic’s diagnosis and treatment at the clinic?

Dr. David P. Dimmock: I was a part a larger team. When we decided that we were going to sequence Nic’s exome, we had to decide how we were going to analyze the data. We sort of already determined how we were going to do the exome sequencing in the platform. What  we were worried about was how the data was going to come back, and what we were going to do with it all, because we knew that we were going find somewhere around 20,000 variants that we were going to have to try and work out to determine if there is one or two of those variants that explained a majority of Nic’s illness. Previously, I had worked in a clinical diagnostic center, and there were certain tools that we used in working out whether a chain in the genome was likely to cause disease. I had long conversations with Liz Worthey, and we discussed what tools were appropriate in this particular case. In due course, we worked out with 20,000 variants, if we could whiz through a variant in six minutes and continue deciphering them for approximately three to four years (had she done each by hand). This sort of helped set the priorities for how we would analyze the data and what variants would be important. Liz, who in many ways is really the star of the analysis, devised a brilliant piece of software that took all of the variants that we got back from Nic’s exome, and allowed us to observe the myriad variations via all of the routine tools that we normally use. We were then able to filter the variants and see which ones are likely to cause disease and which were less likely to have any detrimental effects. Subsequently, we narrowed the variants down to a list of 2,006 genes that were most likely to cause Nic’s problems, and in fact Nic’s genetic change was not on that list of 2,006 genes. We then continued the process to the point where we had a couple of hundred genes we were interested in, and then 36 other genes that we suspected to possibly be interesting Even from the first round of sequencing, we had two genes that sort of jumped out and one of them was in fact the XIAP gene that in fact turned out to be the answer. It was because we didn’t look at the exome as carefully that we should have at that point in time to fully trust the results. That was part of the role. Liz and I also spent a lot of time looking at the sort of short list and determining which of them might be plausible. Looking at the variant that showed the XIAP amongst several others really seemed to disrupt what the gene would do; then looking at XIAP, what the gene did and whether we would expect the genetic change to actually cause what we saw in Nic. That was a vast part of my role. Liz Worthey did a lot of the analysis and constructed the tools and software involved in the diagnosis of Nic. Without her, we wouldn’t be sitting her with an answer. Furthermore, this could not have been done without the collaboration of many people, including the team involved in programming the software. They made it possible to go from an idea on paper to a fully functioning software program. Some of the challenges that my role entailed was talking to Nic’s mom, and tell her what we found and how we plan on going forward with the further analysis of her son, in addition to organizing the clinical testing that we sent out.  Really, at the end of the day someone had to make a decision whether or not we were convinced that this change was real at the cause for Nic to have to XIAP deficiency. That was significant because we were at the point where genetic changes in the XIAP gene cause a disease, which we know if Nic got a viral infection that is common within the population would most likely kill him. Ultimately, the reason we decided to commence treatment with the stem cell transplant was based solely on the fact that we knew that without the stem cell transplant (with the genetic changes occurring in Nic’s body as well as the contraction of the virus) he would die. We weren’t convinced enough, although we were expecting that the transplant would provide benefit to his GI disease, which was his primary problem. We kind of thought that we were obliged to do the transplant because of the risks we knew if we didn’t do it in regards to the XIAP deficiency. There was data from some cases that suggest that some of the children did have bowel diseases, which following the transplant showed improvement in the disease. Ultimately, Dr. Margolis said that he would not perform the transplant unless a physician went on record and said Nic has XIAP deficiency and needs the bone marrow transplant. Once we got all of the data together, it sort of fell on my shoulders to say, “Yes, he does have XIAP deficiency and needs a bone marrow transplant.” 

Was Nic’s entire genome mapped or merely sections that you thought to be of importance?

Dr. David P. Dimmock: We did something called exome sequencing. The clinical testing that we now offer to children routinely is whole genome sequencing. Whole genome sequencing sequences about 95 percent of what we know in the genome.  It’s not a complete sequencing since we can’t get that other five percent for technical reasons. Exome testing (is) a little different. Historically, with genetic testing, if you wanted to find out if you have cystic fibrosis, we would sequence what is called the coding regions (the exomes that actually make the protein). In between each of the exomes is a large space called an intron – we still don’t fully understand what it does. In Nic’s case, when we go back two years, sequencing technology was very expensive compared to where it is now. The difference between performing whole genome sequencing and doing  exome sequencing is that it is about 1.2 to 1.3 % of the whole genome, so in point of fact you would really only need to sequence around one-hundredth of the entire genome. Once again, the whole exome doesn’t actually get quite all of the encoding genes because there are certain genes that we just can’t catch (92 – 93  percent of the exomes; 20,000 genes were sequenced).

Is Nic the only person that you have ever seen with this sort of mutation evident in his genes?

Dr. David P. Dimmock: Yes.

He is the first case recorded?

Dr. David P. Dimmock: Outside of his family, yes, he is the only person in the world who has ever had this exact mutation. There are not very many people walking around who have this sort of mutation in their gene, and those who do have exceptionally significant health problems. We were quite fortunate that we were able to look at Nic’s genetic test in comparison to not only his family, but what’s more various research groups that have sequenced a large number of exomes or genomes – we went and looked in the data system to make sure that they didn’t see his variant or any other similar variants in the gene.

So this is a rather unique case?

Dr. David P. Dimmock: Yes. It is unique. On the other hand, there are other children out there with XIAP deficiency, some of whom had several of the same features that Nic had, however, most of them presented different problems than those referenced from preceding cases.

What are some of the implications as well as important factors involved in genetic testing of children?

Dr. David P. Dimmock: We use genetic testing with children very often in an effort to determine exactly what they have. For a lot of children that come to my clinic, being able to find a genetic answer to what is wrong with them will allow us to identify the best method of treatment for their particular illness. It is very important in general to be able to get a genetic answer because certain forms of diseases that we often see in children are treatable where others are not. Even being able to establish a diagnosis where there is no treatment allows you to be confident that not doing a certain form of treatment is the right choice.  If you can work out what a child has or what an adult has, it allows you to broaden information such as the prognosis as well. Being able to establish a diagnosis as a result of genetic testing really allows you to know what treatment to use in a lot of the cases. It allows you to provide information on prognosis. Establishing something that you do not have a specific treatment for is also useful because it means that you can start looking outside of the box at other options that may provide some benefit. In circumstances such as these, you look into experimental treatments or treatments that may be dangerous or carry certain risks. In Nic’s case, one of the big questions was whether or not we should perform a bone marrow transplant. Cord blood transplants come with risk including death.  All children that have this sort of transplant are at risk for long-term health complications . . . so this is not something that you enter lightly. If we made a diagnosis that showed a particular individual wouldn’t benefit from a transplant that would also be very important information because it means that we wouldn’t have to expose the patient to that sort of risk associated with the transplant. The current way that we test children is we test one gene and move on, we test that one and onto the next, or we may do another test such as an MRI scan or muscle biopsy, and try to narrow down the categories that child falls into and pick the genes most likely to be the culprits. Typically, this process is rather expensive in addition to being time consuming. One may have actually missed the opportunity to treat, and certainly in a case such as Nic’s, if we had a test like this earlier we would have been able to determine the diagnosis far sooner, and perhaps have avoided having to take his colon out. Going into something like a bone marrow transplant when healthy (before you had all of the disease complications) is very useful in terms of improving the outcomes for something like a bone marrow transplant or a liver transplant. We see this as having a huge potential for being able to establish a diagnosis earlier, which allows you to make decisions regarding treatments before the child becomes too sick, where as often times options are too late or treatments are unavailable.

What made Nic’s case in particular so unique and therefore complicated when trying to determine the diagnosis as well as the optimal treatment method?

Dr. David P. Dimmock: Nic’s case was the first case in the world where genome or exome sequencing was implemented in the diagnosis, and that then changed the treatment. Though there are a couple of cases where in research studies, patients have had genetic testing done that proves they had a mutation in the gene that was not expected to be there by any means. I think that Nic was the first for several reasons. The first is that we found a disease presentation that we would never have expected to encounter. We would never have thought that XIAP was the logical gene to test. Based on his presentation, he had a severe bowel disease and not an immune disease.

Is the XIAP deficiency that was evident in Nic’s case the first instance recorded as well?

Dr. David P. Dimmock: XIAP deficiency has been seen in multiple boys before, since it affects the x- chromosome and boys have only one where as girls have two x-chromosomes. They basically have a back-up copy if you will. It has been known for quite a while that missing this protein runs the risk of having this lymphoproliferative syndrome, which is kind of like blood cells not shutting down and the white blood cells continue to multiply and multiply. This is something that has presented itself in children who have immune problems or this lymphoproliferative syndrome. Really, the presentation of this severe bowel disease apparent with Nic is far different than anything we have seen that is linked to deficiency of this protein. His way of coming to medical attention was much different than other children with this deficiency, which is why we wouldn’t have gone in the direction of testing this gene. Nonetheless, some of the children with immune problems have experienced some bowel problems as well.

This is an exceptionally expensive means of testing if I am not mistaken. How did benefit outweigh cost with this case in particular?

Dr. David P. Dimmock: Truth be told, the analysis of the data is in due course far more expensive the genetic testing itself.

How expensive was it?

Dr. David P. Dimmock: I am not at the liberty to discuss that. I am very sorry.

I read somewhere that the sequencing is in the ballpark of $72,000.

Dr. David P. Dimmock: For the genetic testing that would be somewhere in the right ballpark. It is probably a little bit more than that actually.

Did the family have to pay for the genetic testing themselves, or does insurance kick in for a procedure such as this?

Dr. David P. Dimmock: Once again, I apologize because I am not at the liberty to discuss that. I can talk about the steps involved in the diagnosis all of the way through the postoperative treatment, however, I can’t talk really discuss prices.

No worries. I was just wondering if perhaps the clinic wrote off the expenses because you wanted to help this child.

Dr. David P. Dimmock: In part, yes, as well as a number of generous donations that helped defray the cost of the sequencing as well as the analysis that helped in determining Nic’s diagnosis. I am exceptionally grateful to each and every one of those donors who provided funds that helped saved this young boy’s life because without them none of this would have ever been possible. It wasn’t insurance, it wasn’t paid for by commercial funding but rather by people with big hearts and big donations.  Right now, the clinical program that we have in place bills insurance the same way as any other procedure.  That is true. We are getting insurance companies to preauthorize testing, and in fact a particular insurance company approached us saying they want to be billed in clinical situations where we would be doing a lot of expensive testing. Getting to the point where we perform analysis of the data proves to be rather difficult and time consuming because we have a limited number of people.

How long would it take for a team to analyze 20,000 or so different variations?

Dr. David P. Dimmock: With the software program aforementioned, the time it takes to analyze the data is rendered far less than if we had to do it by hand. A task that large would literally take several years to accomplish, and with whole genome, you are actually talking about millions of variants in comparison to the thousands presented otherwise. In Nic’s case, we estimate that Liz worked 16-hour days for three months analyzing  the myriad variants from the sequencing.  I know that we spent an exceptionally long time analyzing the data, however, I have no idea as to how many man-hours it took before reaching an answer. Subsequently, a team of researchers discussed and reviewed the most interesting variants. It took a huge amount of time. Since then, we have further developed the software so that it is much faster now. One of the cases that we did just recently took a couple of weeks before getting a definite answer. In another case, it took mere hours for an answer once the data was encrypted into the software.

What is it like for you knowing that you were a part of the process that allowed a young boy to keep his life and save a family from ruin?

Dr. David P. Dimmock: The satisfaction of seeing Nic healthy is by far the utmost aspect of the entire process we took to get him where he is today. Seeing Nic today is really exciting. If we hadn’t taken the risk that we did, Nic might not be here today. Nic is a very special story, but the reality is that this type of genetic testing can be used to help other children. That is yet another big part of it. Knowing that this is not solely going to save just this one child, but in fact an entire population of pediatric patients. It’s very satisfying. It’s often times heartbreaking when you have the means to determine the diagnosis, however, there is no effectual treatment that can benefit them. It can be tough, but I think that on the flipside stories like that of Nic’s reminds you why you got into medicine and motivates you to work towards finding treatments for each patient. 


 This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.

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If you would like more information, please contact:

Maureen Mack, Director of Media Relations
Medical College of Wisconsin
(414) 955-4744

To read the full report, Decoding Genetics: Sequencing Genomes, click here.


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