Dr. Rania Habib (Host): This is Transformational Pediatrics with Children's Mercy Kansas City. I'm your host, Dr. Rania Habib. Today, we are discussing 5-Base HiFi Sequencing, the world's most advanced genomic sequencing technology from PacBio. This technology is being used in the clinical setting to accelerate diagnoses for more patients and their families.

Our guest today is Dr. Tomi Pastinen, the Director of the Genomic Medicine Center at Children's Mercy Kansas City. Thank you so much for joining us today, Dr. Pastinen, to discuss this cutting edge technology.

Tomi Pastinen, MD: Thank you for having me on.

Host: You created Genomic Answers for Kids. Could you explain Genomic Answers for Kids to our listeners and why you started the program?

Tomi Pastinen, MD: Genomic Answers for Kids is a foundational initiative of Children's Mercy Hospital. We initiated it four and a half years ago. And the goal was to increase the diagnostic yield and access to genomic testing. So, in case of genomic testing, we're focusing on rare disease, which are individually rare, often affecting 1 in 50,000 individuals or so. But there are thousands of these diseases. So collectively, they impact 1 in 30 Americans and over 10 million children in the US.

Host: Impressive numbers.

Tomi Pastinen, MD: So, most of these diseases are caused by alterations in DNA sequence of patient's genome, and the challenge in the testing for these diseases and finding the diagnosis is the requirement to actually sequence the whole genome. So consequently, many families wait years for the correct diagnosis. And they may go through repeated visits and assessments in vain. And we estimate that in our catchment regions, there's over 30,000 families suffering from rare disease without a definitive answer what's causing it. And only about one in three of these diseases are currently diagnosed if the patient gets access to clinical sequencing. So, identifying all these challenges and barriers several years ago, we set out to improve the technologies to increase the diagnostic yield in our program, Genomic Answers for Kids. And to date, it involved over 14,000 individuals and over 7,000 rare disease patients in our study and have pioneered new technologies, which have shown improved yields in clinical diagnosis, even in cases where everything else failed before.

Host: Let's talk about the technology that you use in this program. How is it changing the landscape of pediatric genomics?

Tomi Pastinen, MD: So, the key technology that we spearheaded in Genomic Answer for Kids is called 5-Base HiFi Genome Sequencing. And this technology uses long DNA reads, which are about 100 times longer than the ones that are used in standard clinical sequencing. That gives you this ability to parts of the genome that are never seen by clinical sequencing. And in addition to the long reads, it uses five instead of four different flavors of DNA building blocks that it outputs. So, in addition to A's, C's, T's, and G's, it sees methylcytosines. And these features allow this technology to, as I said, see more of the genome, the current clinical sequencing, but also expand the information content from each sequencing that we do and allow us to see new types of variation. So in practice, the completeness of the data improves the diagnostic rate. And secondly, it reduces need for multiple parallel tests that are currently used in molecular testing.

Host: When you undergo this HiFi sequencing, how long does it actually take to get the results?

Tomi Pastinen, MD: So, we have continuously improved the turnaround time as we call it from patient sample to clinical results. And currently, we stand at about two weeks. We can probably squeeze a couple more days, but in practice, the technology is very advanced. It takes a few days to actually prepare the sample, and the data is vast, so it takes a few days to actually read all the data from the genome.

Host: And are you guys processing those samples in-house, or is it a send-out test for the sequencing?

Tomi Pastinen, MD: We actually do all the testing in-house. And we are the first clinical laboratory that is offering whole genome HiFi sequencing as a clinical test, which we validated a few months ago. So, all the testing is done in-house from collection of the blood to the final clinical report that comes from the sequence.

Host: Wow. That's an impressive service that you're offering your patients. How many diagnoses have been made since starting Genomic Answers for Kids? And could you speak to the impact that it has not only on patients, but also their families?

Tomi Pastinen, MD: As I said, we pursued sequencing of thousands of families. And to date, we've rendered over 1,700 molecular diagnoses, returning those to the patients. And in many cases, these children have and the families have gone through multiple evaluations and years of wait time. So, the first impact to most of the families is getting a resolution to this lengthy diagnostic odyssey that many patients need to go through.

Secondly, we do observe, in about half of the cases, changes in management of the child's rare disease based on the thorough knowledge from the molecular diagnosis of the disease. And lastly, and unfortunately still relatively rarely, we actually can offer a direct treatment based on knowledge of the molecular disease. And this is really the challenge in rare disease field. Only 5% of rare diseases have a specific treatment. But like I said, management can often change for patients. And it's always important to the family to get the answer and end the diagnostic odyssey.

Host: Absolutely. Now, in addition to using the 5-base HiFi Sequencing in research, you mentioned that Children's Mercy recently announced that it's the first pediatric health organization to use this technology in the clinical setting. And you've mentioned how many diagnoses you've already made, and it's so impressive. How does your new expansion set you apart in pediatrics, but also medicine in general?

Tomi Pastinen, MD: So, I believe it represents a paradigm shift where we want to administer the most complete molecular test known to date as early as possible in the family's journey in a rare disease. And I think this is really a paradigm shift in the sense that we see these lengthy evaluations, re-evaluations, retesting, even sometimes treatments that are not effective because testing has been incomplete or even, with previous technology, sometimes impossible to get the answer.

So, I do think we want to change the landscape with our spearheading, clinical testing it for critically ill children that are admitted to the hospital using the 5-base sequencing We often mistimed thorough clinical genomic evaluation to actually do it as early as possible and as thoroughly as possible. It'll live with the patient for the rest of their life. it's a complete genome and you can query that anytime later on in life when new problems emerge. And I think that's really what we want to advocate. We are not yet at the place where we could offer this to every newborn, but I do think this is a test that should be offered to every critically ill pediatric patient admitted to a hospital. Because in those cases, rare disease is very common and often remains undiagnosed after discharge of the patient.

Host: Absolutely. Now, do you see this technology expanding beyond diagnoses to actually using the genomic sequence now in treatment?

Tomi Pastinen, MD: Well, obviously, there's a lot of information in the human genome. Some of it impacts risk for common disease such as asthma. Some of it impacts your response to medication. And in the latter case, it's underutilized. So, we can read dosing for certain drugs better by including the information on what we call pharmacogenetics of the patient into our dosing algorithms. And this is especially important in some toxic drugs, such as cytotoxic drugs used in cancer therapies. So, I do think the field overall and pediatric medicine is starting to get grasp of beyond diagnosis, also utilizing the pharmacogenetic information and perhaps later on also use for prediction of adult illnesses that may occur in the patient and hopefully prevent some of those.

Host: That's fantastic news. I mean technology is just so impressive that you're utilizing. Dr. Pastinen, what's next?

Tomi Pastinen, MD: So, what we are currently focused on in Genomic Answer for Kids is continuing the recruitment of the unsolved rare disease families from our catchment area and beyond. So, really providing access to genomic testing. Secondly, we continue to improve the technologies. For example, we derive living cells from each of the unsolved patient case, kind of in a test tube model, try to understand, even if we didn't see it in the DNA sequence itself, what is different between a rare disease patient cell versus normal cells from other individuals. And this may give us new insight into the cause of disease and actually a new way to diagnose yet unsolved diseases.

But in addition to that, these patient-specific cell models will be the future tool to explore potential new treatments in a test tube. So, I think this is a really critical element for rare diseases. As I said early on, there's thousands of these rare diseases and we need tailored therapies for these. And you need something to test these tailored therapies. And these patient-derived cell models are a key tool to get there. So, we are systematically exploring this. That's one of our key focuses currently.

The other focus is expanded access to underserved populations. So in our catchment area, we have underserved minorities due to restricted access to high coverage medical insurance or just geographically. So, we cover a lot of territory in Kansas, as well as Missouri, that is rural and often these rural populations have much, much lower access to cutting edge genomic medicine. So, we have launched pilots to partner with primary care providers that are serving these underserved populations with the newest genomic technologies offered by Genomic Answer for Kids. And then, I think that is actually the biggest impact that on the short term we can do in terms of rare disease, actually offering testing to many, many families that never got offered testing because of where they live or what sort of a medical insurance they may have.

Host: That is fantastic. I mean, undoubtedly, you are making a huge difference in your community and hopefully nationwide as patients learn about the center and refer their patients to you. As we wrap up, what are the main take-home points you would like to leave with our listeners, Dr. Pastinen?

Tomi Pastinen, MD: It's key for providers to think about rare disease and think about genetic disease whenever they encounter something in a child they don't expect or think that it's unusual. Simple missing of developmental milestones in a healthy child clinic could be an indication severe rare disease that is genetic in nature.

So, I think the key message is think about the genome. There are effective clinical tests. And through programs like ours, these are becoming better and better. And the cost is getting lower. I think that's the key message we get from our patients is that they had to go through many providers. And ultimately, only after referral to specialized care, they got access to genomic medicine. So, access is key.

I think the second message would be to insurers. I think the way we calculate the impact of testing and reimbursement for testing is flawed. I think that has huge impact for families, even if we cannot offer direct therapies for most of these diseases. So, the paradigm how clinical diagnostic tests are reimbursed should be expanded to understand the whole impact of a rare disease that is unsolved for years and bothering the family and generating not only cost for the medical system, but obviously for the families themselves. So, I do think that we need to get insurers playing a greater role in offering this test earlier.

Host: Absolutely. You're making such a difference in the lives of these patients, Dr. Pastinen. And we thank you so much for joining us today to explain all of this exciting technology and development that you're having at Children's Mercy Kansas City.

Tomi Pastinen, MD: Again, thank you for having me.

Host: Thank you for listening. Once again, that was Dr. Tomi Pastinen, MD, PhD, the Director of the Genomic Medicine Center at Children's Mercy Kansas City. To refer your patient or for more information, please visit childrensmercy.org to get connected with one of our providers. Please remember to subscribe, rate, and review this podcast and all other Children's Mercy podcasts. I'm your host, Dr. Rania Habib, This has been Transformational Pediatrics with Children's Mercy Kansas City.