Jonathan D. Grinstein, PhD, the North American Editor of Inside Precision Medicine, hosts a new series called Behind the Breakthroughs that features the people shaping the future of medicine. With each episode, Jonathan gives listeners access to their motivational tales and visions for this emerging, game-changing field.
For the first episode of 2025, North American Editor Jonathan D. Grinstein, PhD, spoke with Tomi Pastinen, MD, PhD, director of the Center for Pediatric Genomic Medicine at Children’s Mercy Kansas City (CMKC), one of the best pediatric hospitals in the United States.
Pastinen has pioneered genomics for mass diagnosis and treatment of pediatric patients at large medical centers, a fundamental capability necessary for precision medicine. With Pastinen at the helm, CMKC became the first pediatric hospital in Missouri to offer in-house pharmacogenetic testing with a test called Kiddose and the first in the country to use a genomic sequencing approach that reads not four but five different nucleotides in the clinical setting.
In addition to discussing the clinical upside of incorporating genomic testing into a pediatric hospital setting, we also discuss some challenges that arise when going from a genetically characterized diagnosis to an actual treatment—such as what happens when a child is diagnosed by identifying a disease-causing variant for which no existing treatment exists—as well as the world beyond well-defined inherited diseases to more complex disorders, including autism.
This interview has been edited for length and clarity.
IPM: What was the rationale for Children’s Mercy Kansas City to become the first health system to use 5-base HiFi genomic sequencing in the clinical setting?
Pastinen: Five years ago, we launched a health system-wide study called “Genomic Answers for Kids” to understand unsolved rare diseases. When we began, about one third or less of patients received a molecular diagnosis for their rare disease. Rare diseases are rare, but for a tertiary care pediatric institution, they cause a lot of morbidity and mortality, and a large percentage of our admissions are due to them. So, it’s troubling that we only know about one-third of [the molecular diagnoses] in our patient population. Rare diseases are primarily genetic, so the answer is always in the patient’s genome and requires genome sequencing.
We’ve been developing technologies with sequencing companies like Pacific Biosciences, which has a HiFi genome sequencing technology that allows you to read the new resolutions to all genetic variants. In addition, the HiFi genome sequencing for the past two years has allowed us to read a fifth base in the genome, 5-methylcytosine (5mC), which is the methylation of the cytosine base in the genome. This opens new opportunities for some known diseases. It’s future-proofing for genome sequencing, allowing us to find new diseases that are linked to the fifth base problems and maybe ultimately in the future link some of the rare diseases to environmental exposure since 5mC is an epigenetic modulation of the DNA that is often linked to environmental exposures in addition to genetic variation.
In addition to being the first to deploy the whole genome fight-based sequencing as a tool at our clinical laboratory here, we’ve also developed other targeted tests. One of them is called Kiddose, which is a targeted panel test for pharmacogenetic variation, which is essential for chronically ill children, especially children with cancer or rare diseases, who are exposed to different medications. Kiddose is a test that rapidly assesses a few key genes for pediatric pharmacogenetics. In parallel, we envision the whole-genome approach with 5-base resolution as the future pharmacogenetic test, looking at all the variants in all the genes, including the ones that cause disease (diagnostic variants), variants that modulate response to therapeutics (pharmacogenetic variants), and even the variants that predispose to later onset disease so that common variants in the genome can all be read from a single test.
IPM: How does genetic testing aid in characterizing diseases with unknown genetic origins, such as complex diseases?
Pastinen: Children do not only develop rare diseases or cancers, which are extremely rare in children. The most frequent diseases that we observe in our health system are things like asthma and attention-deficit/hyperactivity disorder (ADHD). Later in life, psychiatric disorders such as depression are common, and we hope that precision medicine and genome information will aid in the stratification of various types of diseases. For example, we know from a slightly more complex neurobehavioral disease, autism, that some patients with autism have a rare disease. Still, the majority suffer from a common form of autism that is influenced by multiple genetic variants as well as the environment that causes autism.
I believe that the future of precision medicine is to ensure that when you see something relatively common in the population, such as autism, you have not missed a rare, high-impact genetic variant in the genome. A different group of patients will most likely benefit from a different approach. Future targetable molecules involved in diseases will be precision-targeted based on genomic information. However, the more common forms of the disease, such as autism or other diseases, will allow us to examine the population for different subgroups of genetic predisposition within that population, asking the question, as we develop pharmacological and other treatments, do different subgroups respond differently to therapeutics? This goes beyond looking at how individuals metabolize drugs differently; it also looks at how treatments interact with the patient’s genetic makeup. I truly believe that complete genomic information will serve as the foundation for new precision clinical trials for many of these chronic diseases that do not have perfect solutions, such as many neuropsychiatric conditions.
IPM: How often does a patient diagnosed with a rare disease and characterized for a disease-causing variant using genomics have no companion therapeutic, and how does Children’s Mercy Kansas City handle this situation?
Pastinen: Rare diseases encompass a wide spectrum of diseases, with some so rare that only a few families in the United States are currently affected, and that’s always been a difficult starting point on how to develop treatments. That’s not what the industry is tuned for. They are tuned for the masses and potential return on investment.
However, now that the molecular nature is known, I believe there are two possible effects. One, a whole arm of therapeutic approaches is being developed for the “n-of-one” cases, directly targeting the variant, and this has been shown in scientific studies and has even been brought all the way to the patient, so it is possible to pursue. It is currently economically feasible to do so on a large scale. Still, I believe it will be a feature of some of the most devastating diseases we see, such as when a child is born completely normal and then experiences developmental regression due to a progressive brain disease. If you catch that early enough and prevent that gene from causing harm, you may have a normal outcome. This is where you have the opportunities for these “n-of-one” therapies and then mitigate years of problems by targeting such diseases. That’s one area that is growing. At Children’s Mercy, we are developing patient-derived cell models to begin developing therapy. We can create a stem cell model derived from a patient’s blood cells, turn it into an organ on a dish, and begin testing therapeutic strategies.
The second point is that larger groups of altered genes cause many rare diseases. So, in the future, it may be possible to target the common denominator of multiple diseases to build a larger cohort that is more amenable to the complex and costly development of traditional therapeutics that are not tailored to the patient-specific specific variant.
I believe there is a silver lining, but the challenge for our families and us is that in more than 90% of rare disease cases, there is no curative treatment or specific precision therapy. However, in most cases, identifying the molecular defect alters the patient’s management; it is always meaningful for the family to finally understand what is wrong with their child. Often, what we call a diagnostic odyssey lasts for years, with the family going through futile testing as well as potentially therapeutic attempts for a disease that is currently incurable. It is always crucial for families and providers to know what to expect, what the disease name is, and, ultimately, in our research base, generate the critical mass of knowledge of genomes and individual patient genes to begin testing innovative therapeutic strategies, which I believe will form a different foundation for the future of pediatric medicine.
IPM: When does genomics come into the picture with rare disease patients and their treatment?
Pastinen: Many genetic diseases with precision or curative therapy currently are included in newborn screening. While our hospital oversees newborn screening in Missouri and Kansas, our clinical or research laboratory rarely sees these patients because there is a screening test that immediately directs these patients to such precision therapy, which is advancing. However, we have seen cases where genetic disease treatment was not initiated based on newborn screening, which is not completely sensitive to this known treatable genetic condition.
We occasionally see cases where a patient has a treatable condition that went undetected during newborn screening. Unfortunately, in some cases, there is a lag between birth and the final diagnosis, making the treatment inefficient later in life. We now screen for some of these diseases in newborn screening, and different states have different criteria. Still, cases always go unnoticed, and some treatable conditions are not screened at birth and could be screened using genome sequencing.
The current debate is over whether we should switch to genome-based screening instead of newborn screening tests, which are more targeted and broaden the range of diseases detectable at birth. That is the overall challenge for the field and us: how do we ensure that we do not miss an opportunity to treat a condition that can be reversed? We are investigating this by lowering the barrier to genetic testing early in life.
IPM: Does genomic medicine need to be centralized in centers like Children’s Mercy Kansas City?
Pastinen: It is essential to continue centralizing this type of activity in healthcare centers because things in the genome will never manifest in real life. Interpreting the genome requires clinical expertise. It is not as simple as sending a buccal swab and receiving a complete genome sequence. Once an entire genome has been sequenced, it must always be evaluated within the context of the patient or customer. Are these genetic variants relevant, irrelevant, or potentially relevant later? We cannot yet predict their relevance today. We must strike a balance.
I believe that everyone’s genome will be sequenced at some point in their lives. Should we do it at birth? Probably because that provides equitable access to genomics. But we should probably return results as needed throughout life.
