Bringing Whole-Genome Sequencing In House

How does having an in-house whole-genome sequencing lab allow providers to dial in diagnoses, treatments and medication with incredible accuracy?

In 2009, the first human genome sequencing effort opened researchers’ eyes to how understanding genetics could help in identifying, diagnosing and treating countless conditions. This novel approach to medicine allowed doctors to peek inside a person’s DNA and explore protein-coding regions for possible disease-causing mutations. But that work only dove into 3% of the more than 3 billion nucleotides that make each of us unique. “For the longest time, we thought that the areas of the DNA and the genome that don’t code for proteins were just junk,” says Alisa Gaskell, PhD, Scientific Director of Precision Medicine at Children’s Hospital Colorado. “Oh, how wrong we were.” 

The other 97% of the human genome is far from junk, it turns out. Instead, it’s a gold mine of data that allows us to excavate genetic mutations we never knew existed that profoundly impact the human health experience. 

“It’s those regions that will tell you what form of that protein to make or how much of that protein to make, and we now realize how much that impacts disease,” Dr. Gaskell explains. “Instead of having a tiny little flashlight, we now have a floodlight.” 

Once whole-genome sequencing (WGS) became a frequently used tool in medicine, Children’s Colorado providers would send blood samples to external partner laboratories with testing capabilities and get a report of genetic mutations that might be at play in a child’s disease presentation. 

Working that way, providers identified rare diseases, developed drugs targeted at specific mutations and offered more accurate diagnoses than ever before. Still, the process sometimes took months, and fractured lines of communication between external labs and clinicians didn’t always allow for thorough investigation and problem-solving. 

That’s why, a little over a year ago, the team at Children’s Colorado’s Precision Medicine Institute began laying the foundations of an in-house whole-genome sequencing lab to revolutionize the hospital’s capabilities. That, of course, required funding and physical space, but also the creation of a new team of molecular technologists, data scientists and engineers, plus technology and infrastructure to support the work.

In September 2024, the lab opened its doors and began helping even more pediatric patients in an entirely new way. The first differentiator that Dr. Gaskell and her team hoped to put in place was the use of buccal swabs instead of using blood for testing. Because another needle poke and appointment are major barriers to care, Dr. Gaskell’s team decided to employ a simple swab of the inner cheek instead and started mailing kits to families’ homes, where patients can collect samples from the comfort of their living room. This also allows parents to send the team their own DNA samples, which can help create an even more complete picture of their child’s genome. 

And rather than just collecting a patient’s DNA and answering one question, that genomic information is stored and layered into Epic, the hospital’s electronic health record system. According to Nicholas Willard, DO, Medical Director of the Precision Diagnostics Laboratory, taking this extra step not only provides patients with information that could help them in the future, but also allows them to contribute to a larger dataset of human genetic information that could help solve medical mysteries now and in the future. 

“We may not have the answer or diagnosis today, but because we’ve set up our program the way we have, there’s a high chance that we will be able to provide that for the patient one day,” Dr. Willard says. “The desire is to really maximize the likelihood of us finding that answer. And then, by partnering with the research community and making that data totally unidentifiable, we can allow researchers to ask questions in these large data sets too.” 

How whole-genome sequencing works 

The amount of information gathered from one genome is staggering — about 250 gigabytes of data are generated in the process. That would take a whole team of people at least a full year to process. At the Children’s Colorado lab, specialized tools and equipment allow the team to do it in just a few hours. 

Dr. Gaskell likens the sequencing instrument to a satellite, taking pictures of the entire Earth and then working alongside other tools to zoom in and focus on just one house. That large picture of the genome is honed to help researchers understand specific regions with mutations. Those mutations are then matched to known symptoms associated with that change, if any exist. By using algorithms developed internally and by key industry partner Illumina, the team can turn and maneuver the data to uncover important associations between genetic differences and clinical presentation. Parental DNA helps narrow the picture even further by weeding out inherited mutations and dialing in to unique alterations or combinations within the patient’s DNA. 

“I call it the Rubik’s cube,” Dr. Gaskell says. “You have this large data set, and rather than going through it one by one, you start pivoting the data and seeing if something makes sense.” 

But it’s not only technology doing the work. The true strength of the Children’s Colorado whole-genome sequencing lab is its ability to meld machine learning with the expertise of clinicians, researchers and technologists, who approach data like detectives puzzling through clues. 

“It’s a tighter network of colleagues that can be brought together that have been now walking alongside each other for a while,” Dr. Gaskell explains. “We are talking about gray areas. We are getting really good at identifying an alteration, but in many cases there’s no other evidence out there to help us elucidate the impact that alteration has on the clinical presentation, and we don’t really know how that alteration changes the function of the gene. It’s really good to have a discussion with the clinicians to inform on the significance of that change. When you separate those processes, you’re making a decision in a vacuum. Now we’re making a decision as a team.” 

Bringing whole-genome sequencing from bench to bedside 

In just the handful of months the lab has been operational, hundreds of kids have turned to its capabilities for answers. Dr. Willard says he sees one incredible case after another that may have gone differently without the help of such advanced testing. 

In early 2024, a teenage patient with a mass in his thigh visited the hospital for care. Biopsies only revealed spindled cells, which could indicate any number of diagnoses, including a tumor or trauma. Sequencing allowed the team to narrow in on a genetic cause, something that wouldn’t otherwise be possible. 

In this case, the patient had neurotrophic tyrosine receptor kinase (NTRK) gene fusion. When these gene fusions occur, a cell-signaling gene, which tells cells to divide, can’t turn off and on as the body intends. Instead, it is connected to a gene that is always turned on, forcing cells to replicate with no off switch. Thankfully, within just the last five years, researchers elsewhere developed a drug that targets this process and inhibits abnormal genetic events involving NTRK family genes. 

Later in the year though, the patient’s tumor returned, as it had become resistant to treatment. Through additional sequencing, the Children’s Colorado team identified a new mutation that the tumor had acquired to overcome the NTRK inhibitor. Armed with that information, his doctors identified a new drug, already on the market, that the patient could begin taking right away. 

“Without this genetic testing, we would not have rendered the appropriate diagnosis,” Dr. Willard says. “A lot of places wouldn’t be able to catch this genetic event, but we did and there’s a very specific drug to treat it.” 

According to Dr. Willard, this patient’s story is far from a needle in a haystack. Every single day of every single week, he hears of new children who benefit from the team’s ability to turn the complex and mysterious into the known and manageable.