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Seeking Answers: ReSeq Project Doesn't Give Up on Finding a Diagnosis for Critically Ill Kids

Sophia Friesen

For critically ill children with unknown genetic disorders, rapid whole-genome sequencing can be a diagnostic tool of unprecedented power. In the neonatal intensive care unit at University of Utah Health, clinical genome sequencing helps doctors find diagnoses and improve care for kids with rare genetic diseases. But even when doctors have an atlas of a patient’s every genetic variation in hand, more than half of sequenced kids remain undiagnosed. Each individual’s genetic code is unique, and figuring out which of a sick child’s many genetic differences is responsible for their disease can be extremely difficult.

But causes of disease that might not be identified by standard clinical analysis might still be detectable using a different, newer set of analysis tools. That’s where the ReSeq project comes in. When standard clinical genome analysis fails to reach a diagnosis, ReSeq’s team of geneticists, data analysts, and genetic counselors takes an in-depth second look. By pooling their intellectual expertise and reanalyzing genetic data with ever-evolving research tools, the team works to find diagnoses for kids and their families.

A blond woman with light skin speaks with someone out of frame in the NICU. Her hands are in an incubator.
Sabrina Malone Jenkins, MD, the lead investigator on the ReSeq project. Image credit: Charlie Ehlert/ University of Utah Health

A Path to an Answer

For critically sick kids, an undiagnosed genetic disease can mean a long and difficult journey through the medical system. Without knowledge of the basics of a child’s disease, doctors don’t know what the best clinical care is, and kids may end up undergoing many diagnostic tests and spending more time in the hospital. 

Sabrina Malone Jenkins, MD, associate professor of pediatrics in the Spencer Fox Eccles School of Medicine at the University of Utah, calls this trial a “diagnostic odyssey.” As the principal investigator on the ReSeq project, Malone Jenkins’ goal is to end the odyssey by finding diagnoses for sick kids. “We wanted to create a pathway for these patients and these families to try to find an answer,” Malone Jenkins says.

Finding the cause for the disease doesn’t mean doctors will be able to cure it. Despite groundbreaking advances in genetic medicine, there is currently no cure for the vast majority of genetic diseases. But a diagnosis can still be incredibly valuable, says Brian Shayota, MD, medical geneticist in the ReSeq project. Finding a genetic diagnosis can bring families a sense of closure and relief from guilt that they “did something wrong,” Shayota says, as well as help parents make informed decisions about family planning. “Just having that answer makes a huge difference for families.”

Finding a genetic diagnosis can also help connect the dots between people with rare diseases worldwide. Families armed with a diagnosis can find others in the same boat, building support networks and sharing their experiences. And doctors across the globe can pool their knowledge of ultra-rare diseases to better understand how to manage them. “It’s not unusual that we find mutations in genes that have never been known to cause a human disease,” Shayota says. “We’re trying to establish disease mechanisms to identify brand-new genetic conditions we never knew about before.”

Panel of three photos: a man with light brown skin wearing a suit and tie, a man with light skin wearing a suit, and a man with light skin wearing a collared shirt. All are smiling at the camera.
Left to right: Brian Shayota, MD, Carson Holt, PhD, and Steve Boyden, PhD, scientists on the ReSeq project. Image credit: Brian Shayota (left), Kristan Jacobsen Photography (middle), Steve Boyden (right).

Unraveling Complexity

Identifying a mystery genetic disease means understanding the massive amount of information in a patient’s genome: six billion base pairs containing millions of genetic changes per person, most of which have unknown medical significance. One or perhaps a few of those changes cause the disease. ReSeq’s mission is to figure out which.

The first step, deducing a person’s genome from laboratory data, is a puzzle akin to reconstructing a book series from millions of paper scraps—and clinicians who are treating seriously ill children need that puzzle to be solved fast. At U of U Health, the Utah Center for Genetic Discovery enables rapid initial genome analysis via a hefty application of computational power. “It takes over 2000 CPU cores,” explains Carson Holt, PhD, director of the UCGD core. “But our data pipeline is the fastest in the world. Nobody’s beaten it yet. In as little as five minutes I can take a single sample and tell you what’s in it.”

After sequencing a patient’s genome, the hard part begins: figuring out which of their millions of genetic differences cause their disease. To prioritize the differences that are most likely to influence a child’s disease, the ReSeq team relies on recently developed software tools. The tools spotlight genetic changes that affect genes related to patients’ symptoms, changes that are likely to prevent a gene’s function, and those associated with the disease in other family members. 

The scientists then do a deep dive into each genetic difference, investigating what’s known about how the change might affect the gene—and what that might mean for patients’ symptoms. 

Close-up of gloved hands gently cradling a very small baby's feet.
A diagnosis can improve disease management, help with family planning, and provide a sense of closure. Image credit: University of Utah Health Care

The Search Continues

The ReSeq project represents an understanding that, just because a sick kid’s condition was undiagnosable in the past, doesn’t mean there’s no hope for the future. Clinical knowledge of human genetic variation is constantly improving, prompting the ReSeq team to look at patients’ genetic data in a new light. Every month, the team convenes to discuss their findings and decide on next steps, focusing their intellectual resources on a few kids each meeting.

A January meeting of the ReSeq team saw experts swapping ideas about inheritance patterns, comparing patients’ symptoms with those for known genetic disorders, and debating which further tests would be most helpful. The mood was hopeful; new diagnoses seemed just around the corner.

But some of the next tests failed to support the researchers’ best guesses, sending them back to the drawing board. Still, the research team is undeterred. Steve Boyden, PhD, one of the lead analysts at UCGD, explains that the diagnoses that the project attempts are difficult by definition. “All the kids that had something that was easy to solve have been solved already. You do know going into it that your success rate is going to be low. But you’re taking the philosophy that we’re willing to do anything and everything to try to get a diagnosis for these kids.”



Generous financial support from The Center for Genomic Medicine, Primary Children's Center for Personalized Medicine, The Mark and Kathie Miller Pediatric Genomics Fund, ARUP Laboratories, Illumina, The Margolis Foundation, and The Burton Foundation makes this work possible.