One in five of the sickest kids—those in level 4 neonatal intensive care units—are there due to a genetic disease. But of kids with suspected genetic diseases, only a small fraction receives whole-genome sequencing, a process that looks at every letter of the genetic code to try to find changes that might cause disease. This leaves many patients and families not knowing what to expect from the illness or what the best treatments are.
Now, a $9 million collaboration between the Department of Pediatrics at University of Utah Health and Intermountain Primary Children’s Hospital aims to expand genome sequencing to a wider cohort to provide more diagnoses and give kids and families lifelong access to genetic information. The collaboration is funded by $4.5 million each from The Warren Alpert Foundation and donations to Intermountain Health’s Primary Promise campaign. Better diagnostic success, it’s hoped, will lead to more targeted and successful treatments and help patients and families manage their conditions.
“We’re trying to provide diagnostic genome sequencing for any child who needs it,” says Josh Bonkowsky, MD, PhD, professor of pediatric neurology in the Spencer Fox Eccles School of Medicine (SFESOM), medical director of the Center for Personalized Medicine at Intermountain Primary Children’s Hospital, and director of the new project, called Primary Children’s Gene Kids.
The project makes use of comprehensive databases and cutting-edge tools developed at the University of Utah to find diagnoses for patients whose condition may have a genetic cause and to predict long-term outcomes for children with or without a genetic condition.
A successful blueprint
The project will benefit from the extensive human genetics research and expertise developed at the U. It draws inspiration from the NeoSeq Project, launched in 2020 by the University of Utah Center for Genomic Medicine (CGM) to provide rapid genetic diagnoses to critically ill newborns in the Neonatal Intensive Care Unit (NICU) at University Hospital. The project has since found answers for a number of families, improving treatments and giving parents valuable information for the future.
Over the course of the NeoSeq project, researchers have honed their expertise and improved their genetic analysis tools. Gene Kids will build upon this tried-and-tested pipeline. “We have the know-how and the infrastructure,” Bonkowsky says. “We’re not just saying we can do this—we’re showing that we’re already doing it.”
Gene Kids will also use the extensive health information in the Utah Population Database (UPDB) to look for patterns in how diseases are inherited over generations. This can hint at which genetic changes might cause the disease. “Utah has this long and rich history of genomic discovery, and the Utah Population Database played a big role in that,” says Martin Tristani-Firouzi, MD, a clinician-scientist who co-directs the CGM and serves as a co-principal investigator on the Gene Kids project. He adds that the UPDB was instrumental in the discovery of genes that cause breast and colon cancer, heart arrhythmia disorders, and many other conditions.
“It's really our background of genomic and bioinformatic expertise that has allowed us to compete in this space,” Tristani says. “All of that expertise snowballs, and it just keeps getting better and better.”
But the scale of the Gene Kids project is new. Through partnerships in six states, the program will reach kids over a total geographic area of about 400,000 square miles—larger than France and Germany combined. And collaborations with outpatient community clinics aim to help provide kids in remote areas with equal access to genetic diagnoses.
To a new level
Key to this scale-up will be the use of new artificial intelligence (AI) tools to find patterns in clinical and genetic data. The first step is to identify patients whose symptoms suggest an undiagnosed genetic condition. An AI tool will sift through the clinical notes of every patient in the NICU every day, looking for patterns that hint at a genetic cause.
Once likely patients are identified, their genomes will be sequenced in a week or less. But knowing someone’s entire DNA sequence doesn’t mean diagnosis is easy, explains Mark Yandell, PhD, professor of human genetics in SFESOM and a co-principal investigator on the Gene Kids project. “Every time you sequence a genome, there are millions of variants—places where your genome differs from mine,” he says. “The question is, which of those millions of changes might be responsible for a child’s disease?”
Enter another AI tool, developed in part by Yandell’s team, that compares genome sequences to more than 7,000 known genetic diseases to produce a short list of plausible candidates. Then, a clinical geneticist can review the list and determine which changes make sense to follow up on.
The massive amounts of information involved make AI essential to scaling up genetic analysis, according to Yandell. “We’re processing hundreds of pages of clinic notes, millions of genetic variations, thousands of human diseases, and massive databases of papers to try to figure out what’s going on,” he says. “This is a whole new level of integrative medicine that hasn’t previously been possible.”
Lifelong data via the personal genome
Another important aspect of the project is that children and families will have access to their genetic data throughout their lives. As technologies improve and researchers learn more about rare diseases, geneticists can take a second—or third—look at why someone is sick, even if there wasn’t enough information to reach a diagnosis the first time.
While most genetic conditions do not have a cure, finding a diagnosis is the first step to eventually discovering treatments. The current pace of progress in rare disease research means that conditions which currently have no cure might become treatable in a relatively short time, Bonkowsky says. “For diseases that we diagnose today, it’s becoming more and more believable that within the next two to five years, there will be something we can offer for treatment.”
With the launch of Gene Kids, making those diagnoses at large scale is more achievable than ever, Yandell says. “What’s really big about this is that the citizens of the Mountain West are now going to have the most forward-looking genetic care in the world.”
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About U of U Health
University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $522 million research enterprise and trains the majority of Utah’s physicians, along with more than 1,670 scientists and 1,460 health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.
About The Warren Alpert Foundation
The Warren Alpert Foundation focuses on improving the health of the public through grants and programmatic activities that progress toward attaining or perfecting medical treatments or cures through basic research, translational and outcomes research, and health education.