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Many organizations study rare diseases, but few have a mission as impactful as Rady Children’s Institute for Genomic Medicine (RCIGM). “We are all about changing outcomes for children,” explained Dr. Stephen Kingsmore, President and CEO of the group. The institute’s initial goal was to provide rapid diagnoses for critically ill children and shorten their diagnostic odyssey, a term used to describe the long and arduous process it takes patients to obtain an accurate diagnosis. “On average, children wait 5 years to get a diagnosis of a rare genetic disease, so we wanted to collapse that down to a day,” added Kingsmore.
With dedicated efforts, Kingsmore and his team have made that vision come to life. “We've been quite thoughtful about how to create an institute that could scale up to meet the needs of children around the country,” he noted. Their first step was identifying the specific demands at Rady Children’s Hospital-San Diego and establishing an institute to address them. Then, the team developed the facilities to rapidly decode and interpret genomes, and subsequently diagnose any genetic diseases. The third step was finding and providing specific treatments to cure or minimize the disease.
After successfully implementing this model locally, the institute expanded by partnering with 100 other healthcare systems across the U.S. to scale these efforts nationwide. Through these collaborations, facilities without the necessary infrastructure can forward their samples to Rady Genomics for rapid analysis, which handles about 1,200 cases annually.
Key Programs
While the institution's main focus is decoding the genomes of critically ill children, RCIGM also runs several other programs to improve children’s lives. Another priority is genomic newborn screening, with the goal of detecting genetic disorders at birth and beginning treatment prior to the onset of symptoms or disease. Central to this effort is BeginNGS (Begin Newborn Genomic Screening, pronounced "beginnings"), an RCIGM-led initiative. This program enhances newborn screening capabilities by employing rapid whole genome sequencing (rWGS) to identify around 400 genetic conditions with available treatments. BeginNGS complements traditional newborn screening methods by integrating advanced genomic tools and providing immediate, actionable treatment guidance to physicians.
Like the institute itself, many of Rady Genomics’ programs were developed from the ground up. “One thing that we've had to start from scratch is a precision medicine clinic,” stated Kingsmore. He explained that after the initial analysis of their genome, oftentimes a child doesn't have a “medical home”, meaning a coordinated point of care where a child’s healthcare needs are managed. Moreover, it’s not always clear what type of physician should follow the child’s illness. This was a challenge to the group, leading to the development of a brand-new precision medicine clinic. The clinic offers customized care, helping families understand genome results, their implications for the child’s health, and the potential impact on family planning or other relatives. It also explores advanced therapies, including experimental and gene therapies. “This goes way beyond standard medical practice and into this new area of advanced precision medicine… that's not yet generally available,” emphasized Kingsmore.
Advancements
Significant technological advancements have supported these efforts and enabled Kingsmore’s team to set two Guinness World Records for the fastest genetic diagnosis by reducing the time from blood sample collection to physician notification. Kingsmore explained that these accomplishments were also made possible through collaborations with biotechnology, chemistry, software, and computing companies worldwide. The team works with these partners to optimize sequencing speed, streamline sample preparation, and advance data analysis through custom-built software. “We bring these different technologies together and these different companies and then we put that in front of critically ill children to give them what would be miraculous, an almost instant answer to what's causing their problems,” he emphasized.
Kingsmore also pointed to two key areas where the team is making progress but still has significant potential to explore. The first is a program that involves collaborating with medical care teams before surgery to analyze cancerous tissue and guide post-surgical treatments. This level of advanced care was exemplified last year when another group demonstrated the ability to decode a tumor’s genome during surgery, allowing for real-time customization of procedures and therapies based on tumor type and mutations1. “Another area that we're really just scratching the surface today is mental and behavioral health in children,” stated Kingsmore. This includes conditions like autism, depression, and suicidal tendencies. Genomic technologies and precision medicine have yet to make a significant impact in this area, but Kingsmore emphasized his team’s commitment to making an impact, with a determined psychiatrist on staff leading the initiative for these critical cases.
Recent News
Two recent studies published in the American Journal of Human Genetics highlighted RCIGM’s work on newborn screenings2,3. The first study demonstrated that by using sequencing and AI, BeginNGS can significantly reduce false positives in genomic newborn screening by 97% using evolutionary insights through "purifying hyperselection.” The platform also retained over 99% sensitivity and integrated the custom Genome to Treatment (GTRx) system for actionable guidance on rare disorders. Testing on over 3,000 children showed BeginNGS could accelerate diagnoses by 121 days compared to current methods, benefiting 1 in 14 children with suspected diseases and 1 in 13 babies who died in infancy.
The second study evaluated BeginNGS for broader expansion through a neonatal intensive care unit (NICU) pilot trial that screened 120 newborns at Rady Children’s Hospital. Nearly 30% of babies without suspected genetic diseases received diagnoses, matching the rates in suspected cases. Additionally, BeginNGS achieved no false positives, delivered higher true positive rates, significantly impacted care for 1 in 24 cases, and earned strong satisfaction ratings from parents.
Current Challenges
As precision medicine has advanced, the challenges at RCIGM have shifted from technological hurdles to issues of implementation and accessibility. “What we do is now almost routine, and so the new challenges are how do we get reimbursed for this?” asked Kingsmore. It’s estimated that 200,000 children a year could benefit from the work being done at RCIGM, but it’s not clear who would pay for the testing. Currently, less than 4% of children in need can access these services due to cost constraints, as insurance companies have yet to reimburse costs for genome testing and analysis. This severely limits scalability, despite funding from philanthropy and government grants offsetting some costs.
Kingsmore also explained that many physicians are unfamiliar with genome sequencing and how to interpret and apply its results in clinical care. This knowledge gap creates a significant bottleneck, as delivering genomic services depends on doctors understanding the technology, trusting its value, and acting on its findings to improve patient outcomes. To address this, the team at RCIGM focuses on educating and engaging physicians, helping them better understand the institute’s work and enabling more effective treatment for critically ill children.
In addition to this problem, Kingsmore shared that the field has lacked a comprehensive resource for precision medicine, as most information resides in journal publications rather than textbooks accessible to physicians. “We've built out a system on the [RCIGM] website that actually goes through every diagnosis we make and tells doctors, frontline doctors, what they should then do next and what treatment should they consider,” he explained. Currently covering over 500 disorders, the system is continually updated to reflect advancements, including new FDA-approved therapies and research findings. With 10,000 disorders to address, continual work remains, but this system ensures that children receive effective treatment after diagnosis.
Reflections and the Future
Despite all the developments at Rady Genomics, one thing remains the same. “Our long-term vision hasn't changed,” stated Kingsmore. “It's always been how do we take what we do in one or two children and how do we scale it.” He envisions a future where pediatric genomic medicine becomes standard care, moving beyond special cases to become routine practice for all children. However, achieving this goal requires scaling current efforts, training a new generation of physicians to adopt and implement genomic medicine, and addressing disparities in access. “How do we get that into every corner and part of the United States? How do we deliver it to every person, regardless of their ability to pay?” reflected Kingsmore.
Even with these challenges, the staff at RCIGM remains committed to furthering the Institute’s mission. “One of the things that unites the folk I work with is this desire to impact individual children's lives and individual families,” stated Kingsmore. “And so, we share that information and each week it's our goal to say, did we help a child this week?” The team celebrates their impact by cherishing the stories with life-changing outcomes. They often display pictures of these children around their institute and compile an annual book of success stories, sometimes sharing them through short video clips.
Kingsmore noted that these types of life-changing stories never get old. “These are the stories that make what we do meaningful,” he emphasized. “It's what we value as an institute. It's not so much whether or not we publish papers in high-ranked journals or whether we get famous. It's much more these stories, these stories about families who've gone from the worst day in their life to having hope.”
References
- Nasrallah MP, Zhao J, Tsai CC, et al. Machine learning for cryosection pathology predicts the 2021 WHO classification of glioma. Med. 2023;4(8):526-540.e4. doi:10.1016/j.medj.2023.06.002
- Kingsmore SF, Wright M, Smith LD, et al. Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. Am J Hum Genet. 2024;111(12):2618-2642. doi:10.1016/j.ajhg.2024.10.021
- Kingsmore SF, Wright M, Olsen L, et al. Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial. Am J Hum Genet. 2024;111(12):2643-2667. doi:10.1016/j.ajhg.2024.10.020
This interview with Stephen Kingsmore is also highlighted in the NGS segment of our documentary with our colleagues from Biocompare. Check it out today!