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How clinical RNA sequencing at SickKids is accelerating Precision Child Health
Summary:
New studies show how RNA sequencing is helping doctors diagnose and treat childhood conditions more precisely, from cancer to rare disease.
At The Hospital for Sick Children (SickKids), new research is highlighting a powerful tool to support clinical care: RNA sequencing.
While researchers have used RNA sequencing for years to better understand human genetics, its integration into clinical care is much newer. In 2023, SickKids became the first hospital in Canada to validate an RNA sequencing platform for clinical use. This milestone supports the hospital’s Precision Child Health movement, which aims to deliver individualized care for every patient. Translational Genomics, a key theme of Precision Child Health at SickKids, is laser-focused on understanding how new technologies like RNA sequencing can empower families to learn from their genetic information to guide care and access research opportunities.
Just two years later, SickKids-led studies are showing the wide-reaching impact of RNA sequencing to inform clinical decision making, from diagnosing rare genetic conditions to guiding more targeted treatments for children with cancer.
What makes RNA sequencing different?
DNA sequencing, like genome sequencing, gives a snapshot or blueprint of a person’s genetic code. RNA sequencing shows how the body reads and uses that blueprint to make proteins. Sometimes, the way genes are read (RNA) doesn’t match the DNA instructions. These differences can reveal important clues about disease. RNA sequencing can detect gene fusions (when two genes join together) and gene splicing (how genes are cut and rearranged). These changes can have significant implications for diagnosing rare conditions and treating certain tumours.
“RNA sequencing gives us a clearer picture of what’s happening inside a patient's genes. This allows us to diagnose and identify potential therapeutic targets for patients with more precision,” says Dr. Lianna Kyriakopoulou, Director of Genome Diagnostics in the Department of Paediatric Laboratory Medicine.
Helping kids with cancer get the right treatment sooner
In the first large-scale study showcasing the power of clinical RNA sequencing for the diagnosis and treatment of childhood cancer, a SickKids team found that RNA sequencing provided valuable data for 87 per cent of patients.
Published in Nature Medicine, researchers looked at more than 2,300 tumour samples from children and adults across Canada with different types of cancer, including brain, blood, and solid tumours. The results helped doctors revise diagnoses and update treatment plans using targeted therapies.
“Through RNA sequencing, we’re not just looking at what kind of cancer a patient has, we’re looking at the exact changes in their tumour that we can target with treatment,” says study lead Dr. Cynthia Hawkins, Neuropathologist, Senior Scientist in the Cell & Systems Biology program, and Garron Family Chair in Childhood Cancer Research. “RNA sequencing is a feasible and effective way to put Precision Child Health in action by ensuring patients with cancer receive therapies tailored to their specific condition faster and sooner.”
The team, including first authors Aida Glemboki, MSc candidate, and Dr. Robert Siddaway, Diagnostic Innovation Investigator, Project Investigator in the Genetics & Genome Biology program and study co-lead, hopes this research will help expand the use of RNA sequencing in cancer care across Canada and beyond. They are also investigating ways to maximize the platform’s capabilities, by expanding the current targeted sequencing to include more parameters, including cancer-causing pathways and gene expression, which is implicated in some cancers.
This study was funded by the Garron Family Cancer Centre and SickKids Foundation.
Diagnosing the undiagnosed in rare disease
In another study, research co-led by Kyriakopoulou and Dr. Michael Wilson shows RNA sequencing can help refine and revise diagnoses in children with suspected genetic conditions, especially when DNA testing alone isn’t enough.
Published in npj Genomic Medicine, the team, including first authors Drs. Kyoko Yuki, Laboratory Specialist, and Huayun Hou, Bioinformatician, developed a clinical-grade RNA sequencing method and used it to analyze RNA from 134 participants in the SickKids Genome Clinic cohort. The team looked for unusual gene activity, such as missing or extra RNA messages, and changes in how much genes are expressed. In one-third of diagnosed cases, RNA sequencing confirmed what DNA testing had already found, which is an important piece of information for clinical laboratories. RNA results led to new or updated diagnoses and in seven per cent of undiagnosed cases, and RNA helped point to new genes and mechanisms of disease that may explain the condition. This research also defined clinical indications for which RNA studies can provide diagnoses and demonstrated that it can increase diagnostic yields.
“RNA sequencing is a valuable tool that can complement genome sequencing, especially when DNA results are inconclusive,” says Wilson, Senior Scientist in the Genetics & Genome Biology program. “By better understanding the molecular basis of rare conditions, we can deliver more answers and inform tailored care to children who’ve long gone without them.”
This study was funded by Genome Canada.
Uncovering hidden mechanisms of rare conditions
A third study, published in Genome Medicine, showed how RNA sequencing can reveal new and meaningful insights for patients with suspected single-gene disorders (conditions caused by changes in just one inherited gene, like cystic fibrosis or Huntington’s disease).
The team, including resident and first author Dr. Jamie Stark, studied 53 SickKids patients across four real-world clinical scenarios. Among those with possible disease-causing variants identified through genome sequencing, RNA sequencing confirmed a molecular diagnosis in 45 per cent of cases. It also supported DNA findings in 21 per cent of cases and ruled out candidate variants in another 24 per cent. In addition to identifying and confirming diagnoses, RNA sequencing uncovered novel disease mechanisms and two previously unknown disease links involving the PPP1R2 and MED14 genes.
“RNA sequencing doesn’t just confirm what we suspect, it can rewrite the diagnostic story and uncover hidden mechanisms of rare disease, to help us deliver more individualized care,” says study lead Dr. Ashish Deshwar, Staff Physician and Scientist in the Developmental, Stem Cell & Cancer Biology program.
Deshwar co-leads Translational Genomics as part of Precision Child Health at SickKids. This work aims to integrate genomic medicine into clinical care more effectively, and advance the use of new genomic technologies that help complement or expand on the current care approach for patients.
This study was funded by SickKids Research Institute, Canadian Institutes of Health Research (CIHR), University of Toronto McLaughlin Centre, and SickKids Foundation donors including the Feiga Bresver Academic Foundation.