Since 2022, the Care4Rare Canada Consortium (Care4Rare) has collaborated with PacBio on a ground-breaking study looking at some of the most complex and unexplained rare disease cases in Canada. This initiative, led by the CHEO Research Institute, seeks to reveal the underlying biology of genetic disorders that impact as much as 3% of the Canadian population.
We recently had the opportunity to sit down with Kym Boycott, MD, PhD, Chair of the Department of Genetics at CHEO and Senior Scientist at the CHEO Research Institute to check in on project progress and to discuss the impact she is seeing from HiFi data. For context, when we last spoke to Dr. Boycott, she shared how her team had started to apply PacBio HiFi long-read sequencing in instances where the underlying genetic mechanisms could not be understood with conventional exome, genome, and RNA sequencing.
The following is an excerpt from our interview with Dr. Boycott on HiFi-enabled rare disease research at Care4Rare:
PacBio:
When we last spoke, you and your team had started to apply HiFi sequencing to cases where the causes of genetic conditions impacting generations of families have gone unexplained, despite extensive exome, genome, and RNA sequencing. How has using HiFi sequencing impacted your research? Have you been able to find answers in those instances?
Dr. Boycott:
“HiFi sequencing has already shown itself to be incredibly useful in our research program focused on unsolved rare diseases – of the handful of… families in our initial pilot, it helped find an answer for several families who had been [in the dark] for over 40 years. For example, it very quickly helped us find a highly repetitive retroelement insertion in a noncoding region of a known disease gene that had eluded all our previous short-read exome, genome, and RNA-sequencing efforts. HiFi sequencing has also helped us to characterize the size and sequence composition within and around a recently discovered tandem repeat expansion associated with ataxia that impacts numerous families in our unsolved ataxia cohort, something that we would not have been able to do with previous short-read technologies.”
PacBio:
Your initial study using HiFi sequencing was focused on a small subset of families, have you expanded or changed your research focus and goals since then?
Dr. Boycott:
“Learning from and building on our initial pilot study, we have been working to develop new inclusion criteria to help us identify which unsolved families would most benefit from long-read sequencing based on their family history, genetic testing history, or disease presentations. For example, it may be most helpful for clinical indications suggestive of tandem repeat expansions, such as ataxia, or [in cases] where we already have a compelling “single hit” in recessive disease genes, and we are searching for a second variant that has yet to be found. We have been expanding our HiFi cohort to sequence more unsolved families, aiming to assess the utility of HiFi sequencing within these different test indications.”
PacBio:
Your near-term goals in 2022 were to develop a diagnostic pathway for unsolved rare disease patients. What work remains to be done?
Dr. Boycott:
“Care4Rare Canada is focused on several important aspects of the diagnostic care pathway that are needed to deliver diagnoses for unsolved rare disease patients. Some of the remaining work to be done to implement this includes improving access to critical genomic testing technologies, facilitating, and expanding national and global data sharing efforts, and continually evaluating the utility of emerging technologies such as HiFi sequencing, including assessing where they can be most impactful within the clinical [research] pathway.”
PacBio:
What most excites you right now about Care4Rare’s current efforts and accomplishments?
Dr. Boycott:
“Care4Rare is currently focused on optimizing the diagnostic care pathway for difficult to diagnose families, and part of this work focuses on expanding the diagnostic toolbox. We have learned that each undiagnosed family in our research program is unique and poses an independent challenge that requires multiple technologies and hours and hours of analysis. A future where this toolbox could be more streamlined and scaled up to provide access for more families is what excites us and brings us to work every day.”
PacBio:
Do you feel with HiFi sequencing you are getting closer to reaching a future in which families can consult a clinical geneticist and have access to a variety of technologies that can provide the most efficient answers in the shortest time frame?
Dr. Boycott:
“This is an exciting time. A future diagnostic pathway where a single test could be offered to all patients with a suspected rare genetic disease early in their diagnostic journey is the ultimate goal for both healthcare providers and families. We are getting closer to this goal, and we look forward to contributing to the clinical and informatic processes that will need to be in place to achieve this future.”
Ready to make HiFi work for you?
If you want to learn more about how PacBio HiFi sequencing is helping advance our understanding of rare disease, please visit the rare disease page and view our recorded rare disease webinars. Be sure to also check out how HiFi has the potential to replace conventional sequencing assays, and as always, don’t hesitate reach out to us directly!
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