The Care4Rare initiative has revolutionized the way we diagnose rare genetic disorders in Canada through providing access to genetic sequencing and other ‘-omics’ technologies.
Kassandra Bisson, Radhika Mahajan, Paul McKay, and Hamid Farahmand
Imagine having a child who is sick and after years of tireless diagnostic testing and countless specialist appointments, their diagnosis remains inconclusive. That is usually the dilemma facing a parent whose child suffers from a rare disease. A disease is considered ‘rare’ if it affects less than 200,000 people.1 However, rare disorders are, in fact, extremely common, impacting millions of people worldwide. These diseases are generally chronically debilitating and can even be life threatening.2 In Canada, over a million people suffer from one or more of the 7,000 rare genetic diseases (RDs), in which a third have an unknown underlying genetic cause.3 In search of answers, Dr. Kym Boycott has been changing the game of rare disease patient care and diagnosis. Under the Department of Genetics at Children’s Hospital of Eastern Ontario (CHEO), Dr. Boycott has been a pioneer in improving patient care by understanding the molecular pathogenesis of rare diseases. In addition to her role as a Tier 1 Canada Research Chair in Rare Disease Precision Health, she is also a renowned Clinical Geneticist and a Senior Scientist at the CHEO Research Institute.
When asked about what sparked her career path, Dr. Boycott stated that it was a lecture given by Dr. Patrick McLeod during her undergraduate degree that ignited her interest in human genetics. Dr. Boycott stated, “When you look back at your life at my age, you will see those forks in the road and that was one of them.” Her experience working with both clinicians and researchers motivated her to pursue a PhD and MD, followed by FRCPC training in Medical Genetics at the University of Calgary. Throughout the course of her academic journey, one of the most prominent turning points she experienced was in 2011 when she, alongside her colleagues, launched a national network entitled the Finding of Rare Disease Genes in Canada (FORGE Canada) project. This project primarily used next generation sequencing technology (NGS) to study rare diseases4. In the context of diagnosing rare diseases using NGS, she mentioned, “These [were] amongst the first exomes done for rare disease in Canada at scale.” To her surprise, a bioinformatics masters’ student at that time, Jeremy Schwartzentruber, interpreted the genomic data and identified candidate genes for several of the syndromes on the first sequencing runs. She candidly stated, “It had taken me six years to find my first gene. And during this one afternoon in 2011, we’d found six genes for syndromes that had been without a known genetic cause for decades in 1 hour. […] This is going to be something really important for genetics.” With this major advent in NGS technology over the past decade, Dr. Boycott has led genomic sequencing initiatives worldwide, including FORGEand Care4Rare in Canada, in combination with various ‘-omics’ technologies to unlock the secrets behind rare diseases.
What Is Care4Rare?
One of Dr. Boycott’s greatest milestones is the Care4Rare project (Figure 1)5,which focuses on finding diagnoses for individuals with rare diseases that remain undiagnosed. Founded in 2011, Care4Rare is a pan-Canadian consortium consisting of clinicians, bioinformaticians, scientists, and researchers. The consortium is exploring ways to improve the care of patients with rare diseases in Canada and around the world. In addition to its headquarters at CHEO, Care4Rare has 21 academic sites across the country, and is recognized internationally as a pioneer in genomics and personalized medicine.
Care4Rarehas two main goals: 1) access and 2) understanding. The first goal strives to provide access to exome (ES) or genome sequencing (GS) for all eligible individuals with a suspected rare genetic disease in Canada. The second goal aims to better understand how genetic variation contributes to diseases. Over a 10-year period, Care4Rarehas studied more than 5000 families. When asked about Care4Rare’s proudest accomplishment Dr. Boycott cited, “The fact that all of those 5000 families got the opportunity to access this sequencing technology before it was available in the clinic.” Over 50% of those families have already received answers from this research, while the remaining 50% are still being investigated after inconclusive genomic sequencing results. Dr. Boycott expects that within the next few years, genomic sequencing will become incorporated early on in the diagnostic care pathway for individuals with suspected rare genetic syndromes. Dr. Boycott explained further, “The more we can push it to the front of the diagnostic pathway, the better.” The early integration of genetic sequencing will likely shorten the diagnostic timeline and avoid other inconclusive testing and specialist referrals.
The type of sequencing most appropriate for clinical use is hotly debated. Dr. Boycott stated, “genome sequencing provides about a 5% increase in diagnostic yield over exome sequencing. [There is] not much ‘genome’ can find that an exome didn’t already find for you, especially if you’ve had a microarray done, but our understanding of the genome will improve over time.” She did acknowledge the importance of genome sequencing in playing a critical role in revealing mutational mechanisms and ‘hidden answers’ not accessible by exome sequencing alone. These revelations will push genomic understanding further and make the data produced by ES/GS much more medically actionable6.
Integrating The ‘-omics’ Technologies
Care4Rare – SOLVE, the third phase of the project, is currently focussing on optimizing the delivery of both clinical genome-wide sequencing and multi ‘-omics’ approaches6. This is alongside global data sharing and new bioinformatics, facilitating delivery of innovative diagnostic care for rare diseases. Any individual still undiagnosed after ES, with no candidate variants identified, likely has a complex disease mechanism which will be challenging to detect. For example, a disease mechanism involving long range genomic interactions or heterogeneity in the genetic makeup of the affected tissue means that ‘deeper digging’ is often required to uncover a diagnosis6. For families who failed to receive a clear diagnosis from initial ES, Care4Rare’s clinical laboratory teams will follow-up by supplementing this genomic data with multi ‘-omics’ technologies (Figure 2)6,7,8. The integration of these newer ‘-omics’ technologies is a current focus of Care4Rare, with the hope that this can help ‘solve’ the underlying disease mechanism in individuals or families that were undiagnosed after clinical ES6. Dr. Boycott particularly emphasized the impact of using long-read genome sequencing, transcriptomics, methylomics, metabolomics and lipidomics methodologies in rare disease diagnostics6. Due to their relative novelty, understanding these technologies is a primary focus. Care4Rare subsequently hopes to develop a decision-making tool for determining which ‘-omics’ technologies to use next in the clinical diagnostic pathway based on the suspected disease mechanism. Combining these technologies generates valuable data which increases the potential for clinical actionability6. From this increased understanding of genomic variation and disease, novel therapeutic targets can be elucidated allowing the development of more precise treatment approaches tailored to an individual.
When asked about any potential barriers in the current expansion of the Care4Rare initiative, Dr. Boycott said the only real challenge recently has been the impact of the COVID-19 pandemic restrictions. Particularly, their ability to readily collect samples and therefore the recruitment had been reduced, however, this has been improving as restrictions are being lifted. At CHEO, the aim is to set up a clinic for undiagnosed patients supported by the collaboration between clinical research staff, clinical geneticists, and genetic counselors. Since various sample types can be required for use in other ‘-omics’ technologies, the clinic’s mission is to provide a central location for families to undergo multi-sample collection. This clinic will thereby help to ease the length of time in the research and testing process and ultimately further Care4Rare’s main goal of improving access to genetic testing.
The RareConnect Platform
The RareConnectplatform, initially set up by EURODIS (Rare Diseases Europe), accompanies the research of Care4Rare.9 It offers a private, supportive, and safe social network platform in 13 languages for families that have ultra-rare diseases who wish to connect, ask questions, and share their experiences and stories.9 The RareConnectplatformis divided into disease specific online discussion groups and communities based on topics pertaining to many disease areas.9 It also offers a community for those without a current diagnosis.9 Dr. Kym Boycott pointed out, “These tools have helped address the isolation that families often experience when they have a rare disease”. The CHEO initiatives led by Dr. Boycott have helped thousands of individuals reach a diagnosis for their rare genetic disease, oftentimes providing families affected by rare genetic disease with immediately actionable therapeutic avenues upon finally receiving their highly elusive diagnosis.
Future Prospects for Medical Genomics
The Care4Rare initiative has been a pioneering project leading the way for integration of medical genomics into clinical practice. This project has demonstrated the usefulness of ES/GS alongside multiple ‘-omics’ technologies in diagnosing individuals and families with rare genetic diseases6. Identification of new disease-causing genes will help clinicians and researchers better understand what causes a rare disease and may inform approaches to development of subsequent therapeutics6. While there is currently limited knowledge regarding the epidemiology, diagnosis, and treatment of RDs, global efforts are ongoing to increase awareness, treatment options, and education.
When asked about why she thinks medical genomics research is so important, Dr. Boycott stated, “I think it’s so important because we don’t understand the medical genome – and this impacts patient care – its clinical utility will only increase with our increased understanding”. Dr. Boycott emphasized the importance of medical genomics research in impacting rare diseases and cancer management in the future. As the integration of genomics/other ‘-omics’ becomes more widely used, all that data produced will need to be interpreted. She also noted how interesting it will be to see how “ultimately patients’ treatment might change.” As the Care4Rare initiative has demonstrated, this advancement of genomic and other ‘-omics’ technologies greatly increases the necessity for individuals and researchers that are trained in the medical genomics field. Overall, Care4Rare serves as a fantastic model for other rare genetic disease research and will pave the way for novel research, therapeutic approaches, and diagnostic care.
References
1. Diseases | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. https://rarediseases.info.nih.gov/diseases (Accessed 2022).
2. Boycott, K. M., Vanstone, M. R., Bulman, D. E. & MacKenzie, A. E. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14, 681–691 (2013).
3. Care4Rare Canada: Harnessing multi-omics to deliver innovative diagnostic care for rare genetic diseases in Canada (C4R-SOLVE) | Genome Canada. https://www.genomecanada.ca/en/care4rare-canada-harnessing-multi-omics-deliver-innovative-diagnostic-care-rare-genetic-diseases/ (Accessed 2022).
4. Beaulieu, C. L. et al. FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project. Am. J. Hum. Genet. 94, 809–817 (2014).
5. CARE for RARE. CARE for RARE http://care4rare.ca/ (Accessed 2022).
6. Driver, HG. et al. Genomics4RD: An integrated platform to share Canadian deep-phenotype and multiomic data for international rare disease gene discovery. Hum Mutat. doi: 10.1002/humu.24354. Epub ahead of print. PMID: 35181971 (2022).
7. Computational Multi-Omics. Computational Multi-Omics https://comics.dcv.fct.unl.pt/ (Accessed 2022).
8. Labory, J. et al. Multi-Omics Approaches to Improve Mitochondrial Disease Diagnosis: Challenges, Advances, and Perspectives. Front. Mol. Biosci. 7, 590842 (2020).
9. RareConnect. https://www.rareconnect.org/en/ (Accessed 2022).
The MedGen Project 