Conditions impacting brain development in children and youth, such as neurodevelopmental conditions (NDDs) and acquired brain injury (ABI) are prevalent, impairing and costly. NDDs and related mental conditions impact at least one in five individuals, persist across the lifespan and cost up to two million dollars in lifetime cost per individual in Canada. ABI further impacts brain development, affecting 4.4 per cent of children 1-17 years, (with up to a third of such injuries leading to persistent post-concussive symptoms. Despite recent advances in our understanding of the biology of these conditions, our ability to change long term outcomes remains limited. Accumulating data from sequencing studies highlights significant biological heterogeneity in NDDs, and emerging studies in ABI also suggest significant genomic heterogeneity. There is an urgent need to understand such heterogeneity, provide tailored anticipatory guidance, discover biomarkers that will allow patient stratification and ultimately develop precision health interventions. In this effort, we have brought together nine research cohorts across NDDs, mental health and ABI, collecting rich phenotyping data, and assembled a highly accomplished multidisciplinary team of genomic scientists, clinicians, engineers and other stakeholders, to whole genome sequence 10,000 samples, using both short and long read sequencing, link genomic data to environmental exposures and phenotypes, and use advanced computational approaches to facilitate precision health solutions. 

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Disorders of childhood are highly penetrant, heritable, often polygenic and have lifelong impact, especially as advances in medicine have resulted in improved survival into adulthood. These disorders engender a high burden on patients, families and healthcare resources across a lifetime. Early diagnosis is essential to inform preventive and pre-emptive management to reduce complications and improve survival and quality of life. The yield from conventional genetic testing is suboptimal in disorders with genetic heterogeneity. Whole genome sequencing (GS) provides comprehensive genetic characterization by exploring both rare and common alterations not only the protein-coding regions but also variants in the “dark matter” of the genome, complex structural variants, tandem repeat expansions, and regulatory variants in the noncoding genome. The goal of the Precision Child Health (PCH) – Comprehensive Sequencing for Childhood Life-long Onset disorders (PCHSeq) project is to leverage the power of genomics to enable early and more accurate diagnosis and prediction of health trajectory and identification of novel therapeutic targets to guide personalized care and improve outcomes. The backbone of these efforts is the generation of short-read GS on DNA samples from 9,500 participants (including family members) with a diversity of childhood onset disorders coupled with long read sequencing (LRS) in a subset of 800 “genotype-elusive” patients. With access to a highly diverse patient population with rare and complex disorders referred to SickKids from Ontario and across the country, the PCHSeq team has already enrolled 9,296 potentially eligible participants with childhood onset disorders into existing biobanks. The cohorts are clinically and geographically diverse, with sex and ethnic composition reflecting that of the larger Canadian population. In addition to these existing eligible participants, 3,500 new participants will be recruited using a targeted approach to invite patients from underserved communities to participate. Overall, this study will provide a rich genomic dataset linked to clinical phenotypes and other molecular/omics datasets that are representative of the ethnic and clinical diversity of Canadians across a spectrum of childhood-onset disorders that have life-long impact. Immediate clinical impact will be achieved through return of medically actionable findings to physicians and participants after review by SickKids Genome Board. Health technology assessment will be performed to assess patient and community perspectives on use of GS as a clinical diagnostic test. Industry collaborations will focus on development of targeted therapies. Our team has a long-track record in precision health research generating many of the first and largest publicly available GS datasets. We also believe investment in GS of paediatric cohorts and their families is most strategic because they encompass rare and common genetic disease, and the data will be of value across the lifespan.

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Newborn screening (NBS) is a public health program that identifies treatable rare diseases (RDs) at birth. Newborn Screening Ontario performs NBS for Ontario, Newfoundland, part of Quebec and Qikiqtaaluk (~150,000/yr). Most of the current 31 NBS RDs are identified via metabolomics. However, the emergence of transformative therapies for non-metabolic RDs has created an urgent need for DNA screening methods. Pilot programs worldwide are assessing whole genome sequencing (WGS) in NBS, termed genomic NBS (gNBS), and Canada is behind. gNBS will revolutionize precision health by enabling early detection of an expanding array of treatable RDs, optimizing patient outcomes and reducing health care costs. Our current NBS program identifies ~0.5% of infants requiring RD treatment; with gNBS, based on comparable studies, we would triple the number of infants detected and treated for RDs. We will collaborate with gNBS pilots in England, Australia and the US, building on their success, to establish a Canadian gNBS pilot. Activity 1: Establish a panel of RDs for testing. gNBS requires targeted WGS analysis for target RDs. Consulting with gNBS collaborators and the Canadian RD community (medical experts and patients/families), we will define a set of RDs appropriate for Canadian gNBS. Deliverable: Panel of RDs to be used in gNBS (Q2/Y1) Activity 2: WGS of 9,000 infants born in Ontario, Quebec, Newfoundland and Qikiqtaaluk. We will recruit 9,000 infants from the general population through social-media and advertisements targeting designed to capture the diversity of the Canadian population. Participants will undergo short read WGS with analysis of our gNBS panel using residual dried blood spots (DBS) collected for routine NBS. Their clinical phenotypes, metadata, and metabolomic data will be provided to the Pan Canadian Genome Library (PCGL). Two subsets of patients will have additional testing and data for PCGL: ~500 will be screened for Type 1 diabetes risk through the CanScreenT1D Project, and 1,000 will undergo untargeted metabolomic analysis. Together, our unselected cohort has broad geographic and ancestral diversity, overcoming the biases in studies with targeted cohorts. Milestones: 400 samples (Y1), 2,900 samples/yr (Y2-3), 2,800 samples (Y4) Deliverable: WGS and associated data for ~9,000 infants from the general population Activity 3: Confirm the sensitivity of NBS by gNGS. NSO identifies ~1,000 screen positive infants annually. To confirm the sensitivity of gNBS for routine NBS disorders, we will recruit these infants. All data will be deposited at PCGL along with clinical data on their RD. Milestones: 100 samples(Y1), 300 samples/yr (Y2-4) Deliverable: WGS from 1,000 infants with NBS disorders. Evaluation of gNBS sensitivity for current NBS conditions Our study will pilot an equitable program to ensure that Canadian infants benefit from the precision health initiative, laying the groundwork for the much-anticipated future of NBS. 

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Care4Rare EXPAND is a four-year collaborative research project to build a rare disease (RD) dataset. We will generate a diverse genomic asset of 17,650 datasets from 7,150 families with RD, including: 13,000 short-read genomes, 2,000 long-read genomes, 650 transcriptomes, and 2,000 methylomes. Our datasets will reflect diverse genetic ancestries as participating institutions serve vast catchment areas (urban, rural, remote), new Canadians and communities unique to Canada (French Canadians, Indigenous and Anabaptist). EXPAND will use Care4Rare’s established workflows to capture comprehensive phenotypic data, metadata and other omics. We will deposit clinical data into our centralized repositories, Genomics4RD and Centre Québécois de Données Génomiques, which will be integrated into the Pan-Canadian Genome Library (PCGL). We will also use our All for One Connect REB-approved registry protocol to collect re-contact data, which will also be incorporated into the PCGL. EXPAND builds on Care4Rare’s 15 years of success applying genomics for RD diagnosis and discovery. We expect a diagnostic yield of 30-35 per cent, ending a costly and burdensome diagnostic odyssey for 2,200 families. Families living with RD are marginalized, facing substantial barriers to accessing appropriate care and social services. C4R-EXPAND will reduce these disparities by enabling accurate diagnoses and increasing visibility. Comprehensive data generated from C4R-EXPAND will ultimately improve interpretation and access to testing, and advance genomic health for all.

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We are embarking on a transformational project to sequence 10,000 genomes (short reads) from Black people, including African Nova Scotian communities in Canada, with a focus on the clinical phenotypes of hypertension, adult-onset diabetes, and triple-negative breast cancer. In addition to these 10,000 genomes, we will also study an additional 1,100 genomes using long read sequencing. We have a long-standing history of community engagement and have established community advisory groups. We will address the intersectionality of social and structural determinants of health (SSDOH) in our research. By integrating SSDOH, we seek to deepen our understanding of the impacts of selected chronic disorders on the health, morbidity, and mortality of Black peoples, ultimately contributing to more anti-racist equitable health outcomes. Our team has successfully identified a cohort of over 3,000 participants from previous COVID-19 studies who have consented to be re-contacted, demonstrating our deep-rooted trust and engagement within these communities. This foundation enables us to effectively recruit and execute this large-scale genomic project. Additionally, genomes of people of African ancestry have already been sequenced by our team members, providing a crucial foundation for our ongoing efforts. Our collaboration with core genomic facilities enhances our research capabilities, ensuring comprehensive bioinformatics and associated analyses. Furthermore, our strong connections with international networks will amplify the global relevance of our work.

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This project will leverage the existing resources of the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) to bring a pediatric component to the Pan Canadian Genome Library and allow CPNDS to continue its work in making medications safer for children locally, nationally and internationally. Over the past 20 years, the CPNDS has collected DNA and biological samples from over 12,350 patients together with comprehensive demographic and clinical data that characterize their responses to over 100,000 medication uses and over 10,000 severe adverse drug reactions. This number is remarkable given that pediatric diseases like cancers are rare and severe adverse drug reactions are rare occurrences as well. Some patients have more than 40 years of longitudinal data. These patients were recruited and enrolled from 14 academic health centres in geographically diverse locations across eight provinces in Canada (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia and Newfoundland). This funding is critical for the continuation of this network. This project has four primary objectives to support the Pan-Canadian Genomics Library (PCGL): 1. Contact previously recruited patients in the CPNDS databank and re-consent them for inclusion of their de-identified clinical and genomic data into the Pan-Canadian Genomics Library (PCGL) (n=6,985). [Activities 1 & 2] 2. Continue to prospectively recruit and enroll patients at our 10 existing study sites over the course of this four-year project (n=4,000). This additional recruitment will be conducted through the lens of significantly enhancing inclusion, diversity, equity and accessibility (IDEA) of the cohort. These samples are being added to ensure that future research beyond this project has a richer and more diverse database of clinical and genomic data to work with. [Activities 1 & 2] 3. Improve the genomic data holdings from genome-wide genotype typing data (GWAS) to whole-genome sequencing data – short-read sequencing will be conducted for n=10,985 and long-read sequencing will be conducted for n=1,000. [Activities 3, 4 and 5] This will allow for much more in-depth investigations of drug-induced harm. 4. Conduct genomic analyses using the generated whole-genome sequencing data to explore and identify biomarkers that are predictive of drug-induced harm associated with seven severe adverse drug reactions experienced by pediatric oncology patients in Canada [Activity 6] while facilitating dialogue and engaging with the multidisciplinary team assembled for this project [Activity 7]. The generation of this data will facilitate research and innovation to improve drug safety and effectiveness in children by making these data more widely accessible to researchers from academic, charitable organizations, health centres, for-profit private companies and health regulatory agencies.

Genome Canada’s Project Page