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Introduction: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings., Methods and Analysis: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives., Ethics and Dissemination: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals., Trial Registration Number: NCT06455384., Competing Interests: Competing interests: YB and MC are cofounders of Genetics Adviser., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs., Competing Interests: Declarations of interests M.B. has an equity interest in PhenoTips, which licenses software used in the Genomics4RD database. The remaining authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Exome sequencing (ES) can rapidly identify disease-causing variants responsible for rare, single-gene diseases, and potentially reduce the duration of the diagnostic odyssey. Our study examines how parents and families value ES., Methods: We developed a discrete choice experiment (DCE) survey that was administered to parents of children with rare diseases. The DCE included 14 choice tasks with 6 attributes and 3 alternatives. A valuation-space model was used to estimate willingness to pay, willingness to wait for test results, and minimum acceptable chance of a diagnosis for changes in each attribute., Results: There were n = 319 respondents of whom 89% reported their child had genetic testing, and 66% reported their child had a diagnosis. Twenty-six percent reported that their child had been offered ES. Parents were willing to pay CAD$6590 (US$4943), wait 5.2 years to obtain diagnostic test results, and accept a reduction of 3.1% in the chance of a diagnosis for ES compared with operative procedures., Conclusion: Timely access to ES could reduce the diagnostic odyssey and associated costs. Before ES is incorporated routinely into care for patients with rare diseases in Canada and more broadly, there must be a clear understanding of its value to patients and families.

Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease. The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity-by-descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4) gene. The carrier frequency of this mutation was estimated in >1,300 Hutterite individuals to be 1 in 27. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose and Scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals., Methods of Statement Development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada., Results and Conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Birth cohorts are a common tool used in epidemiological studies about pregnancy; yet these datasets systematically miss pregnancies that are spontaneously lost or terminated. This study examined the feasibility of linking administrative and clinical datasets from Alberta Canada to identify a pregnancy cohort that includes spontaneous and medical pregnancy losses., Methods: Deterministic linkage was used to link data from twelve clinical and administrative datasets for women who conceived between November 2007 and February 2008. Descriptive statistics were used to characterize the relative contribution of each dataset to the overall dataset., Results: Overall, 6,477 unique pregnancies were eligible for inclusion, resulting in a live birth rate of 94.1%, a stillbirth rate of 0.5%, a fetal death rate of 4.1%, and an estimated 1.3% of the cohort moving out of the study area. No single dataset could identify all pregnancies. Individual databases identified 2.0-99.1% of the cohort. Fetal deaths were most frequently identified in outpatient physician claims, emergency room visits, ultrasound data, or from the cytogenetic laboratory., Conclusions: Linkage of clinical and administrative databases to identify pregnancy is feasible and can overcome many limitations associated with the use of a single dataset; however, fetal deaths continue to be under-ascertained., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Epigenetics is revealing how "nature is nurtured", with environmental factors such as nutrition, environmental neurotoxicants, and psychological stress influencing DNA expression. In this current opinion paper, we argue that understanding the dynamic interplay between the genome acquired at conception and environmental exposures throughout life requires pregnancy and birth cohorts, and that greater Canadian national commitment to the infrastructure needed for sustaining such cohorts is warranted. We present a framework that is now being implemented in Alberta.