Generating solutions

Goal: To generate tangible socioeconomic benefits by improving health care and disease management for individuals, families and communities in Atlantic Canada burdened by devastating single gene disorders.

The Atlantic Medical Genetic and Genomics Initiative (AMGGI) project is a Canadian research initiative to identify new genes that have a major impact on health. AMGGI will utilize the Atlantic region’s unique population structure and history, as well as the high quality of the health care system to provide a streamlined discovery process. The project will generate tangible socioeconomic benefits by improving health care and disease management for individuals, families and communities in Atlantic Canada burdened by devastating single gene disorders.

Mark Samuels, (then Associate Professor at Dalhousie University, now Associate Professor of Medicine at the Université de Montréal), and Terry-Lynn Young (then Assistant Professor of Medicine and now Professor of Medicine at Memorial University of Newfoundland), are the project leaders of AMGGI. AMGGI draws together a multidisciplinary team of experts in clinical ascertainment, gene discovery, genetic diagnostics, genetic counselling, health economics and human ethics. The research team will investigate Atlantic Canada’s population structure and history, identify genes and genetic mutations that cause single gene disorders, and interact closely with health­care providers to determine the impact of genetic information on human health. Given the issues that arise when monogenic disorders are identified, this project will study the well­being and value systems of patients and families, as well as the value systems of physicians and genetic counsellors.

An important component of AMGGI will be to study the potential impacts of genetic discovery on the provision of health care services. Anticipated outcomes of AMGGI include medical breakthroughs based on novel gene discovery, the transfer of new knowledge to health care providers, health policy recommendations regarding the impact of genetic information on society, and improved clinical management of affected patients.

Integrated GE³LS Research:  Assessing economic, social, and ethical barriers to the implementation of genetic services

GE³LS Project Leaders:  Daryl Pullman, Memorial University

Summary

The study of monogenic disorders is likely to yield clinically relevant results in the near term. Although specific therapeutics are probably several years down the line in most cases, the prospects for diagnostics are much more positive. Indeed, it is likely that the current project will yield a number of diagnostic tests for a variety of conditions. As the number of genetic diagnostics continues to expand in succeeding years, difficult decisions will need to be made regarding both the social utility and economic practicality of adopting these new technologies.   The primary objective of the GE³LS component of this project is to provide systematic evaluation of selected existing and potential genetic screening programs in Atlantic Canada. The goal is to facilitate effective and efficient uptake of genetic services. More specifically, the aims are to:

• Evaluate the economics of selected existing and potential genetic screening programs in Atlantic Canada in the short and long-term.
• Identify the range of barriers and benefits relating to social utility and economic practicality of adopting these new technologies.
• Understand the range of social, historical, cultural and economic barriers to access and use of genetic services from the perspectives of patients, physicians, populations/communities, and government policy makers.
• Facilitate effective and efficient uptake of genetic services.
• Identify needs and provide ethics training for genomics researchers.
• Develop goals and strategies for transparent and open public debate in Atlantic Canada.
• Create policy documents which will outline the steps and capital investment necessary to fulfill genetic testing needs of Atlantic Canada.

Project Outcomes*

Memorial University team

• Identified TMEM43 gene that causes Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and characterized differences in its presentation in young men and women. Gene found in 25 families in Atlantic Canada, over six or seven generations. Families can undergo genetic testing and understand who is at risk and who is not.
• This project has saved lives. Several hundred patients in Canada have undergone testing for ARVC caused by the p.S358L mutation in TMEM43 and received an Implantable Cardioverter Defibrillator (ICD) – avoiding sudden fatalities and unnecessary anxiety for families. It has also extended the lives of male ARVC patients who were provided an ICD based solely on the presence of the mutation by 31years (at last assessment in 2015).
• Developed new guidelines for diagnosis and treatment of ARVC that apply genetic testing on the basis of family history before symptoms arise. If testing is positive, patient receives an ICD to restart the heart after electrical failure. Guidelines now used in clinical practice for this mutation in many medical centres around the globe.
• Used historical data and reconstructed family trees to determine optimal time for medical intervention (at least five years prior to youngest death found in study), through surgical implantation of ICD, or potentially, through drug therapies.
• Collaborated with German research team (Ruhr University) to trace 1,000-year-old European origin of the TMEM43 mutation.
• Identified gene (FOXL1) that causes otosclerosis, a form of hearing loss in the middle ear.
• Studied phenotypes of hereditary eye disease and epilepsy.
• Lab-size quadrupled under Genome Canada grant, enabling team to accelerate research and identify genes in short time-frame. Assembled multidisciplinary research team, including clinicians and genetic counsellors, with local, national, and international connections.
• Collaborated with Canadian Hard of Hearing Association (CHHA) and received major research funding from Canadian Institutes for Health Research (CIHR), Atlantic Canada Opportunities Agency (ACOA), and Canada Foundation for Innovation (CFI) to create the Craig L Dobbins Genetics Research Center, a specialized living audiology laboratory in Grand Falls-Windsor, Newfoundland, for families with genetic hearing loss to obtain testing and treatment.
• Received major funding from ACOA to pursue genomics-based diagnostic tools to prevent sudden cardiac death (2010-2017).
• Graduate students and postdoctoral fellows funded under Genome Canada project have gone on to promising research careers at Memorial University, University of Alberta, University of Calgary, Auburn University in Alabama, King Abdullah University of Science and Technology and the Imperial College of London.
• Continue to use clinical data, DNA samples, and historical pedigrees acquired under Genome Canada project as foundation for further gene sequencing and research.
• Provided impetus for creation of a database of all early deaths from 1997-2017 in Newfoundland and Labrador for assessment of the impact of early sudden cardiac death and other early causes of death.
• New funding from other sources allowing team to conduct research on animal models with goal of understanding what occurs at the cellular level in ARVC (TMEM43 gene) and hearing loss (FOXL1 gene), as well as explore potential drug therapies and gene editing techniques (e.g., CRISPR) that may potentially slow or cure the condition.
• Invited by CHHA to lead Expert National Workshop on Hearing Loss. Appointed to Governing Council, CIHR, Gairdner Medical Review Panel, Beatrice Hunter Cancer Research Institute, and Research and Development Corporation (RDC) of Newfoundland. Presentation made to International Rare Diseases Consortium, raising international profile of project.
• Received 2018 Governor General’s Innovation Award, President’s Award for Outstanding Research (Memorial University), and Community Hearing Association’s Community Recognition (Advocacy) Award.
• Published 12 journal articles and filed two patents on direct results of the 2005 Genome Canada grant in respected publications such as Clinical Genetics, European Heart Journal, and American Journal of Human Genetics.
• GE³LS component: Lead GE³LS researcher and ethics specialist developed white paper for the provincial government on policy issues related to research governance of genetic research, leading to changes in the research ethics review process in Newfoundland and Labrador. New Regulation 57/11 enacted under the Health Research Ethics Authority Regulations Act (2006) makes Newfoundland and Labrador one of the most advanced jurisdiction in North America with regard to genetic research oversight. All research conducted in the province with human subjects now undergoes arms-length review to ensure protection of research subjects and patients in clinical trials and return of benefits to patients and society. Led to Memorial University policy on consent for participation in research for clinical trials related to rare lethal genetic disorders that requires patients to learn test results, facilitating the “duty to warn” other family members. GE³LS researchers have published numerous articles in leading academic journals such as American Journal of Bioethics, Clinical Genetics and numerous others.

Dalhousie University team

• Built a state-of-the-art molecular genomics research laboratory in the Sir Charles Tupper Medical building.
• Hired and trained new staff in genomics technologies including high throughput DNA sequencing (using Sanger capillary electrophoresis technology, AMGGI pre-dated the advent of next generation ultra-high throughput systems), bioinformatic analysis and interpretation of human DNA sequencing, statistical genetics.
• Established strong collaborative relationship with Medical Genetics team at the IWK Women and Children’s Hospital, with joint purchase and use of a capillary electrophoresis DNA sequencing instrument.
• Performed wide outreach to clinicians in all medical subspecialties at Dalhousie Medical School, with successful creation of multiple collaborative projects.
• Identification of 10 novel genes for rare medical genetic disorders. In addition to providing many new scientific insights, molecular characterization of these disorders has allowed medical diagnoses in the patients and their families, ending their “diagnostic odysseys”, with significant improvement in patient management in many cases.
• Molecular characterization of several Maritime families with eye syndromes that were extensively studied previously without identification of the causal gene. A family with a rare form of Stargardt-like disorder, resembling late onset common macular degeneration, was shown to carry a mutation in the known gene PRHP2. Another family with an unusual type of patterned retinal dystrophy was shown to carry a mutation in the known gene RHO (rhodopsin). These results allowed definitive diagnoses for the affected families, together with potential carrier screening to identify young family members at risk of the disease with increased age.
• Publications in high impact journals: Nature Genetics (2), American Journal of Human Genetics (2), PLoS One (2), PLoS Genetics (1), Molecular Vision (1), Brain (1), Journal of Neuroscience (1). Together these and other project publications have been cited 350 times in journals indexed by the Science Citation Index.

Follow-on benefits of AMGGI in Maritime Canada/Dalhousie University.

• Led directly to the Genome Canada IGNITE project, which capitalized on and extended AMGGI’s gains, including a trial of a targeted pharmaceutical intervention for a rare disease developed on the basis of a specific AMGGI gene discovery.
• IGNITE and FORGE teams worked together to generate the Care4Rare Genome Canada funded initiative.
• led to an ACOA-AIF funded intiative to establish the scientific and clinical hub for orphan drug development in Halifax which is moving therapies toward first in human trials.
• Led to fostering of relationships in the genomic ethics committee in particular with Dr. Bartha Knoppers’ group at the Center of Genomics and Policy, and with the Public Population Project in Genomics and Society. The ongoing collaborations that arose out of this have resulted in both joint empiric research endeavours and policy statements; these collaborations extend to the current Terry Fox Research Institute PROFYLE program – a $25-million dollar Canada wide undertaking to in part sequence high risk pediatric and young adult cancers.
• Produced a number of patent submissions around AMGII discoveries.
• Established Dalhousie’s presence on the national stage, enabling a large CFI.
• Created conditions favorable to nurturing related technologies within Dalhousie, such as the zebrafish facility.
• Led to the creation of CGEM, a network of more than 50 investigators at Dalhousie from a variety of faculties and departments.
• Elevated the profile of genetics within the Faculty of Medicine at Dalhousie University to tier-1 status.
• Greatly increased genetic “literacy” and awareness in the teaching hospitals associated with Dalhousie.

*Revised July 2018