Advertisement
Canadian Journal of Cardiology

Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach

Published:October 26, 2021DOI:https://doi.org/10.1016/j.cjca.2021.10.006

      Abstract

      Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for nondisclosure of research results and others following clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals, are discussed. Finally, the National Hearts in Rhythm Organisation (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition, and availability of clinical resources.

      Résumé

      Les équipes de recherche qui mettent sur pied des biobanques ou des bases de données en génomique doivent élaborer des politiques en matière de divulgation et de déclaration des résultats de tests génomiques potentiellement exploitables aux participants des études. À l’heure actuelle, il existe un vaste éventail d’approches en matière de retour des résultats; dans certaines études, les chercheurs optent pour la non-divulgation des résultats de recherche alors que dans d’autres, ils respectent les lignes directrices de pratique clinique en matière de retour des résultats de séquençage potentiellement exploitables. Cet article de synthèse vise à décrire les pratiques en vigueur et à mettre en évidence les décisions qu’une équipe de recherche doit prendre lors de l’élaboration d’une politique en matière de retour des résultats, et ce, du consentement éclairé aux pratiques en matière de divulgation, en passant par les options de validation clinique. Nous discuterons des défis propres au retour de résultats fortuits relatifs aux gènes cardiaques, y compris une réduction de la pénétrance et l’absence de normes en matière de dépistage clinique des personnes dont le phénotype est négatif. Finalement, l’approche relative au registre de la National Hearts in Rhythm Organisation (HiRO) est décrite pour justifier le retour sélectif des données sur des variants propres à un domaine à ceux qui participent à des projets de recherche portant une maladie précise. Notre objectif est de fournir aux chercheurs une ressource adaptée à leur programme de recherche qui les aidera à élaborer une politique en matière de retour des résultats, en fonction des facteurs circonstanciels relatifs au plan de l’étude, à la composition de l’équipe de recherche et à la disponibilité des ressources cliniques.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wolf S.M.
        • Crock B.N.
        • van Ness B.
        • et al.
        Managing incidental findings and research results in genomic research involving biobanks and archived data sets.
        Genet Med. 2012; 14: 361-384
        • Bombard Y.
        • Brothers K.B.
        • Fitzgerald-Butt S.
        • et al.
        The responsibility to recontact research participants after reinterpretation of genetic and genomic research results.
        Am J Hum Genet. 2019; 104: 578-595
        • Amendola L.M.
        • Dorschner M.O.
        • Robertson P.D.
        • et al.
        Actionable exomic incidental findings in 6503 participants: challenges of variant classification.
        Genome Res. 2015; 25: 305-315
        • Tang C.S.
        • Dattani S.
        • So M.T.
        • et al.
        Actionable secondary findings from whole-genome sequencing of 954 East Asians.
        Hum Genet. 2018; 137: 31-37
        • Hart M.R.
        • Biesecker B.B.
        • Blout C.L.
        • et al.
        Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.
        Genet Med. 2019; 21: 1100-1110
        • Green R.C.
        • Berg J.S.
        • Grody W.W.
        • et al.
        ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
        Genet Med. 2013; 15: 565-574
        • Kalia S.S.
        • Adelman K.
        • Bale S.J.
        • et al.
        Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
        Genet Med. 2017; 19: 249-255
        • Miller D.T.
        • Lee K.
        • Chung W.K.
        • et al.
        ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Gnomics (ACMG).
        Genet Med. 2021; 23: 1381-1390
        • Boycott K.
        • Hartley T.
        • Adam S.
        • et al.
        The clinical application of genome-wide sequencing for monogenic diseases in Canada: position statement of the Canadian College of Medical Geneticists.
        J Med Genet. 2015; 52: 431-437
      1. UK Biobank Ethics And Governance Framework. October 2007.
        (Available at:)
        • All of US Research Program Investigators
        The “All of Us” research program.
        N Engl J Med. 2019; 381: 668-676
        • Carey D.J.
        • Fetterolf S.N.
        • Davis F.D.
        • et al.
        The Geisinger MyCode community health initiative: an electronic health record–linked biobank for precision medicine research.
        Genet Med. 2016; 18: 906-913
        • eMERGE Clinical Annotation Working Group
        Frequency of genomic incidental findings among 21,915 eMERGE Network participants.
        Genet Med. 2020; 22: 1470-1477
        • Papaz T.
        • Liston E.
        • Zahavich L.
        • et al.
        Return of genetic and genomic research findings: experience of a pediatric biorepository.
        BMC Med Genomics. 2019; 12: 173
        • Nestor J.G.
        • Marasa M.
        • Milo-Rasouly H.
        • et al.
        Pilot study of return of genetic results to patients in adult nephrology.
        Clin J Am Soc Nephrol. 2020; 15: 651-664
        • Davies B.
        • Roberts J.D.
        • Tadros R.
        • et al.
        The Hearts in Rhythm Organisation: a Canadian national cardiogenetics network.
        CJC Open. 2020; 2: 652-662
        • Bycroft C.
        • Freeman C.
        • Petkova D.
        • et al.
        The UK Biobank resource with deep phenotyping and genomic data.
        Nature. 2018; 562: 203-209
        • Schwartz M.L.
        • McCormick C.Z.
        • Lazzeri A.L.
        • et al.
        A model for genome-first care: returning secondary genomic findings to participants and their healthcare providers in a large research cohort.
        Am J Hum Genet. 2018; 103: 328-337
        • Buchanan A.H.
        • Kirchner H.L.
        • Schwartz M.L.
        • et al.
        Clinical outcomes of a genomic screening program for actionable genetic conditions.
        Genet Med. 2020; 22: 1874-1882
      2. Canada Panel on Research Ethics. Human Genetic Research. TriCouncil Policy Statement for the Ethical Conduct of Research Involving Humans Version 2 (2018). Chapter 13.
        (Available at:) (Accessed November 13, 2020)
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-423
        • Holm I.A.
        Pediatric issues in return of results and incidental findings: weighing autonomy and best Interests.
        Genet Test Mol Biomarkers. 2017; 21: 155-158
        • Jarvik G.P.
        • Amendola L.M.
        • Berg J.S.
        • et al.
        Return of genomic results to research participants: the floor, the ceiling, and the choices in between.
        Am J Hum Genet. 2014; 94: 818-826
        • Savatt J.M.
        • Wagner J.K.
        • Joffe S.
        • et al.
        Pediatric Reporting of Genomic Results Study (PROGRESS): a mixed-methods, longitudinal, observational cohort study protocol to explore disclosure of actionable adult-and pediatric-onset genomic variants to minors and their parents.
        BMC Pediatr. 2020; 20: 222
        • Mand C.
        • Gillam L.
        • Delatycki M.B.
        • Duncan R.E.
        Predictive genetic testing in minors for late-onset conditions: a chronological and analytical review of the ethical arguments.
        J Med Ethics. 2012; 38: 519-524
        • Clayton E.W.
        • McCullough L.B.
        • Biesecker L.G.
        • et al.
        Clinical Sequencing Exploratory Research (CSER) Consortium Pediatrics Working Group. Addressing the ethical challenges in genetic testing and sequencing of children.
        Am J Bioethics. 2014; 14: 3-9
        • Caron N.R.
        • Chongo M.
        • Hudson M.
        • et al.
        Indigenous genomic databases: pragmatic considerations and cultural contexts.
        Front Public Health. 2020; 8: 111
      3. Silent Genomes Project.
        (Available at:)
        https://www.bcchr.ca/silent-genomes-project
        Date accessed: August 29, 2021
        • Wonkam A.
        • de Vries J.
        Returning incidental findings in African genomics research.
        Nat Genet. 2019; 52: 17-20
        • Abul-Husn N.S.
        • Soper E.R.
        • Braganza G.T.
        • et al.
        Implementing genomic screening in diverse populations.
        Genome Med. 2021; 13: 17
        • Lewis A.C.F.
        • Knoppers B.M.
        • Green R.C.
        An international policy on returning genomic research results.
        Genome Med. 2021; 13: 115
        • Davies B.
        • Bartels K.
        • Hathaway J.
        • et al.
        Variant reinterpretation in survivors of cardiac arrest with preserved ejection fraction (the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) by clinicians and clinical commercial laboratories.
        Circ Genom Precis Med. 2021; 14: 303-312
      4. Genetic Non-Discrimination Act (S.C. 2017, c. 3).
        (Available at:) (Accessed August 10, 2021)
        • Bernhardt B.A.
        • Roche M.I.
        • Perry D.L.
        • et al.
        Experiences with obtaining informed consent for genomic sequencing.
        Am J Med Genet Part A. 2015; : 2635-2646
        • Sakurai-Yageta M.
        • Kawame H.
        • Kuriyama S.
        • et al.
        A training and education program for genome medical research coordinators in the genome cohort study of the Tohoku Medical Megabank Organization.
        BMC Med Educ. 2019; 19: 297
        • Amendola L.M.
        • Jarvik G.P.
        • Leo M.C.
        • et al.
        Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium.
        Am J Hum Genet. 2016; 98: 1067-1076
        • Splawski I.
        • Timothy K.W.
        • Tateyama M.
        • et al.
        Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.
        Science. 2002; 297: 1333-1336
        • Giudicessi J.R.
        • Roden D.M.
        • Wilde A.A.
        • Ackerman M.J.
        Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing.
        Circulation. 2018; 137: 619-630
        • Strande N.T.
        • Riggs E.R.
        • Buchanan A.H.
        • et al.
        Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource.
        Am J Hum Genet. 2018; 100: 895-906
        • Ackerman J.P.
        • Bartos D.C.
        • Kapplinger J.D.
        • et al.
        The promise and peril of precision medicine: phenotyping still matters most.
        Mayo Clin Proc. 2016; 91: 1606-1616
        • Riggs E.R.
        • Andersen E.F.
        • Cherry A.M.
        • et al.
        Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).
        Genet Med. 2019; 22: 245-257
        • Mars N.
        • Koskela J.T.
        • Ripatti P.
        • et al.
        Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers.
        Nat Med. 2020; 26: 549-557
        • Hylind R.J.
        • Chandler S.F.
        • Beausejour Ladouceur V.
        • et al.
        Phenotypic characterization of individuals with variants in cardiovascular genes in the absence of a primary cardiovascular indication for testing.
        Circ Genom Precis Med. 2019; 12e002463
        • Yogasundaram H.
        • Alhumaid W.
        • Dzwiniel T.
        • Christian S.
        • Oudit G.Y.
        Cardiomyopathies and genetic testing in heart failure: role in defining phenotype-targeted approaches and management.
        Can J Cardiol. 2021; 37: 547-559
        • Cheung C.C.
        • Tadros R.
        • Davies B.
        • Krahn A.D.
        Genetic testing in inherited arrhythmias: approach, limitations, and challenges.
        Can J Cardiol. 2020; 36: 584-587
        • Giudicessi J.R.
        • Ackerman M.J.
        Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.
        Transl Res. 2013; 161: 1-14
        • Campuzano O.
        • Fernandez-Falgueras A.
        • Sarquella-Brugada G.
        • et al.
        Personalized interpretation and clinical translation of genetic variants associated with cardiomyopathies.
        Front Genet. 2019; 10: 450
        • Walsh R.
        • Thomson K.L.
        • Ware J.S.
        • et al.
        Reassessment of mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.
        Genet Med. 2017; 19: 192-203
        • Kullo I.J.
        • Olson J.
        • Fan X.
        • et al.
        The Return of Actionable Variants Empirical (RAVE) study, a Mayo Clinic genomic medicine implementation study: design and initial results.
        Mayo Clin Proc. 2018; 93: 1600-1610
        • Campuzano O.
        • Sarquella-Brugada G.
        • Fernandez-Falgueras A.
        • et al.
        Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes.
        EBioMedicine. 2020; 54: 102732
        • VanDyke R.E.
        • Hashimoto S.
        • Morales A.
        • Pyatt R.E.
        • Sturm A.C.
        Impact of variant reclassification in the clinical setting of cardiovascular genetics.
        J Genet Couns. 2021; 30: 503-512
        • Glazer A.M.
        • Wada Y.
        • Li B.
        • et al.
        High-throughput reclassification of SCN5A variants.
        Am J Hum Genet. 2020; 107: 111-123