Abstract
Genomic sequencing (GS) can reveal secondary findings (SFs), findings unrelated to the reason for testing, that can be overwhelming to both patients and providers. An effective approach for communicating all clinically significant primary and secondary GS results is needed to effectively manage this large volume of results. The aim of this study was to develop a comprehensive approach to communicate all clinically significant primary and SF results. A genomic test report with accompanying patient and provider letters were developed in three phases: review of current clinical reporting practices, consulting with genetic and non-genetics experts, and iterative refinement through circulation to key stakeholders. The genomic test report and consultation letters present a myriad of clinically relevant GS results in distinct, tabulated sections, including primary (cancer) and secondary findings, with in-depth details of each finding generated from exome sequencing. They provide detailed variant and disease information, personal and familial risk assessments, clinical management details, and additional resources to help support providers and patients with implementing healthcare recommendations related to their GS results. The report and consultation letters represent a comprehensive approach to communicate all clinically significant SFs to patients and providers, facilitating clinical management of GS results.
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Data availability
The data and findings in this study are available in the manuscript and/or supplemental material.
Change history
08 September 2022
The article is updated to correct the acknowledgement.
References
Adam MP, Ardinger HH, Pagon RA et al. (1993–2022) GeneReviews. University of Washington, Seattle
Bennette CS, Gallego CJ, Burke W, Jarvik GP, Veenstra DL (2015) The cost-effectiveness of returning incidental findings from next-generation genomic sequencing. Genet Med 17:587–595. https://doi.org/10.1038/gim.2014.156
Bombard Y, Hayeems RZ (2021) How digital tools can advance quality and equity in genomic medicine. Nat Rev Genet 21:505–506. https://doi.org/10.1038/s41576-020-0260-x
Bombard Y, Clausen M, Shickh S et al (2020) Effectiveness of the genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial. Genet Med 22:727–735. https://doi.org/10.1038/s41436-019-0702-z
Dean L (2012) Warfarin therapy and VKORC1 and CYP genotype. In: Pratt VM, Scott SA, Pirmohamed M et al (eds) Medical genetics summaries [Internet]. National Center for Biotechnology Information, Bethesda, pp 613–625
Dorschner MO, Amendola LM, Shirts BH et al (2014) Refining the structure and content of clinical genomic reports. Am J Med Genet C Semin Med Genet 166C:85–92. https://doi.org/10.1002/ajmg.c.31395
Facio FM, Eidem H, Fisher T et al (2013) Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study. Eur J Hum Genet 21:261–265. https://doi.org/10.1038/ejhg.2012.179
Fatumo S, Chikowore T, Choudhury A et al (2022) A roadmap to increase diversity in genomic studies. Nat Med 28:243–250. https://doi.org/10.1038/s41591-021-01672-4
Federici G, Soddu S (2020) Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers. J Exp Clin Cancer Res 39:46. https://doi.org/10.1186/s13046-020-01554-6
Franke A, McGovern DP, Barrett JC et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125. https://doi.org/10.1038/ng.717
Green RC, Berg JS, Grody WW et al (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15:565–574. https://doi.org/10.1038/gim.2013.73
Haga SB, Mills R, Pollak KI et al (2014) Developing patient-friendly genetic and genomic test reports: formats to promote patient engagement and understanding. Genome Med 6:58. https://doi.org/10.1186/s13073-014-0058-6
Hamosh A, Scott AF, Amberger J, Bocchini C, Valle D, McKusick VA (2002) Online Mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 30:52–55. https://doi.org/10.1093/nar/gki033
Karczewski KJ, Francioli LC, Tiao G et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7
Landrum MJ, Lee JM, Riley GR et al (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42:D980-985. https://doi.org/10.1093/nar/gkt1113
McLaughlin HM, Ceyhan-Birsoy O, Christensen KD (2014) A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet 15:134. https://doi.org/10.1186/s12881-014-0134-1
Mighton C, Carlsson L, Clausen M et al (2019) Development of patient “profiles” to tailor counseling for incidental genomic sequencing results. Eur J Hum Genet 27:1008–1017. https://doi.org/10.1038/s41431-019-0352-2
Mighton C, Carlsson L, Clausen M et al (2020) Quality of life drives patients’ preferences for secondary findings from genomic sequencing. Eur J Hum Genet 28:1178–1186. https://doi.org/10.1038/s41431-020-0640-x
Miller N, Lacroix EM, Backus JE (2000) MEDLINEplus: building and maintaining the national library of medicine’s consumer health web service. Bull Med Libr Assoc 88:11–17
Miller DT, Lee K, Chung WK et al (2021) 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 genomics (ACMG). Genet Med 23:1381–1390. https://doi.org/10.1038/s41436-021-01172-3
O’Leary NA, Wright MW, Brister JR et al (2016) Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 44:D733–D745. https://doi.org/10.1093/nar/gkv1189
Popejoy AB, Fullerton SM (2016) Genomics is failing on diversity. Nature 538:161–164. https://doi.org/10.1038/538161a
Reble E, Gutierrez Salazar M, Zakoor KR et al (2021) Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings. Hum Genet 140:493–504. https://doi.org/10.1007/s00439-020-02220-9
Recchia G, Chiappi A, Chandratillake G, Raymond L, Freeman ALJ (2020) Creating genetic reports that are understood by nonspecialists: a case study. Genet Med 22:353–361. https://doi.org/10.1038/s41436-019-0649-0
Rehm HL, Bale SJ, Bayrak-Toydemir P et al (2013) ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15:733–747. https://doi.org/10.1038/gim.2013.92
Rehm HL, Berg JS, Brooks LD et al (2015) ClinGen–the clinical genome resource. N Engl J Med 372:2235–2242. https://doi.org/10.1056/NEJMsr1406261
Relling MV, Klein TE (2011) CPIC: clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharm Ther 89:464–470. https://doi.org/10.1038/clpt.2010.279
Richards S, Aziz N, Bale S et al (2015) 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 17:405–424. https://doi.org/10.1038/gim.2015.30
Sebastian A, Carroll JC, Vanstone M et al (2021) Widening the lens of actionability: a qualitative study of primary care providers’ views and experiences of managing secondary genomic findings. Eur J Hum Genet. https://doi.org/10.1038/s41431-021-00876-z (Epub ahead of print)
Sebastian A, Carroll JC, Vanstone M et al (2022) Challenges and practical solutions for managing secondary genomic findings in primary care. Eur J Med Genet 65:104384. https://doi.org/10.1016/j.ejmg.2021.104384
Shickh S, Clausen M, Mighton C et al (2019) Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial. BMJ Open 9:e031092. https://doi.org/10.1136/bmjopen-2019-031092
Shickh S, Mighton C, Uleryk E, Pechlivanoglou P, Bombard Y (2021) The clinical utility of exome and genome sequencing across clinical indications: a systematic review. Hum Genet 140:1403–1416. https://doi.org/10.1007/s00439-021-02331-x
Solomon BD, Nguyen AD, Bear KA, Wolfsberg TG (2013) Clinical genomic database. Proc Natl Acad Sci USA 110:9851–9855. https://doi.org/10.1073/pnas.1302575110
Stark Z, Dolman L, Manolio TA et al (2019) Integrating genomics into healthcare: a global responsibility. Am J Hum Genet 104:13–20. https://doi.org/10.1016/j.ajhg.2018.11.014
Suwinski P, Ong C, Ling MHT, Poh YM, Khan AM, Ong HS (2019) Advancing personalized medicine through the application of whole exome sequencing and big data analytics. Front Genet 10:49. https://doi.org/10.3389/fgene.2019.00049
Tweedie S, Braschi B, Gray K et al (2021) Genenames.org: the HGNC and VGNC resources in 2021. Nucleic Acids Res 49:D939–D946. https://doi.org/10.1093/nar/gkaa980
Vassy JL, Lautenbach DM, McLaughlin HM et al (2014) The MedSeq project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials 15:85. https://doi.org/10.1186/1745-6215-15-85
Vassy JL, McLaughlin HM, MacRae CA et al (2015) A one-page summary report of genome sequencing for the healthy adult. Public Health Genom 18:123–129. https://doi.org/10.1159/000370102
Vassy JL, Davis JK, Kirby C et al (2018) How primary care providers talk to patients about genome sequencing results: risk, rationale, and recommendation. J Gen Intern Med 33:877–885. https://doi.org/10.1007/s11606-017-4295-4
Weymann D, Laskin J, Roscoe R et al (2017) The cost and cost trajectory of whole-genome analysis guiding treatment of patients with advanced cancers. Mol Genet Genom Med 5:251–260. https://doi.org/10.1002/mgg3.281
Yu Y, Bhangale TR, Fagerness J et al (2011) Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 20:3699–3709. https://doi.org/10.1093/hmg/ddr270
Acknowledgements
This study was supported by a Foundation Grant from the Canadian Institutes of Health Research and a Quality of Life Grant from the Canadian Cancer Society Research Institute awarded to Yvonne Bombard (Grant #s 143310 and 705665, respectively). Yvonne Bombard was supported by a New Investigator Award from the Canadian Institute of Health Research (Grant #136664) during the conduct of this study. Jordan Lerner-Ellis was funded by the McLaughlin Centre (Grant #MC-2012-13 and #MC-2014-11-1) and CIHR-Champions of Genetics: Building the Next Generation Grant (FRN: 135730).
Incidental Genomics study team: Yvonne Bombard1,2,9, Susan Randall Armel2,7, Melyssa Aronson3, Nancy Baxter12,13,14,20, Kenneth Bond15, José-Mario Capo-Chichi4, June C. Carroll2,3, Timothy Caulfield16,17,18, Marc Clausen1, Tammy J. Clifford19, Iris Cohn5, Irfan Dhalla12,20,21,22,23, Craig C. Earle22, Andrea Eisen6, Christine Elser2,3, Michael Evans12, Emily Glogowski24, Tracy Graham2,6, Elena Greenfeld25,26, Jada G. Hamilton27, Wanrudee Isaranuwatchai12,20, Monika Kastner12,20,28, Raymond H. Kim2,3,4,5, Andreas Laupacis12,20, Jordan Lerner-Ellis2,3,10,11, Chantal F. Morel4, Michelle Mujoomdar29, Abdul Noor25,26, Kenneth Offit27, Seema Panchal3, Mark E. Robson27, Stephen W. Scherer5,22,30, Adena Scheer12,13, Kasmintan A. Schrader8, Terrence Sullivan20 and Kevin E. Thorpe31,32.
12St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada. 13Department of Surgery, University of Toronto, Toronto, Canada. 14Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia. 15Institute of Health Economics, Edmonton, AB, Canada. 16Faculty of Law, University of Alberta, Edmonton, AB, Canada. 17School of Public Health, University of Alberta, Edmonton, AB, Canada. 18Health Law Institute, University of Alberta, Edmonton, AB, Canada. 19School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada. 20Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada. 21Institute for Clinical Evaluative Sciences, Toronto, ON, Canada. 22Department of Medicine, University of Toronto, Toronto, ON, Canada. 23Health Quality Ontario, Toronto, ON, Canada. 24GeneDx, Gaithersburg, MD, USA. 25Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 26Division of Diagnostic Medical Genetics, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. 27Memorial Sloan Kettering Cancer Center, New York, NY, USA. 28Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. 29Canadian Agency for Drugs and Technologies in Health, Ottawa, ON, Canada. 30Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 31Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada. 32Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
Funding
This study was supported by a Foundation Grant from the Canadian Institutes of Health Research and a Quality of Life Grant from the Canadian Cancer Society Research Institute (grant numbers 143310 and 705665, respectively).
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JS, ER, RK, AS, MGS, SS, YB, and JLE conceptualized the study. Formal analysis was performed by JS, ER, RK, MGS, SS, JLE, and YB. Investigation was performed by JS, ER, AS, RK, MGS, and SS. This study was supervised by YB and JLE. JS was involved in visualization. The original draft was written by JS, ER, RK, and AS. Manuscript review and editing involved JS, ER, RK, YB, JLE, JCC, SRA, AS, MC, MGS, SS, CM, MA, JMCC, IC, AE, CE, TG, KO, SP, CP, KAS, and RHK. All the authors have approved the final draft submitted.
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This study was approved by the Research Ethics Board of Unity Health Toronto–St.Michael’s Hospital (CTO0819); ClinicalTrial.gov identifier NCT03597165. Informed consent was obtained from all the participants involved in this study. Any individual-level data, including clinical data, found in this manuscript or supplementary files have been de-identified and pseudonyms were used where appropriate.
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Sam, J., Reble, E., Kodida, R. et al. A comprehensive genomic reporting structure for communicating all clinically significant primary and secondary findings. Hum Genet 141, 1875–1885 (2022). https://doi.org/10.1007/s00439-022-02466-5
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DOI: https://doi.org/10.1007/s00439-022-02466-5