Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A systematic literature review of disclosure practices and reported outcomes for medically actionable genomic secondary findings

Abstract

Purpose

Secondary findings (SFs) are present in 1–4% of individuals undergoing genome/exome sequencing. A review of how SFs are disclosed and what outcomes result from their receipt is urgent and timely.

Methods

We conducted a systematic literature review of SF disclosure practices and outcomes after receipt including cascade testing, family and provider communication, and health-care actions. Of the 1,184 nonduplicate records screened we summarize findings from 27 included research articles describing SF disclosure practices, outcomes after receipt, or both.

Results

The included articles reported 709 unique SF index recipients/families. Referrals and/or recommendations were provided 647 SF recipients and outcome data were available for 236. At least one recommended evaluation was reported for 146 SF recipients; 16 reports of treatment or prophylactic surgery were identified. We found substantial variations in how the constructs of interest were defined and described.

Conclusion

Variation in how SF disclosure and outcomes were described limited our ability to compare findings. We conclude the literature provided limited insight into how the American College of Medical Genetics and Genomics (ACMG) guidelines have been translated into precision health outcomes for SF recipients. Robust studies of SF recipients are needed and should be prioritized for future research.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Study selection process per PRISMA guidelines.
Fig. 2: Data from included studies mapped to a secondary finding (SF) disclosure and outcomes paradigm.

Data availability

The submitted manuscript (including supplemental information) includes all data analyzed during this review.

References

  1. 1.

    Hart MR, Biesecker BB, Blout CL, Christensen KD, Amendola LM, Bergstrom KL, 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.

    PubMed  Article  Google Scholar 

  2. 2.

    Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012;91:97–108.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Katz AE, Nussbaum RL, Solomon BD, Rehm HL, Williams MS, Biesecker LG. Management of secondary genomic findings. Am J Hum Genet. 2020;107:3–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Sapp JC, Johnston JJ, Driscoll K, Heidlebaugh AR, Miren Sagardia A, Dogbe DN, et al. Evaluation of recipients of positive and negative secondary findings evaluations in a hybrid CLIA-research sequencing pilot. Am J Hum Genet. 2018;103:358–366.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–574.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, 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.

    PubMed  Article  Google Scholar 

  7. 7.

    Miller DT, Lee K, Chung WK, Gordon AS, Herman GE, Klein TE, 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 Genomics (ACMG). Genet Med. 2021 May 20; https://doi.org/10.1038/s41436-021-01172-3. Online ahead of print.

  8. 8.

    Christenhusz GM, Devriendt K, Dierickx K. To tell or not to tell? A systematic review of ethical reflections on incidental findings arising in genetics contexts. Eur J Hum Genet. 2013;21:248–255.

    PubMed  Article  Google Scholar 

  9. 9.

    Jackson L, Goldsmith L, O’Connor A, Skirton H. Incidental findings in genetic research and clinical diagnostic tests: a systematic review. Am J Med Genet A. 2012;158a:3159–3167.

    PubMed  Article  Google Scholar 

  10. 10.

    Mackley MP, Fletcher B, Parker M, Watkins H, Ormondroyd E. Stakeholder views on secondary findings in whole-genome and whole-exome sequencing: a systematic review of quantitative and qualitative studies. Genet Med. 2017;19:283–293.

    PubMed  Article  Google Scholar 

  11. 11.

    Ormond KE, O’Daniel JM, Kalia SS. Secondary findings: How did we get here, and where are we going? J Genet Couns. 2019;28:326–333.

    PubMed  Article  Google Scholar 

  12. 12.

    Bertier G, Hétu M, Joly Y. Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views. BMC Med Genomics. 2016;9:52.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    de Wert G, Dondorp W, Clarke A, Dequeker E, Cordier C, Deans Z, et al. Opportunistic genomic screening. Recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2021;29:365–377.

    PubMed  Article  Google Scholar 

  14. 14.

    Delanne J, Nambot S, Chassagne A, Putois O, Pelissier A, Peyron C, et al. Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature. Eur J Med Genet. 2019;62:103529.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Salari P, Larijani B. Ethical issues surrounding personalized medicine: a literature review. Acta Med Iran. 2017;55:209–217.

    PubMed  Google Scholar 

  16. 16.

    All of Us Research Program I, Denny JC, Rutter JL, Goldstein DB, Philippakis A, Smoller JW, et al. The “All of Us” Research Program. N Engl J Med. 2019;381:668–676.

    Article  Google Scholar 

  17. 17.

    Kaye J, Hurles M, Griffin H, Grewal J, Bobrow M, Timpson N, et al. Managing clinically significant findings in research: the UK10K example. Eur J Hum Genet. 2014;22:1100–1104.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–269.

  19. 19.

    Booth A, Papaioannou D, Sutton A. Systematic approaches to a sucessful literature review. Thousand Oaks, CA: SAGE publications; 2012.

  20. 20.

    Gale NK, Heath G, Cameron E, Rashid S, Redwood S. Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol. 2013;13:117.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Baldridge D, Heeley J, Vineyard M, Manwaring L, Toler TL, Fassi E, et al. The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med. 2017;19:1040–1048.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Basel D, McCarrier J. Ending a diagnostic odyssey: family education, counseling, and response to eventual diagnosis. Pediatr Clin North Am. 2017;64:265–272.

    PubMed  Article  Google Scholar 

  23. 23.

    Catenacci DV, Amico AL, Nielsen SM, Geynisman DM, Rambo B, Carey GB, et al. Tumor genome analysis includes germline genome: are we ready for surprises? Int J Cancer. 2015;136:1559–1567.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Chirita-Emandi A, Andreescu N, Zimbru CG, Tutac P, Arghirescu S, Serban M, et al. Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels. Sci Rep. 2020;10:223.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Helm BM, Langley K, Spangler BB, Schrier, Vergano SA. Military health care dilemmas and genetic discrimination: a family’s experience with whole exome sequencing. Narrat Inq Bioeth. 2015;5:179–186.

    PubMed  Article  Google Scholar 

  26. 26.

    Pendrick DM, Oberg JA, Hsiao SJ, Chung WK, Koval C, Sireci A, et al. Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: a case for sequencing the germline. Cold Spring Harb Mol Case Stud. 2019;5:a003889.

  27. 27.

    Leppig KA, Thiese HA, Carrel D, Crosslin DR, Dorschner MO, Gordon AS, et al. Building a family network from genetic testing. Mol Genet Genomic Med. 2017;5:122–129.

    PubMed  Article  Google Scholar 

  28. 28.

    You YN, Borras E, Chang K, Price BA, Mork M, Chang GJ, et al. Detection of pathogenic germline variants among patients with advanced colorectal cancer undergoing tumor genomic profiling for precision medicine. Dis Colon Rectum. 2019;62:429–437.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Hao J, Hassen D, Manickam K, Murray MF, Hartzel DN, Hu Y, et al. Healthcare utilization and costs after receiving a positive BRCA1/2 result from a genomic screening program. J Pers Med. 2020;10:7.

  30. 30.

    Haukkala A, Kujala E, Alha P, Salomaa V, Koskinen S, Swan H, et al. The return of unexpected research results in a biobank study and referral to health care for heritable long QT syndrome. Public Health Genomics. 2013;16:241–250.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Horiuchi Y, Matsubayashi H, Kiyozumi Y, Nishimura S, Higashigawa S, Kado N, et al. Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients. Hum Genet. 2021;140:321–331.

  32. 32.

    Lewis KL, Hooker GW, Connors PD, Hyams TC, Wright MF, Caldwell S, et al. Participant use and communication of findings from exome sequencing: a mixed-methods study. Genet Med. 2016;18:577–583.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Schwartz MLB, McCormick CZ, Lazzeri AL, Lindbuchler DM, Hallquist M, Manickam K, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Thompson ML, Finnila CR, Bowling KM, Brothers KB, Neu MB, Amaral MD, et al. Genomic sequencing identifies secondary findings in a cohort of parent study participants. Genet Med. 2018;20:1635–1643.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    CSER Consortium. https://cser-consortium.org. Accessed 5 January 2021.

  36. 36.

    Amendola LM, Lautenbach D, Scollon S, Bernhardt B, Biswas S, East K, et al. Illustrative case studies in the return of exome and genome sequencing results. Per Med. 2015;12:283–295.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Mackley M, McGuire K, Taylor J, Watkins H, Ormondroyd E. From genotype to phenotype. Circ Genom Precis Med. 2018;11:e002316.

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Nestor JG, Marasa M, Milo-Rasouly H, Groopman EE, Husain SA, Mohan S, et al. Pilot study of return of genetic results to patients in adult nephrology. Clin J Am Soc Nephrol. 2020;15:651–664.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Papaz T, Liston E, Zahavich L, Stavropoulos DJ, Jobling RK, Kim RH, et al. Return of genetic and genomic research findings: experience of a pediatric biorepository. BMC Med Genomics. 2019;12:173.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Rego S, Dagan-Rosenfeld O, Bivona SA, Snyder MP, Ormond KE. Much ado about nothing: a qualitative study of the experiences of an average-risk population receiving results of exome sequencing. J Genet Couns. 2019;28:428–437.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Rego S, Dagan-Rosenfeld O, Zhou W, Sailani MR, Limcaoco P, Colbert E, et al. High-frequency actionable pathogenic exome variants in an average-risk cohort. Cold Spring Harb Mol Case Stud. 2018;4:a003178.

  42. 42.

    Westphal DS, Leszinski GS, Rieger-Fackeldey E, Graf E, Weirich G, Meitinger T, et al. Lessons from exome sequencing in prenatally diagnosed heart defects: a basis for prenatal testing. Clin Genet. 2019;95:582–589.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Wynn J, Martinez J, Bulafka J, Duong J, Zhang Y, Chiuzan C, et al. Impact of receiving secondary results from genomic research: a 12-month longitudinal study. J Genet Couns. 2018;27:709–722.

    PubMed  Article  Google Scholar 

  44. 44.

    Ormondroyd E, Harper AR, Thomson KL, Mackley MP, Martin J, Penkett CJ, et al. Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes. Eur J Hum Genet. 2020;28:1486–1496.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Lee K, Berg JS, Milko L, Crooks K, Lu M, Bizon C, et al. High diagnostic yield of whole exome sequencing in participants with retinal dystrophies in a clinical ophthalmology setting. Am J Ophthalmol. 2015;160:354–363.e359.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014;311:1035–1045.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Menko FH, Ter Stege JA, van der Kolk LE, Jeanson KN, Schats W, Moha DA, et al. The uptake of presymptomatic genetic testing in hereditary breast-ovarian cancer and Lynch syndrome: a systematic review of the literature and implications for clinical practice. Fam Cancer. 2019;18:127–135.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Nycum G, Avard D, Knoppers BM. Factors influencing intrafamilial communication of hereditary breast and ovarian cancer genetic information. Eur J Hum Genet. 2009;17:872–880.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Roberts MC, Dotson WD, DeVore CS, Bednar EM, Bowen DJ, Ganiats TG, et al. Delivery of cascade screening for hereditary conditions: a scoping review of the literature. Health Aff (Millwood). 2018;37:801–808.

    PubMed  Article  Google Scholar 

  50. 50.

    Sharaf RN, Myer P, Stave CD, Diamond LC, Ladabaum U. Uptake of genetic testing by relatives of lynch syndrome probands: a systematic review. Clin Gastroenterol Hepatol. 2013;11:1093–1100.

    PubMed  Article  Google Scholar 

  51. 51.

    Whyte S, Green A, McAllister M, Shipman H. Family communication in inherited cardiovascular conditions in Ireland. J Genet Couns. 2016;25:1317–1326.

    PubMed  Article  Google Scholar 

  52. 52.

    Wiseman M, Dancyger C, Michie S. Communicating genetic risk information within families: a review. Fam Cancer. 2010;9:691–703.

    PubMed  Article  Google Scholar 

  53. 53.

    Christensen KD, Vassy JL, Jamal L, Lehmann LS, Slashinski MJ, Perry DL, et al. Are physicians prepared for whole genome sequencing? A qualitative analysis. Clin Genet. 2016;89:228–234.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Garrison NA, Brothers KB, Goldenberg AJ, Lynch JA. Genomic contextualism: shifting the rhetoric of genetic exceptionalism. Am J Bioeth. 2019;19:51–63.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Lohn Z, Adam S, Birch PH, Friedman JM. Incidental findings from clinical genome-wide sequencing: a review. J Genet Couns. 2014;23:463–473.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This study was supported by National Institutes of Health (NIH) grant HG200387-07. The authors are grateful to Alexandra Gomes and Elaine Sullor at George Washington University for their assistance with preliminary search strategies, M. Anna Buser and Jennifer Johnston for their critical review of the manuscript, and Darryl Leja for graphics support.

Author Information:

Conceptualization: J.C.S, K.L.L., P.v.d.W., D.C. Data curation: J.C.S, F.M.F. Formal analysis: J.C.S, F.M.F., E.M. Funding acquisition: L.G.B. Investigation: J.C.S, F.M.F., D.C., E.M. Methodology: J.C.S, D.C. Project administration: J.C.S, L.G.B. Resources: L.G.B. Supervision: J.C.S., P.v.d.W., L.G.B. Validation: J.C.S., F.M.F., D.C., K.L.L. Writing—original draft: J.C.S, F.M.F. Writing—reviewing & editing: J.C.S, K.L.L. F.M.F., P.v.d.W., D.C., E.M., L.G.B.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Julie C. Sapp.

Ethics declarations

Competing interests

L.G.B. is an uncompensated member of the Illumina Medical Ethics Committee, receives in-kind research support from Merck and Novartis, and honoraria from Cold Spring Harbor Press. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sapp, J.C., Facio, F.M., Cooper, D. et al. A systematic literature review of disclosure practices and reported outcomes for medically actionable genomic secondary findings. Genet Med (2021). https://doi.org/10.1038/s41436-021-01295-7

Download citation

Search

Quick links