Subjects

Abstract

Purpose

Clinical sequencing emerging in health care may result in secondary findings (SFs).

Methods

Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene–condition pair list; we assessed clinical and psychosocial actions.

Results

The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0–$678) and $421 (recommended, range: $141–$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene–condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care.

Conclusion

Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.

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Acknowledgements

The National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI) funded the CSER Consortium: CSER Coordinating Center U01HG007307; NEXT Medicine U01HG006507; BASIC3 U01HG006485; MedSeq U01HG006500; NextGen UM1HG007292; PediSeq U01HG006546; HudsonAlpha U01HG007301; DFCI U01 HG006492, NCGENES U01HG006487; ZIAHG200359 09 and ZIAHG200387 04 from the Intramural Research Program of the NHGRI support ClinSeq®. R.C.G. was supported by U01HG006500, R01-CA154517, R01-AG047866, and funding from the Broad Institute and Department of Defense. J.L.V. is employed by the US Department of Veterans Affairs (VA) and supported by IK2-CX001262 from the VA Office of Research & Development. K.D.C. was supported by K01-HG009173. The views expressed here do not necessarily reflect those of the US Government or VA. We acknowledge Julia Fekecs and Melpi Kasapi for technical and logistical assistance.

Author information

Author notes

  1. These authors contributed equally: David L. Veenstra, Jonathan S. Berg, Robert C. Green, Leslie G. Biesecker and Lucia A. Hindorff.

Affiliations

  1. Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA

    • M. Ragan Hart MS
    • , Laura M. Amendola MS, CGC
    •  & Gail P. Jarvik MD, PhD
  2. Clinical Sequencing Exploratory Research Coordinating Center, University of Washington, Seattle, WA, USA

    • M. Ragan Hart MS
    • , Laura M. Amendola MS, CGC
    • , Gail P. Jarvik MD, PhD
    • , Jeffrey Ou BSc, BA
    •  & David L. Veenstra PhD, PharmD
  3. Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    • Barbara B. Biesecker PhD, CGC
    • , Ane Miren Sagardia MSc
    •  & Erin Turbitt PhD
  4. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Carrie L. Blout MS, CGC
    • , Kurt D. Christensen PhD
    • , Joel B. Krier MD, MMSc
    • , Jason L. Vassy MD, MPH
    •  & Robert C. Green MD, MPH
  5. Harvard Medical School, Boston, MA, USA

    • Kurt D. Christensen PhD
    • , Heidi L. Rehm PhD
    • , Jason L. Vassy MD, MPH
    •  & Robert C. Green MD, MPH
  6. Department of Pediatrics, Oncology Section, Baylor College of Medicine, Houston, TX, USA

    • Katie L. Bergstrom MS, CGC
    •  & Sharon E. Plon MD, PhD
  7. Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Sawona Biswas MS, CGC
  8. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

    • Kevin M. Bowling PhD
    • , Greg M. Cooper PhD
    • , Kelly M. East MS, CGC
    • , Candice R. Finnila PhD
    • , Whitley V. Kelley MS, CGC
    •  & Michelle L. Thompson PhD
  9. Department of Pediatrics, University of Louisville, Louisville, KY, USA

    • Kyle B. Brothers MD, PhD
  10. Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital, Philadelphia, PA, USA

    • Laura K. Conlin PhD
    • , Matthew C. Dulik PhD
    • , Edward J. Romasko PhD
    •  & Nancy B. Spinner PhD
  11. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Laura K. Conlin PhD
    •  & Matthew C. Dulik PhD
  12. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    • Jessica N. Everett MS, CGC
  13. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA

    • Jessica N. Everett MS, CGC
  14. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Arezou A. Ghazani PhD
  15. Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR, USA

    • Marian J. Gilmore MS
  16. Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA

    • Katrina A. B Goddard PhD
    • , Tia L. Kauffman MPH
    •  & Carmit McMullen PhD
  17. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    • Jennifer J. Johnston PhD
    • , Katie L. Lewis ScM
    •  & Leslie G. Biesecker MD
  18. Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA

    • Amy L. McGuire JD, PhD
  19. Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, MA, USA

    • Heidi L. Rehm PhD
  20. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Heidi L. Rehm PhD
    •  & Robert C. Green MD, MPH
  21. Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA

    • C. Sue Richards PhD
  22. VA Boston Healthcare System, Boston, MA, USA

    • Jason L. Vassy MD, MPH
  23. Department of Pediatrics and Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA

    • Benjamin S. Wilfond MD
  24. Department of Pharmacy, University of Washington, Seattle, WA, USA

    • David L. Veenstra PhD, PharmD
  25. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Jonathan S. Berg MD, PhD
  26. Partners Personalized Medicine, Boston, MA, USA

    • Robert C. Green MD, MPH
  27. Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    • Lucia A. Hindorff PhD, MPH

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Disclosure

C.S.R. and H.L.R. are employed by a testing laboratory that offers commercially available sequencing. R.C.G. receives compensation for consultation from AIA, Americord, Helix, and Veritas; is cofounder, advisor, and equity holder in Genome Medical, Inc.; and is employed by a testing laboratory that offers commercially available sequencing. L.G.B. is an uncompensated advisor to the Illumina Corp., receives royalties from Genentech, Inc., and honoraria from Wiley-Blackwell. S.E.P. is a member of the Scientific Advisory Panel of the Baylor Genetics Laboratory. D.L.V. is a consultant to Roche Sequencing Systems. The other authors declare no conflicts of interest.

Corresponding authors

Correspondence to M. Ragan Hart MS or Lucia A. Hindorff PhD, MPH.

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DOI

https://doi.org/10.1038/s41436-018-0308-x