Multicenter Study

. 2019 May;21(5):1100-1110.

doi: 10.1038/s41436-018-0308-x. Epub 2018 Oct 5.

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study

M Ragan Hart^{1

2}, Barbara B Biesecker³, Carrie L Blout⁴, Kurt D Christensen^{4

5}, Laura M Amendola^{6

7}, Katie L Bergstrom⁸, Sawona Biswas⁹, Kevin M Bowling¹⁰, Kyle B Brothers¹¹, Laura K Conlin^{12

13}, Greg M Cooper¹⁰, Matthew C Dulik^{12

13}, Kelly M East¹⁰, Jessica N Everett^{14

15}, Candice R Finnila¹⁰, Arezou A Ghazani¹⁶, Marian J Gilmore¹⁷, Katrina A B Goddard¹⁸, Gail P Jarvik^{6

7}, Jennifer J Johnston¹⁹, Tia L Kauffman¹⁸, Whitley V Kelley¹⁰, Joel B Krier⁴, Katie L Lewis¹⁹, Amy L McGuire²⁰, Carmit McMullen¹⁸, Jeffrey Ou⁷, Sharon E Plon⁸, Heidi L Rehm^{5

21

22}, C Sue Richards²³, Edward J Romasko¹², Ane Miren Sagardia³, Nancy B Spinner¹², Michelle L Thompson¹⁰, Erin Turbitt³, Jason L Vassy^{4

5

24}, Benjamin S Wilfond²⁵, David L Veenstra^#^{7

26}, Jonathan S Berg^#²⁷, Robert C Green^#^{4

5

22

28}, Leslie G Biesecker^#¹⁹, Lucia A Hindorff^#²⁹

Affiliations

¹ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA. hartmr@uw.edu.
² Clinical Sequencing Exploratory Research Coordinating Center, University of Washington, Seattle, WA, USA. hartmr@uw.edu.
³ Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA.
⁶ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
⁷ Clinical Sequencing Exploratory Research Coordinating Center, University of Washington, Seattle, WA, USA.
⁸ Department of Pediatrics, Oncology Section, Baylor College of Medicine, Houston, TX, USA.
⁹ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
¹¹ Department of Pediatrics, University of Louisville, Louisville, KY, USA.
¹² Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital, Philadelphia, PA, USA.
¹³ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁷ Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR, USA.
¹⁸ Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
¹⁹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²⁰ Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA.
²¹ Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, MA, USA.
²² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²³ Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.
²⁴ VA Boston Healthcare System, Boston, MA, USA.
²⁵ Department of Pediatrics and Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
²⁶ Department of Pharmacy, University of Washington, Seattle, WA, USA.
²⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁸ Partners Personalized Medicine, Boston, MA, USA.
²⁹ Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. hindorffl@mail.nih.gov.

^# Contributed equally.

PMID: 30287922
PMCID: PMC6450774
DOI: 10.1038/s41436-018-0308-x

Multicenter Study

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study

M Ragan Hart et al. Genet Med. 2019 May.

. 2019 May;21(5):1100-1110.

doi: 10.1038/s41436-018-0308-x. Epub 2018 Oct 5.

Authors

Affiliations

¹ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA. hartmr@uw.edu.
² Clinical Sequencing Exploratory Research Coordinating Center, University of Washington, Seattle, WA, USA. hartmr@uw.edu.
³ Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA.
⁶ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
⁷ Clinical Sequencing Exploratory Research Coordinating Center, University of Washington, Seattle, WA, USA.
⁸ Department of Pediatrics, Oncology Section, Baylor College of Medicine, Houston, TX, USA.
⁹ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
¹¹ Department of Pediatrics, University of Louisville, Louisville, KY, USA.
¹² Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital, Philadelphia, PA, USA.
¹³ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁷ Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR, USA.
¹⁸ Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
¹⁹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²⁰ Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA.
²¹ Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, MA, USA.
²² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²³ Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.
²⁴ VA Boston Healthcare System, Boston, MA, USA.
²⁵ Department of Pediatrics and Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
²⁶ Department of Pharmacy, University of Washington, Seattle, WA, USA.
²⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁸ Partners Personalized Medicine, Boston, MA, USA.
²⁹ Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. hindorffl@mail.nih.gov.

^# Contributed equally.

PMID: 30287922
PMCID: PMC6450774
DOI: 10.1038/s41436-018-0308-x

Erratum in

Correction: Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.
Hart MR, Biesecker BB, Blout CL, Christensen KD, Amendola LM, Bergstrom KL, Biswas S, Bowling KM, Brothers KB, Conlin LK, Cooper GM, Dulik MC, East KM, Everett JN, Finnila CR, Ghazani AA, Gilmore MJ, Goddard KAB, Jarvik GP, Johnston JJ, Kauffman TL, Kelley WV, Krier JB, Lewis KL, McGuire AL, McMullen C, Ou J, Plon SE, Rehm HL, Richards CS, Romasko EJ, Sagardia AM, Spinner NB, Thompson ML, Turbitt E, Vassy JL, Wilfond BS, Veenstra DL, Berg JS, Green RC, Biesecker LG, Hindorff LA. Hart MR, et al. Genet Med. 2019 May;21(5):1261-1262. doi: 10.1038/s41436-019-0440-2. Genet Med. 2019. PMID: 30670880

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.

Keywords: genomic sequencing; health-care resource utilization; secondary findings.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: LMA, BBB, CLB, JSB, KBB, KLB, KMB, SB, KDC, GMC, LKC, MCD, JNE, KME, CRF, AAG, MJG, KABG, LAH, MRH, GPJ, JJJ, JBK, TLK, WVK, KLL, ALM, CM, JO, EJR, AMS, NBS, ET, MLT, JLV, BSW, none; CSR and HLR are employed by a testing laboratory that offers commercially available sequencing. RCG receives compensation for consultation from AIA, Americord, Helix and Veritas; and is co-founder, advisor and equity holder in Genome Medical, Inc; and is employed by a testing laboratory that offers commercially available sequencing. LGB is an uncompensated advisor to the Illumina Corp, receives royalties from Genentech, Inc, and honoraria from Wiley-Blackwell. SEP is a member of the Scientific Advisory Panel of the Baylor Genetics Laboratory. DLV is a consultant to Roche Sequencing Systems.

Figures

**Figure 1.**
A) Unique variants reported following re-classification, which included downgraded variants. B) Gene-specific adjusted prevalence, which excluded downgraded variants originally disclosed as pathogenic or likely pathogenic. VUS: variant of uncertain significance LP: likely pathogenic P: pathogenic

**Figure 2.**
Family history known prior to result disclosure and following SF results disclosure

See this image and copyright information in PMC

References

1. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(25):2418–2425. - PubMed
1. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine. 2013;15(7):565–574. - PMC - PubMed
1. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 updated (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genetics in Medicine. 2017;19(2):249–255. - PubMed
1. Johnston JJ, Rubinstein WS, Facio FM, 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(1):97–108. - PMC - PubMed
1. Natarajan P, Gold NB, Bick AG, et al. Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. Science Translational Medicine. 2016;8(364ra151). - PMC - PubMed

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Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study

Affiliations

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical