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Clinical interpretation and implications of whole-genome sequencing.

Publication ,  Journal Article
Dewey, FE; Grove, ME; Pan, C; Goldstein, BA; Bernstein, JA; Chaib, H; Merker, JD; Goldfeder, RL; Enns, GM; David, SP; Pakdaman, N; Ormond, KE ...
Published in: JAMA
March 12, 2014

IMPORTANCE: Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES: To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS: An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES: Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS: Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE: In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

March 12, 2014

Volume

311

Issue

10

Start / End Page

1035 / 1045

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Reproducibility of Results
  • Pharmacogenetics
  • Mutation
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genome, Human
  • Genetic Variation
 

Citation

APA
Chicago
ICMJE
MLA
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Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., … Quertermous, T. (2014). Clinical interpretation and implications of whole-genome sequencing. JAMA, 311(10), 1035–1045. https://doi.org/10.1001/jama.2014.1717
Dewey, Frederick E., Megan E. Grove, Cuiping Pan, Benjamin A. Goldstein, Jonathan A. Bernstein, Hassan Chaib, Jason D. Merker, et al. “Clinical interpretation and implications of whole-genome sequencing.JAMA 311, no. 10 (March 12, 2014): 1035–45. https://doi.org/10.1001/jama.2014.1717.
Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014 Mar 12;311(10):1035–45.
Dewey, Frederick E., et al. “Clinical interpretation and implications of whole-genome sequencing.JAMA, vol. 311, no. 10, Mar. 2014, pp. 1035–45. Pubmed, doi:10.1001/jama.2014.1717.
Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, Merker JD, Goldfeder RL, Enns GM, David SP, Pakdaman N, Ormond KE, Caleshu C, Kingham K, Klein TE, Whirl-Carrillo M, Sakamoto K, Wheeler MT, Butte AJ, Ford JM, Boxer L, Ioannidis JPA, Yeung AC, Altman RB, Assimes TL, Snyder M, Ashley EA, Quertermous T. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014 Mar 12;311(10):1035–1045.
Journal cover image

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

March 12, 2014

Volume

311

Issue

10

Start / End Page

1035 / 1045

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Reproducibility of Results
  • Pharmacogenetics
  • Mutation
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genome, Human
  • Genetic Variation