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JAMA. 2014 Mar 12;311(10):1035-45. doi: 10.1001/jama.2014.1717.

Clinical interpretation and implications of whole-genome sequencing.

Author information

  • 1Stanford Center for Inherited Cardiovascular Disease, Stanford, California2Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California4Stanford Center for Genomics and Personalized.
  • 2Stanford Center for Genomics and Personalized Medicine, Stanford, California5Department of Genetics, Stanford University, Stanford, California.
  • 3Department of Medicine, Stanford University, Stanford, California.
  • 4Department of Pediatrics, Stanford University, Stanford, California.
  • 5Department of Pathology, Stanford University, Stanford, California.
  • 6Biomedical Informatics Training Program, Stanford University, Stanford, California.
  • 7Department of Genetics, Stanford University, Stanford, California10Stanford Center for Biomedical Ethics, Stanford, California.
  • 8Stanford Center for Inherited Cardiovascular Disease, Stanford, California2Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California7Department of Pediatrics, Stanford University.
  • 9Division of Medical Oncology, Stanford University, Stanford, California.
  • 10Department of Genetics, Stanford University, Stanford, California.
  • 11Division of Cardiovascular Medicine, Stanford University, Stanford, California6Department of Medicine, Stanford University, Stanford, California.
  • 12Department of Pediatrics, Stanford University, Stanford, California12Division of Systems Medicine, Stanford University, Stanford, California.
  • 13Department of Medicine, Stanford University, Stanford, California12Division of Systems Medicine, Stanford University, Stanford, California14Stanford Prevention Research Center, Stanford, California15Department of Health Research and Policy, Stanford Unive.
  • 14Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California.
  • 15Department of Genetics, Stanford University, Stanford, California6Department of Medicine, Stanford University, Stanford, California16Department of Bioengineering, Stanford University, Stanford, California.
  • 16Stanford Cardiovascular Institute, Stanford, California4Stanford Center for Genomics and Personalized Medicine, Stanford, California5Department of Genetics, Stanford University, Stanford, California.

Abstract

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.

PMID:
24618965
[PubMed - indexed for MEDLINE]
PMCID:
PMC4119063
Free PMC Article
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