Clinical interpretation and implications of whole-genome sequencing
Frederick E Dewey, Megan E Grove, Cuiping Pan, Benjamin A Goldstein, Jonathan A Bernstein, Hassan Chaib, Jason D Merker, Rachel L Goldfeder, Gregory M Enns, Sean P David, Neda Pakdaman, Kelly E Ormond, Colleen Caleshu, Kerry Kingham, Teri E Klein, Michelle Whirl-Carrillo, Kenneth Sakamoto, Matthew T Wheeler, Atul J Butte, James M Ford, Linda Boxer, John P A Ioannidis, Alan C Yeung, Russ B Altman, Themistocles L Assimes, Michael Snyder, Euan A Ashley, Thomas Quertermous, Frederick E Dewey, Megan E Grove, Cuiping Pan, Benjamin A Goldstein, Jonathan A Bernstein, Hassan Chaib, Jason D Merker, Rachel L Goldfeder, Gregory M Enns, Sean P David, Neda Pakdaman, Kelly E Ormond, Colleen Caleshu, Kerry Kingham, Teri E Klein, Michelle Whirl-Carrillo, Kenneth Sakamoto, Matthew T Wheeler, Atul J Butte, James M Ford, Linda Boxer, John P A Ioannidis, Alan C Yeung, Russ B Altman, Themistocles L Assimes, Michael Snyder, Euan A Ashley, Thomas Quertermous
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.
Conflict of interest statement
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dewey reported that he is a stockholder and member of the scientific advisory board of Personalis Inc, a privately held genome interpretation company, and receives royalties for patented technology related to genome sequencing.Ms Grove reported that she has received speaker’s fees from Illumina Inc. Dr Klein reported that that she is a member of the scientific advisory board for Coriell Inc. Mss Caleshu and Ormond and Dr Wheeler reported that they receive royalties for patented technology related to genome sequencing. Drs Butte, Altman, and Snyder and Mr Ashley are founders, stockholders, and members of the scientific advisory board of Personalis Inc and receive royalties for patents related to genome sequencing. Dr Butte reported that he is a stockholder and member of the scientific advisory board of NuMedii Inc; consultant to Lilly, Regeneron, Johnson & Johnson, Roche, Geisinger, Verinata, Pfizer, and Samsung; has received speaker’s fees from Pfizer, Lilly, Siemens, Bristol-Myers Squibb, and Genentech; and holds stock in Carmenta, Eceos, Assay Depot, and Genstruct/Selva. Dr Snyder reported that he is a member of the scientific advisory board and stockholder of Genapsys Inc. Dr Quertermous reported that he is a member of the scientific advisory board of Aviir Inc. No other disclosures were reported.
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Source: PubMed