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).
There’s a great Patton Oswalt quote about science being “all about coulda, not about shoulda”. We love to rush headstrong into new technology without understanding its implications and possibly harms.
I know lots of people (including colleagues) who think we’re just around the bend from everyone having their DNA sequenced and finding out all sorts of useful stuff. This study (while small) showed we ain’t there yet. WGS didn’t find some of the genes linked to inherited diseases. It had low reproducibility with respect to its ability to detect variations in genes that would have the most potential clinical effects. There was also a lot of variability in the certainty of some of the “reportable” findings.
One patient discovered that she had a variation that increased her risk for breast and ovarian cancer. She had surgery and is now being screened more aggressively for cancer. But we have no idea what might have happened in an alternate universe where she wasn’t screened. This could be mammograms all over again.
We should be careful before we adopt new technology, especially before it’s studied more widely in actual practice.