Findings Indicate Technical Challenges Remain Before Reliably Using Whole-Genome Sequencing For Clinical Applications


Media Advisory: To contact corresponding authors Euan A. Ashley, M.R.C.P., D.Phil., or Thomas Quertermous, M.D., call Krista Conger at 650-725-5271 or email To contact editorial author William Gregory Feero, M.D., Ph.D., call 207-453-3030 or email
Chicago – In an exploratory study involving 12 adults, the use of whole-genome sequencing (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, although in certain cases WGS will identify genetic variants warranting early medical intervention, according to a study in the March 12 issue of JAMA.

As technical barriers to human DNA sequencing decrease and costs approach $1,000, whole-genome sequencing (WGS) is increasingly being used in clinical medicine. Sequencing can successfully aid clinical diagnosis and reveal the genetic basis of rare familial diseases. Regardless of context, even in apparently healthy individuals, WGS is expected to uncover genetic findings of potential clinical importance. However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed, according to background information in the article. The technical sensitivity and reproducibility of clinical genetic findings using sequencing and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings remain undefined.

Frederick E. Dewey, M.D., of the Stanford Center for Inherited Cardiovascular Disease, Stanford, Calif., and colleagues recruited 12 volunteer adult participants 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.

The researchers found that the use of WGS was associated with incomplete coverage of inherited-disease genes (important parts of the genome for diseases that run in families are not as easy to read as other regions); there was low reproducibility of detection of genetic variation with the highest potential clinical effects (disagreement around the types of variation particularly important for disease); and there was uncertainty about clinically reportable WGS findings (experts disagree on which findings are most meaningful). Two to 6 personal disease-risk findings were discovered in each participant. Physician review of sequencing findings prompted consideration of a median (midpoint) of 1 to 3 initial diagnostic tests and referrals per participant.

The authors write that their clinical experience with this technology illustrates several challenges to clinical adoption of WGS, including that although analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. In addition, the human resource needs for full clinical interpretation of WGS data remains considerable, and much uncertainty remains in classification of potentially disease-causing genetic variants.

“These issues should be considered when determining the role of WGS in clinical medicine.”

(doi:10.1001/jama.2014.1717; Available pre-embargo to the media at

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Clinical Application of Whole Genome Sequencing – Proceed With Care

“Medical application of genomic and personalized medicine technologies hold out the real promise of improved decision making and patient outcomes by providing an increased knowledge of the determinants of health and disease at the level of the individual patient,” writes William Gregory Feero, M.D., Ph.D., of the Maine Dartmouth Family Medicine Residency, Fairfield, Maine, (and Associate Editor, JAMA), in an accompanying editorial.

“Like the personal computer, Internet, smartphones, and electronic health records, turning back now from the use of genomic technologies in health care is inconceivable. Studies like that of Dewey et al provide a glimpse of what is possible but demonstrate that much remains to be learned about previously assumed to be ‘known’ information as well as myriad ‘known unknowns’ and ‘unknown unknowns’ before truly successful widespread integration can occur. A question facing potential early adopters of genome sequencing as an adjunct to patient care is whether or not having WGS data, at this time, will decrease uncertainty and improve outcomes or merely exponentially increase the complexity of clinical care.

(doi:10.1001/jama.2014.1718; Available pre-embargo to the media at

 Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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