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Clinical Sequencing Hurdles

Whole-genome sequencing may not be quite ready for prime time, at least not if prime time means being widely used to test for genetic disease genes in clinical medicine, according to the results of a trial published yesterday in the Journal of the American Medical Association.

The Stanford University study, which used Illumina and Complete Genomics' sequencing platforms to sequence 12 men and women between 2011 and 2012, found "incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainly about clinically reportable findings."

The authors also found that 10 percent to 19 percent of the known American College of Medical Genetics and Genomics-reportable inherited disease genes were not sequenced to the required standards, and it found variations between the different sequencing platforms for some genetic variants.

In other words, it found that challenges to be addressed, uncertainties to be confronted, and issues to be worked out.

"We need to be very honest about what we can and cannot do at this point in time," says Euan Ashley, one of the paper's senior authors, in a statement. "Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful."

The whole-genome sequencing and analysis of some 100 genetic variations cost around $17,000, the study reports, and it took about an hour of investigation to assess each variation, a process that included hunting through scientific literature and determining whether a change was actually likely to affect disease risk.

There was certainly at least one win for WGS in the study. In one of the 12 cases, the researchers found that a woman with no family history of breast or ovarian cancer had a possibly high-risk deletion in her BRCA1 gene, which was confirmed via another test, a finding that enabled her to take action to reduce her future risk of these cancers.

Writing in response to the study in an editorial in JAMA, Dartmouth professor and NHGRI Special Adviser Greg Feero finds some bright spots amid the "sobering" study.

Feero notes that the sequencing did not stir the participants to order an avalanche of other tests. That has been a worry about clinical sequencing, that it might drive up healthcare costs as people pursue all sorts of follow-up tests. This study found that an estimated one to three additional diagnostic tests or referrals were suggested, at a cost of $351 to $776, which he says suggests "that concerns about expensive immediate downstream actions in every sequenced individual may be unfounded."

Feero says that genomic and personalized medicine tools hold real promise to improve patient outcomes and help individuals make decisions, but there will be some growing pains.

Studies like this one give "a glimpse of what is possible," he says, but also show that much more needs to be learned about the unknowns, the known unknowns, and of course the unknown unknowns.

"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," he writes.