Does Whole Genome Sequencing Have A Role in Primary Care?

–Pilot study confirms feasibility, but clinical value for healthy-seeming people is not obvious

Whole genome sequencing (WGS)may one day play an important role in routine medical practice. But the results of a small study suggest that WGS, though perhaps promising, is certainly not ready for prime time.

The price of WGS has dropped spectacularly in recent years, from $350,000 in 2008 to roughly $1,000 today. The cost will almost certainly continue to fall, as it will for other genetic tests. The easier availability of genetic tests increases the need to figure out whether and how these tests should be used in clinical practice.

Jason Vassy, MD, MPH, of VA Boston Healthcare System and colleagues performed a small pilot study testing the impact of WGS in usual care. They randomized 100 patients to receive from their primary care physicians either a family history report by itself or in combination with WGS. The WGS contained information about the patient’s risk for rare inherited diseases as well as “carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits.” The report was published in Annals of Internal Medicine.

In the WGS group 11 out of 50 patients (22%) were found to have a genetic variation linked to an inherited Mendelian disorder, but a clinical diagnosis was only made in two of these patients. One patient, for instance, was found to have a genetic variant for long QT syndrome but had no abnormalities on a resting ECG or exercise stress test. Genetics experts assessed the primary care doctors’ actions in these cases and said that 8 took appropriate action and 2 took inappropriate action.

WGS tests found that nearly all the patients (48 out of 50) had a genetic variant indicating a nonstandard response to medications, including 5 patients who were taking simvastatin and 1 patient who was taking metformin, but the new information from the WGS did not result in any change in the patients’ medications.

The authors reported that there was “no evidence that WGS enhanced or detracted from preventive care” or that it had either a negative or beneficial effect on health, anxiety, or depression scores.

“The results of this pilot study do not support the use of WGS in primary care but suggest that, if a healthy adult has WGS, some of the resulting increased healthcare use may be clinically appropriate,” the authors concluded.

“There is currently no role for WGS in the primary care of a healthy adult patient without a family history concerning for a genetic condition,” said Vassy in an email interview. He pointed out that the pharmacogenetic tests do not require WGS and “could be ordered at much lower expense with simpler array-based tests.”

For patients who ask their doctors whether they should undergo WGS out of pocket, Vassy said he would “see it as moment to engage the patient in what value he/she is hoping to get from it. Can WGS deliver on that value, and/or is there a better way to answer the same question? But physicians no longer have the excuse that patients can’t handle such vast, uncertain, potentially anxiety-provoking information.”

“These findings demonstrate that genetic variants indicative of disease risk, carrier status, or altered response to medications are frequent (indeed, universal) and that primary care physicians are largely capable of managing such findings,” wrote Teri Manolio, MD, PhD, of the National Human Genome Research Institute, in an accompanying editorial.

“Healthy patients tolerate this information well, and many report making health behavior changes that could be considered salutary. Use and costs, however, do appear to increase, particularly (and not unexpectedly) in patients with new… findings,” according to Manolio. “Whether this increased use will truly improve patient outcomes remains to be seen and will be a key factor influencing decisions to reimburse such testing in healthy patients.”

Ken Weiss, PhD, is a professor of anthropology and genetics at Penn State who has long been interested in the impact of the genetic revolution. He pointed out that the paper appears to confirm the view that “people randomly selected (i.e., ‘healthy’) carry a number of ‘disease’ alleles.” There is currently no consensus on what can or should be done with these findings. Weiss is concerned that primary care physicians “may not realize that their findings don’t necessarily call for follow-up or intervention measures.”

Weiss also warned that “major, obvious disease-mutations found in one population, have essentially no effect of the nominal kind in other populations. Even obvious ‘disease’ mutations, such as in BRCA1 carriers, have very different risks and/or age of onset patterns in different populations or samples.”

Even more problematic is incorporating knowledge concerning genetic variations of more complex traits, though this was not a focus of the current study, Weiss said.


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  2. Solid article here. I really like the frame of “not yet, but eventually.” That said, I think it’s mostly about the costs coming down and maybe some improvement on overall accuracy (sensitivity+specificity). But I also don’t know that this kind of testing will ever be so accurate as to be determinative in guiding patients and doctors on health decisions. Maybe more so on healthy lifestyle factors.

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