Clinical sequencing technologies are here—big time. But do medical professionals know what to do with them? Not always.
This admission haunts an article that appeared June 19 in the New England Journal of Medicine. The article—contributed by Leslie G. Biesecker, M.D., of the National Human Genome Research Institute and Robert C. Green, M.D., of Brigham and Women’s Hospital and Harvard Medical School—is by no means an occasion for handwringing. It is, rather, a call for the medical community to “up its game.”
Notwithstanding its bland title—“Considerations for Diagnostic Clinical Genome and Exome Sequencing”—the article reflects the authors’ sense of urgency.
“[Sequencing applications have] come much faster and developed more quickly and become more useful clinically than I think any reasonable person would have suggested just 10 years ago,” said Dr. Biesecker. “At that time, I don’t think anybody would have taken you seriously if you had said that in 2014, tens of thousands of patients would be getting clinical genome and exome sequencing.”
Some experts have questioned whether genome and exome sequencing is ready for broad application—or more precisely, whether the medical community is well enough versed in genetics to recognize the strengths and weaknesses of the testing. The authors note that, ready or not, the technology is here, and physicians are ordering genome and exome sequencing for their patients and use will only increase.
To help physicians make the most of genome and exome sequencing, the authors offer numerous insights into how clinicians should order tests, interpret the results, and communicate the results to patients. Just a few of these insights have been summarized in the following list of do’s and don’ts:
DO Manage Patient Expectations: Counseling patients and their families about what to expect is essential, but challenging because they may be disappointed if extensive and expensive tests yield results that are inconclusive or indicated that no treatment is available.
Most of the time, identifying a genetic cause won’t lead to a cure. But even in these cases, exome sequencing may still be useful because it can end an expensive and potentially invasive and stressful diagnostic odyssey.
DON’T Ignore the Limitations of the Sequencing Technologies: Whole-genome sequencing, whole-exome sequencing—they sound comprehensive, don’t they? But so-called whole-genome sequencing doesn’t cover 100% of the genome, any more than whole-exome sequencing covers 100% of the exome. Because of the way the target DNA sequences are gathered and assembled, not all of the DNA can be sequenced.
Sequencing may not pick up longer variations or repetitions of sequences, or long deletions that are responsible for some genetic disorders. Rather, it is best at detecting single-nucleotide variants, or alterations in sequences of no more than 8–10 base pairs.
Exome sequencing may not provide a diagnosis. On average, about 25% of such tests identify a gene variant that causes disease; most tests come up empty. Because of the technology’s gaps, however, a negative result doesn’t necessarily rule out a genetic cause for the disease.
DO Explore Family Histories and Conduct Literature Searches: A little homework can reveal which patients are most likely to benefit from clinical sequencing. For example, patients for whom the technology is most promising are those with rare disorders that seem to be the result of variants in a single gene.
Physicians should explore family history—the presence and pattern of similar disorders among relatives. In addition, physicians should carry out an extensive literature search before ordering exome sequencing. Informed consent is essential.
DON’T Overlook Incidental Findings: Analysis of the results may produce incidental findings—discovery of a gene variant that is unrelated to the patient's primary disorder but that could cause disease and require medical surveillance or treatment for a separate condition.
The items in this list reflect the authors’ decision to confine their overview to the analysis of germline sequence variants for diagnostic purposes. This decision reflects how most sequencing tests still serve to establish “diagnoses for rare, clinically unrecognizable, or puzzling disorders that are suspected to be genetic in origin.”
The authors acknowledged that sequencing has been hailed as an important tool in the implementation of predictive and individualized medicine, and that there is intense research interest in the clinical benefits and risks of sequencing for screening healthy persons. The authors, however, also noted that “current practice recommendations do not support the use of sequencing for this purpose.” Accordingly, the authors avoided discussing various topics of interest to researchers, such as the use of sequencing to uncover somatic variants in cancer to individualize cancer therapy.
Despite such circumspection, the authors also realize that the indications and approaches that they have outlined “are sure to evolve over time, as more data are generated for various clinical disorders, data interpretation is improved, and [sequencing] is studied in new clinical situations.”
“While our focus in this article is on the use of sequencing in cases where diagnosis is difficult, the sequence is just the beginning,” added Dr. Green. “We can expect these technologies to help us transition our entire approach in medicine to more personalized and preventive care.”
In the meantime, physicians already have their hands full. “We think that physicians from different specialties can order a sequencing test if they’re willing to take the time and commit to the effort to learn what the test is, what it isn’t, how it works, what it tells you and doesn’t tell you, and how to use the results,” Dr. Biesecker concluded. “If you’re willing to learn those things, I think you can use the test clinically. If you’re not willing to learn those things, you probably shouldn't be ordering the test, and you probably should refer the patient to somebody who is willing to learn these things.”