By Jeremy Lazarus

Whole genome sequencing and whole exome sequencing are becoming more common in the clinical setting and offer promise for improving health outcomes. These techniques are becoming more commonly used in complex cases in which a patient's disease appears to be genetic, but examination of individual candidate genes has not yielded a diagnosis. However, significant hurdles must be overcome before the benefits offered by next-generation sequencing can be fully realized.

Of significant concern for physicians are the work-related demands required to guide patients through WGS or WES. Prior to sequencing, patients must undergo extensive genetic counseling covering such issues as medical history, inheritance patterns, false-positive and false-negative results, privacy and informed consent. In medical centers with WGS programs, it takes about 6-8 hours to fully counsel patients prior to sequencing. Some question whether the current system is equipped to deliver such intensive care, especially as the nation experiences a shortage of medical geneticists and genetic counselors. Left unaddressed, these shortages will place an incredible strain on genetics professionals. Will other physicians or health care providers be capable of stepping in? Research shows that a genetics educational gap exists among non-geneticist physicians. To address this gap, undergraduate and residency training programs must work to better educate students about the underlying role of genetics in disease. The creation of certificate-like programs for practicing non-geneticist physicians who wish to undergo additional genetic-specific training has also been suggested.

Once a patient completes genetic counseling, the actual genetic sequencing can occur. These tests generate large amounts of extremely complex data. Typically, WGS will detect more than 3 million variants in an individual's genome, but only a small percentage of those variants are causal of disease. Software programs sort through these variants and pick out those that are clinically meaningful, but even then, hundreds may remain. Physicians, genetic counselors and other health care professionals must spend a significant amount of time examining each variation to determine its potential role in a patient's disease. As research identifies new variants associated with the patient's disease, software programs that identify clinically meaningful variants will require updating. Thus, a patient's genome may need to be reanalyzed to detect variants that are newly classified as clinically meaningful. At this point, no guidelines exist on whose responsibility it is to direct the re-analysis or how often it should be done.

Next-generation sequencing has been most successful in identifying genetic causes of disease where standard diagnostic procedures have failed. However, whole genome sequencing will yield many clinically meaningful variants unrelated to the disease being targeted. One of the most important decisions a patient undergoing WGS will make is whether to receive results on all variants that are clinically meaningful, or only those that are pertinent to the disease under consideration. For example, a patient may want to know if she carries a mutation in the BRCA1 gene since this genetic variation dramatically increases her risk for breast and ovarian cancers. If patients choose to receive results on all variants that are clinically meaningful, physicians will spend many hours fully explaining all of these variants to patients.

Meanwhile, physicians must also decide what "clinically meaningful" means in the context of each patient's clinical situation and wishes. The most common definition of this term applies to genetic variants that will lead to a change in care. Some medical specialty societies have examined the issue of incidental findings from WGS, and one organization has undertaken an effort to identify variations and diseases that, even if found incidentally, would meet criteria for a physicians' duty to inform. These include diseases that are well understood and that have associated treatments. While WGS may end the diagnostic odyssey for the disease a patient and their physician are seeking to diagnose and treat, incidental findings almost always lead to follow-up confirmatory testing and additional diagnostic procedures.

Whole genome sequencing offers promise for improving health outcomes, particularly for patients with rare genetic diseases, diseases that cannot be identified by a candidate gene approach, and cancers in which genetic tumor variations can be profiled. Though cost and time barriers have been largely reduced, work remains to streamline and address clinical application concerns. Important practice, payment, and regulatory issues, including how to compensate physicians and other health care professionals for the considerable work-related demands required, must also be considered. Privacy protections must also be in place to protect a patient's genetic information from misuse. Attention to these and clinical application challenges will help ensure that patients and physicians benefit from rapidly advancing genetic technologies so that these new advances can realize their full potential in improving health outcomes.       


Jeremy A. Lazarus, MD, is President of the American Medical Association.

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