The medical literature describes numerous cases where doctors order imaging studies - X-rays, CAT scans or MRI's - on a patient for a condition affecting one organ, but then see an unexpected abnormality in another organ. Is it cancer? Should the doctor tell the patient? Who should follow up? And will failure to follow up mean a missed chance to catch a cancer at an earlier, more treatable stage?
Or, could that unexpected abnormality be meaningless, what some doctors call an incidentaloma (-oma from cancer, as in carcinoma, but completely incidental and innocuous). In that case, the doctor may fruitlessly order numerous expensive, perhaps invasive tests to evaluate a ghostly image that is completely benign.
Doctors make these kinds of difficult decisions every day. Researchers and healthcare professionals aiming to move genomics from the laboratory to hospitals and clinics will soon face similar challenges as they work to realize the potential of genomic medicine.
At its recent annual meeting, the Board of Directors of the American College of Medical Genetics and Genomics (ACMG) approved the first set of practice guidelines to help doctors begin to navigate this new area. These practice guidelines represent an important step in using genomic information for routine medical care, a key goal put forward in NHGRI's 2011 strategic plan for genomics: Charting a course for genomic medicine from base pairs to bedside
Here is the issue: As the cost for sequencing a human genome drops to a level typical of many other diagnostic tests, doctors will less and less often order analyses for individual genetic conditions (as they do now) and instead will order a complete genome sequence. But, like the X-ray intended to examine one organ incidentally identifying an abnormality in another organ, it is possible that examination of a patient's genome sequence will turn up unexpected genomic variants known to be associated with an increased risk for health conditions unrelated to the reason the genome sequence was acquired in the first place.
As in similar scenarios, doctors call these types of results incidental findings. Some genomicists call the collection of such findings the "incidentalome." The challenge for doctors and patients alike is establishing which of the incidental findings are important to the patient and which are not.
ACMG has made an important first step in establishing standards for implementing the practice of genomic medicine. Since November 2011, a committee appointed by the ACMG Board of Directors has worked to determine how best to deal with issues related to incidental findings encountered in patients' genome sequences. In March 2013, ACMG issued clinical guidelines based on the committee's work - guidelines that break ground for this new area of medicine and that will likely lead to further vigorous debate and discussions.
The guidelines recommend that doctors tell patients (and the families of children or impaired adult patients) if their genome analysis reveals the presence of one of several types of genomic variants in 50 or so genes that have been strongly associated with about two dozen diseases. A key factor in selecting these genes and diseases was that the disorder is serious and that there are practical things that the patient and doctor can do to mitigate the associated risks. If genome sequencing reveals any of these, the standard of care will now be for the laboratory to return the information to the doctor and for the doctor to then tell the patient, prompting appropriate follow-up care to keep the patient healthy.
Most of the genomic variants included in the new recommendations are rare, causing rare diseases such as familial hypercholesterolemia (which leads to premature heart disease), retinoblastoma (a type of inherited eye cancer), and Marfan syndrome (which weakens connective tissue and sometimes causes the aortas of athletes to rupture under physical stress). Because of the way the initial list of variants to report was developed, relatively few patients will be told about such incidental findings. The list, however, will evolve as ongoing research links more variants to more diseases. The set of recommendations include one to the ACMG Board of Directors to update regularly these guidelines.
From NHGRI's viewpoint, ACMG has taken an important and courageous step. The development of these initial recommendations is consistent with our Institute's goal of using genomics to improve healthcare. NHGRI continues to invest in technology development to make genome sequencing practical, in terms of cost and accuracy, for use in clinical care. And, a recent reorganization of the Institute brought the creation of the new Division of Genomic Medicine to focus NHGRI's efforts in studying the application of genomics in medicine.
For example, NHGRI has partnered with the National Cancer Institute to lead a flagship study called The Cancer Genome Atlas, wherein researchers use genome sequencing to search for the genomic roots of cancer. As essentially a genomic disorder, cancer will likely be among the first diseases whose clinical care will be profoundly changed due to genomics. Another relevant effort now underway is the Clinical Sequencing Exploratory Research program. Projects within this program engage researchers from a range of disciplines - from physicians to bioinformaticians to ethicists - so as to focus on the technical, ethical, psychosocial and clinical implications of returning patients' genomic information to healthcare providers and, in turn, their patients.
Another new NHGRI initiative, called the Clinically Relevant Variants Resource, will develop ways to identify genomic variants that are clinically relevant for a wide range of disorders. It is likely that these efforts will eventually contribute to ACMG's effort to continually expand the list of genomic variants and diseases covered by their practice guidelines.
Several other NHGRI projects also involve using genome sequencing as part of clinical research, from ClinSeq® to the Undiagnosed Diseases Program (and soon the Undiagnosed Diseases Network) to the Genomic Medicine Demonstration Projects to the Electronic Medical Records and Genomics (eMERGE) project. Work done by ClinSeq®, for example, led to one of the key publications that supported the new approach advocated by ACMG.
Inevitably, there will be setbacks and controversies in the application of genomics to medical care. The ACMG guidelines will challenge some long-held principles as we work to incorporate this new genomic knowledge into practice. For example, it has long been held that individuals should actively choose whether they wish to learn about certain genomic findings. However, ACMG is recommending that if patients agree to undergo genome sequencing through an informed consent process that describes the approach to incidental findings, then the default approach is that they will be told about any discovered genomic variants that are on the recommended list. The rationale being that this information is of such high medical importance and utility it's returned to the patient, just like an incidental finding on an x-ray. In essence, the ACMG guidelines treat genomic information like any other medical information that doctors and patients need to discuss when planning medical care.
The ACMG has done their colleagues and the genomics community a service in establishing these practice guidelines and advancing the discussion about incidental findings in clinical care. This is an exciting time for genomics, but much still needs to be learned and discussed as we establish how best to make genomics a standard part of medical care. NHGRI is certainly working hard to see genomic medicine become a reality!
Read the ACMG report
Read the ACMG press release
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1. Anonymous (March 26, 2013, 20:07)
Use of incedential findings can increase cancer survival rates.
2. faizulabdulrahmanmalaysia (December 12, 2012, 12:22)
can gene therapy help autistic people one day, to reduce their burden in life?
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Updated: May 8, 2013