Abstract
Last year, the American College of Medical Genetics and Genomics (ACMG) created a stir by issuing its recommendations for reporting incidental findings in clinical genome or exome sequencing. According to these recommendations, a critical subset of genes needs to be scrutinized whenever genome or exome sequencing is performed, and that clinicians should communicate all the findings to patients, whether or not they concern genes that were originally thought to be of interest.
The original guidelines also included an “opt out” provision for patients. That is, the ACMG said that after testing, patients should have the opportunity to opt out of the analysis of medically actionable genes. Now, with its updated recommendations, the ACMG says that the opt-out discussion should occur before testing.
“This update to our recommendations moves the opt-out discussion to the point where the sample is sent rather than at the time when results are received by the ordering clinician, as was originally recommended,” explained Gail Herman, M.D., Ph.D., FACMG, president of the American College of Medical Genetics and Genomics. According to the revised guidelines, the opt-out option and its implications should be part of the general education and informed consent process undertaken by the ordering clinician prior to ordering the test.
Other aspects of the original recommendations remain in place. For example, the ACMG continues to call for testing 56 genes for pathogenic mutations. The ACMG adds, however, that the precise list of genes that should be routinely and fully analyzed (and reported) will gradually evolve. According to the ACMG, a special committee has been set up by the ACMG board to address the specific process by which genes are considered for inclusion on the list.
The exact number of genes is not, however, the main source of controversy. After the ACMG's original recommendations were issued, critics asserted that they embodied a bundling concept. That is, patients, clinicians, and laboratories were being asked to accept the idea that if genomic testing were to be done at all, a certain minimum number of genes would have to be assessed. This idea, some critics charged, could even blur the meaning of the phrase “incidental finding.”
In response, the ACMG has at least demonstrated that it is open to criticism. For example, the organization's official journal, Genetics in Medicine, has run articles with challenging titles such as “ACMG recommendations on incidental findings are flawed scientifically and ethically” and “Paternalism and the ACMG recommendations on genomic incidental findings: Patients seen but not heard.”
Also, in the press release that accompanied the new guidelines, the ACMG indicated that its board was sensitive to the views of its members: “The positions … regarding the issues raised by the recommendations have been assessed through a variety of mechanisms, including direct feedback, participation by board members in numerous forums exploring these issues, informal conversations, published articles, commentaries and, most recently, through an extensive member survey.”
Preliminary survey results were presented at the ACMG business meeting at the 2014 ACMG Annual Clinical Genetics Meeting in Nashville on Thursday, March 27. When GEN asked for details of the survey results, the ACMG said, “We need to complete further analyses of the data and plan to publish a summary in Genetics in Medicine in 2014.”
When asked if laboratories have been following the ACMG's recommendations, the organization responded that it does not formally track such activities. Nonetheless, by means of informal exchanges at the 2014 ACMG meeting and other venues, the ACMG gathers that most laboratories (about 90%) offer an opt-out option already. Also, it appears that more than 90% of patients undergoing clinical exome or genome sequencing have elected to have incidental results returned (that is, not opt out) when offered a choice.
A notable exception is the clinical sequencing laboratory at the Baylor College of Medicine. According to the ACMG, the lab has not yet offered patients a way to opt-out of the 56 genes in its consent procedure. Moreover, the lab will return data for selected additional genes/disorders. (Last October, in the New England Journal of Medicine, Baylor reported that it had provided a diagnosis to 25% of the first 250 such patients with suspected genetic diseases referred to its whole-genome laboratory.)
Despite the potential for continued controversy, the ACMG seems optimistic that a workable consensus can be reached. Last year, in a summary of ACMG practice guidelines published in Genetics in Medicine, the authors wrote: “As always, the diagnostic community will collectively benefit by discussing the newest and most pressing NGS issues together. This will require an ongoing dialogue among those already engaged in this pursuit, those determining how to become involved in this new paradigm of molecular testing, and those who will be responsible for ordering and communicating NGS results to patients.”
More recently, with the release of its updated guidelines, Dr. Gail Herman added, “The vibrancy of the debate is a testament to the importance and relevance of our field to the lives of our patients. There remain many complex issues to be addressed regarding the implementation of genome-scale sequencing in clinical care and we plan to keep having dialogue. It was our understanding from the beginning and was stated in the recommendations that they would evolve over time. The ACMG is committed to working to ensure that promising new technologies are used now and in the future for the benefit of our patients and their families.”