The Association for Molecular Pathology (AMP) is offering a new perspective from the laboratory, highlighting the need for increased understanding and transparency of complex genomic testing. It also outlines important recommendations, including the need for laboratories to establish clear and patient-friendly policies for delivering ancillary information generated from genome-wide genetic tests. A copy of the embargoed paper is available by request.
The AMP Incidental Findings Working Group has closely followed the incidental findings debate since early 2013, when the American College of Medical Genetics (ACMG) published its guidelines on incidental findings reporting. These recommendations primarily focused on the content of secondary information obtained from genetic tests, and not the pitfalls of technology limitations, which has placed a significant burden on laboratories to educate patients, as well as physicians, about the strengths and limitations of genetic testing.
Lead author and chair of the AMP Incidental Findings Working Group, Madhuri Hegde, PhD, Emory Genetics Laboratory, department of human genetics, found that patient and physician education regarding how genomic data are interpreted as well an appreciation for technology limitations placed on the lab had been overlooked.
“Patients have a choice whether or not to receive additional information that may be available as a result of a genetic test that looks across an entire genome of DNA. In most cases, patients are interested in learning more, but it’s critical that we educate them, as well as the ordering physician, about their options and what can and cannot be reported,” noted Dr. Hegde. “While genetic testing technologies have revolutionized the way we diagnose and treat disease, we must appreciate the technical limitations that still exist today. If a report comes back with no known genetic abnormalities, it doesn’t mean that a pathogenic variant might not exist — we just can’t see it or interpret it from the data we have right now.”
Even though sequencing technology is far more sophisticated than it was even 2 years ago, the limitations of the technology must be accounted for. Hedge mentioned relying on a singular technology, incomplete regions within the human genome (as is common with Lin syndrome), the inability of the technology to sequence through low coverage regions and an inability to differentiate between a real change and one with a homologous sequence.
“Out of 40,000 exomes, 40 are not covered properly,” she clarified. “We need to make sure [the entire] gene is covered start to finish. We need a way to pull in exome. We tried to put that in document. Next gen technology is not a standalone test but looks at complex genotypes. It doesn’t capture the fragile X syndrome, which was one of the earlier genes discovered. It needs to [be] complemented with other assays to make it a complete test.”
Consent Form Components
In many cases, she remarked, the debate comes down to what should be listed on the consent form. “Patients’ rights are important, and they can now opt out for what they don’t want to know, but the lab can mask the data completely. When you look at the exome, you look at everything. So, it comes down to what you can and cannot report. Because there are over 20,000 variants with exome sequencing, labs need guidelines to set internal policies are far as what can and cannot be reported.”
According to Hedge, there are some must-haves when drafting a consent form, including diagnostic findings related to genotype, those not related to genotype, carrier findings, pharmacological findings, changes in genomes, adult onset actionable and clinically non-actionable findings. Often, she said, the last category presents the most ethical challenges.
“It’s tricky because patients can opt out of knowing adult onset conditions,” she shared. “Nowadays, parents are getting tested at the same time as their children. If you find the gene change in the child, it will most likely be in the parent as well, and you’re essentially telling them they’ll get the disease.”
Hedge also noted that it’s physicians, not always geneticists, ordering the tests. “Not every practice has genetic counselors anymore, and that gets sticky as well,” Hedge remarked.
As technology becomes more sophisticated, Hedge said consent forms must also adapt. Her lab at Emory University has edited their consent form at least three times in the past few years. “Genome sequencing is very exposed in the media, and therefore, everyone wants to know everything. We have very few people opt out.”
Laboratory regulation also plays an important role in how incidental findings are reported. Clinical Laboratory Improvements Amendments (CLIA) regulations, proficiency testing, lab accreditation and other quality measures oversee and govern laboratories and the tests that they develop. If the U.S. Food and Drug Administration (FDA) steps in, as proposed in their recent draft framework, it could make access to important tests challenging.
Last February, AMP leadership and 75 other stakeholders provided feedback on “Draft Guidance for Industry, Food and Drug Administration Staff and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs),” which would apply regulations designed for medical device manufacturers to clinical laboratories.
“While we want to underscore the need for continued discussion among stakeholders to improve our understanding of the effect of different test result disclosure policies on patients, providers and laboratories, we don’t want to lose any progress that we have achieved since the completion of the human genome project,” said Elaine Lyon, PhD, AMP past president. “The proposed laboratory-developed test regulation framework imposes substantially new requirements on clinical laboratories, hospitals, physicians and other healthcare providers. This interference with the practice of medicine poses significant impact on patient access to vital molecular testing services necessary for improving patient care.”