Those of us in genetics work within the realm of the red herring fallacy. Physicians, patients, and all of us alike are drawn to the “red herring” genetic test result, i.e., the variant of uncertain significance (VUS) or the positive but not all-encompassing result. These variants are waiting to be misattributed or stretched to clinically fit the patient like a Lycra jumpsuit.
In politics, literature, and everyday conversations a red herring is purposely used to distract the audience from the actual issue at hand. In an Agatha Christie novel, the red herring may lead the reader down an alternate path of suspicion so that the plot twist keeps us on edge until the dramatic end. The origin of this phrase is that of a kipper, or a cured herring, which turns red during the curing process, producing a pungent odor1. Red herrings were used to train hunting horses to be comfortable with the chaos and various smells during a hunt.
Large, multigene panel results or exome/genome sequencing reports are reviewed with the patient’s clinical features in mind. Of course, we are drawn toward genes and variants with overlapping features and a plausible inheritance pattern for that specific patient. The red herring comes up repeatedly in VUS conversations with providers and patients. It also occurs with patients who have a positive test result that does not fully explain the reason for genetic testing. With our ever-expanding knowledge of the penetrance and variability for so many conditions, this can be a tricky balance to find.
Have you ever imagined the personification of a variant? Are some variants detected to intentionally distract their audience members from the real cause of the condition at hand? Does a VUS know it misled providers for variable increments of time before a functional study resulted in a variant downgrade? If a VUS could feel, would they be laughing at us? “Ha! There you are looking at that measly variant when I am right here! You didn’t even find my in trans partner in crime, the Single Exon Deletion.” As the genetic counselor we may never know what the “real” condition is for a particular patient or how the story ends based on the clinical relationship. The art lies in the counseling and follow-up recommendations one makes based on the limited information available.
A red herring variant can be a disappointment for patients that are grasping for a confirmation of a genetic diagnosis. The hunt for accuracy continues. What’s next in their evaluation journey? As I gain more years of experience in this field, I continue to develop intentional care in making correlations between VUSs and the patient’s features. The advice I have received and now give is to keep an open mind during these conversations - consider all the strengths and limitations of the technology being used. For those of us practicing in rare diseases, the frequency of variants that are downgraded from VUS to likely benign is just not well known. Don’t be distracted by a variant simply because the gene could fit the phenotype. If possible, keep searching until the truth is found. As historian Yuval Noah Harari puts it, “Scientists generally agree that no theory is 100 percent correct. Thus, the real test of knowledge is not truth, but utility.”
Quinion, Michael. “The Lure of the Red Herring.” World Wide Words, 25 Oct. 2008, http://www.worldwidewords.org/articles/herring.htm.