There can be little doubt that the future of medicine, the next penicillin if you will, is genomics. Why wouldn't it be? The double helix forms the foundation of biology.

Already, great strides have been made. During the plenary session at the 2013 Heart Rhythm Society Sessions, President Bill Clinton boasted that he spent $3 billion to sequence the human genome. Now, it can be done for thousands. Personal genomic medicine has arrived. And so has the entrepreneur.

For-profit companies offer—and aggressively market—personal genome testing for a myriad of diseases. In cardiology, the ailments for which genetic testing are available are toughies. The inherited channelopathies and cardiomyopathies, for instance, are not diseases doctors see everyday. Clinicians on the front lines are drawn to the idea that knowledge of their patients' genes could make a diagnosis or suggest a treatment. In rare diseases, all involved parties welcome a test that might map the right course.

Genetic tests, however, are far from binary. Like any diagnostic test in the practice of medicine, context is everything. The signal-to-noise ratio for genetic tests is high. It's often hard to hear anything over the roar of the band.

This is one of the reasons why I carved out time at EUROPACE 2013 to attend a session on genetic testing. The other was that Dr Michael Ackerman (Mayo Clinic, Rochester, MN) was giving the talk. He's a compelling speaker, natural teacher, and true expert on genomics. I've sent a number of patients to his Mayo genetics clinic, and they have had excellent experiences. His letters back to me should count as CME.

During the session, he shared five reasons not to do a genetic test. Here's my translation:

  1. When the phenotype is weak or absent. Ackerman used examples we have all seen: a 13-mm LV wall thickness, isolated T-wave inversions in V1 and V2, vasovagal syncope in a patient with a 440-ms QTc. Such nonspecific findings are not in anyway suggestive of a disease phenotype. Clinical suspicion of an inherited disease must be strong. It's a paradox: strong clinical suspicion strengthens the reason to test while weak suspicion lessens it.

  2. When the phenotyper's sword is dull. He asks clinicians to consider their own batting average for being right about the test. How often do we get phenotype matched with genotype? Being right more than 75% of the time means one is likely underutilizing the test, while rarely matching implies possession of a dull sword. He reiterates: "If you are not suspicious of the phenotype, don't obtain a genotype." In bold letters comes the message: Get to know the phenotype.

  3. When the test's diagnostic, prognostic, and therapeutic impact is not understood. Ackerman spoke of one of his more common scenarios. The message from the referring cardiologist goes something like this: "Will you screen my patient to see if he/she has one of those bad 'thingamabobs' or 'whatchamacallits' (ie, disease-associated mutations) so that I know whether or not to implant an ICD?" This is a problem because so few of us on the front lines of cardiology (me included) stay ahead of the fast-moving field of personal genomics and channelopathies. His next slide emphasized that other than a small number of long-QT variants, most gene tests provide little prognostic value. The bottom line: the diagnostic and prognostic impact of genetic tests is disease dependent. He prods the audience to do homework before doing these tests. Roger that.

  4. When the test's yield is not understood. To illustrate this point, he showed us a few visually impressive slides. The first slide featured a picture of a heart with h ypertrophic cardiomyopathy ( HCM). Fading in were 25 text boxes with various associated chromosome and gene variants involving the myofibril apparatus. It was dizzying. Did you know, for instance, that only 19% of sigmoidal–shaped HCM have a positive gene test while 59% of those with the reverse-curve variant are positive? Perhaps echo findings in HCM should guide genetic testing. Clinical markers of disease correlate with yield. Again, it's the same message: the yield of genetic tests is disease dependent.

  5. When the test's dark side is not respected. The Achilles' heel of genetic testing is the background noise. Here Ackerman shows us the famous quote: "With great power comes great responsibility." His next slides describe the dreaded "maybe" results. If you have done genetic testing, you've seen the words, "possibly deleterious" and "variant of uncertain significance." He calls this genetic purgatory—and warns it is a real and scary place! This resonates with me, as one of my chief concerns in medicine is inflicting fear. Our world does that well enough; doctors shouldn't add to it.

Plus, I've seen this purgatory place firsthand. Yes, I once made the mistake of ordering a gene test on a healthy young patient with a very borderline QT. Darn it if we didn't find a nonspecific missense mutation in a disease-causing region. Now what? Let me assure you, it took a lot of money, time, and effort undoing that bobble. I won't go there again unsuspectingly.

In the matter of genetic tests, the message I took away from Ackerman was to be a wise user and wise interpreter. For folks who love doctoring, that's terrific stuff.

JMM

Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011; 8:1308-1339. Article

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