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Genetic Incidentalomas

Genetic Incidentalomas

Picture of Ricki Lewis

Brandon Alspaugh is worried. He's an interventional radiologic technologist at South University in Charlotte, NC, taking human genetics in preparation for physician's assistant school. When he got to the end of my textbook, where I ask students to e-mail me their concerns, he wrote the following:

"Dr. Lewis,

Coming from the medical field, I worry that personal genomics, while useful in terms of screening for genetic disease, will come to have the same effect as full-body CT scans, where the amount of noisy data generated will drown out the important bits. As with atypical anatomy, a person might spend a month chasing down a suspicious allele only to find it's a normal variant of a beneficial gene."

Brandon's describing a new breed of incidentaloma, looking for one sign of abnormality that turns up what could be another. I went in for a CT scan of my lungs, for example, and the doctor fretted over my polycystic liver. A friend had it much worse. She volunteered to be a control in an Alzheimer's imaging trial, and her scan revealed two brain aneurysms!

The term "incidentaloma" was coined to describe an adrenal tumor (hence the "oma") found on a scan looking for something else. More recently, incidentalomas are arising as collateral damage from the sequencing of the human genome and the genetic testing it has spawned. We now have too much information, and too few people (genetic counselors) to translate what we do know.

The founding fathers (there were no mothers in the famed "amino acid club") who deciphered the genetic code back in the 1960s would not have predicted genetic incidentalomas; surely all DNA was translated into protein. Over the years, the percentage fell, precipitously, so that now we know (or suspect) that a mere smidge under 2% of the genome actually encodes proteins – a little like a John Grisham novel in which much of the story turns out to be, if not irrelevant, then not central to the main story.

Genetics is about variation, not just disease, and I fear that because of this, a direct-to-consumer genetic testing company, anxious to spew as much information as possible at its clientele, could indeed impart a sequence or two that is innocuous, as Brandon the astute student suggests. And genetic incidentaloma-ism extends to well known protein-encoding genes. I saw this the day after I heard from Brandon, when a nurse-midwife at the practice where I provide genetic counseling called me, alarmed at a lab result for a patient.

"What's SMN? The blood test results came back with a risk of 1 in 632 for SMA, based on SMN copy number. What's that?"

If the nurse-midwife didn't recognize it (and why would she?), I feared, the patient certainly wouldn't. And so I explained that SMN is the gene "survival motor neuron" and various versions of it are implicated in the most common type of spinal muscular atrophy (SMA),a recessive disease in the same general incidence ballpark as cystic fibrosis – 1 in 38 of us is a carrier. (I elected not to get into copy number variants, a recently-recognized form of mutation.)

I knew that more widespread testing for SMA was beginning because of pending legislation (The SMA Treatment Acceleration Act) "to authorize the Secretary of Health and Human Services to conduct activities to rapidly advance treatments for spinal muscular atrophy, neuromuscular disease, and other pediatric diseases, and for other purposes." Some three dozen labs offer carrier testing at GeneTests.org.

I also knew about SMA from a young hospice patient I'd visited in a nursing home. She was 7, a long-term survivor for this disease known as "baby ALS" that is usually fatal by age 3. (Also see Families of SMA.)

So should the midwife tell the patient, who must have signed something but likely has no idea her blood was tested for SMA, her carrier risk? Would the patient understand that the test indicates her risk is well BELOW that of the average person for something that she probably doesn't know exists? Does alerting and possibly alarming many people justify the additional SMA cases that screening might prevent by detecting potential parents who are both carriers? After all, this is the approach that has nearly vanquished Tay-Sachs disease. (See A Brief History of Genetic Testing.)

A slippery slope looms.

How far are we from personal genome scans that yield long lists of risks, some meaningful, some not? Who will develop the criteria for what is meaningful, for what a patient should know? Should a health care practitioner disclose ALL genetic information so as not to be paternalistic, or shield the patient from test results to "do no harm?" What happens when a genetic risk identified today declines with a future discovery? (Not everyone taps into 23andMe on a daily basis to check for updates.) Or should a patient indeed be told absolutely everything, in case there is something he or she can do, environmentally speaking, to alter genetic destiny?

As with all matters scientific, the more we learn, the more we find out that we don't know. It will be interesting to see how the impending avalanche of genetic incidentalomas plays out.

Photo credit for exhibit from London Science Museum: John Goode via Flickr

Comments

Picture of Angilee Shah

Thanks for the post Ricki. How should journalists explain this type of testing? Have you seen any good examples of reporting on personal genomics?

Picture of Ricki Lewis

The news sections of Science and Nature are always accurate -- I'm afraid I do not read much of the general media on personal genomics. I tend to stop at the first error. There are a few general pitfalls.

 

One is "he has the gene for that, she has the gene for this." We all have all 20,350 or so genes, just different versions of them. A more subtle inaccuracy is to promote what we nerds call genetic determinism -- that we are our genes. You can inherit genes predisposing you to develop lung cancer, but possibly not do so if you never smoke or inhale pollution. That is, for many genotypes, there is much we can do to alter the phenotype. But the error that usually just stops me in my tracks is the genetic code error. We don't have personal genetic codes. The code is the correspondence between 3 bases of DNA and the amino acid type that it encodes, and its universality, in all species, is the basis of nearly all biotechnology. When articles talk about "his genetic code," they typically mean his genome sequence. There is no human genetic code. Even Craig Venter and Francis Collins use this oversimplification, and I once got into an argument with an editor at Scientific American over it. But I'm not the only geneticist who cringes at the usage. The genetic code was cracked in the 1960s.

 

I suppose making light of genetics isn't good, but I loved the New Yorker take on "spit parties" and assigned it to my students. It was fairly accurate. Wired articles tend to be excellent too. Coverage of Steven Quake's genome sequencing was accurate and interesting. Most newspaper articles on personal genomics I've skimmed have done a good job.

 

Since blogs came into existence I shifted from magazine writing to nearly 100% textbook writing, so I apologize for being such a stickler. But I have to get every detail, every use of language absolutely accurate, so I tend to be highly critical of the media. But overall, they've done a great job of a fast-moving field.

 

Picture of Laura Newman

This is a very important topic. Glad to see some informed criticism of the bandwagon to rush and get tested. Far too many journalists seem awestruck about gene testing, making the mistake that getting tested is likely to be empowering.

Hope that your post inspires more critical thinking.

Picture of Ricki Lewis

I think I may be in the minority. In my "Genethics" class, most students say they will take genetic tests, and am surprised that I probably will not.

Picture of Angilee Shah

Thanks Ricki -- being a stickler is a great thing. This is really helpful.

Picture of

Dear Ricki,

What an excellent, and insightful discussion. Also, if you're interested in a first-person take on the repercussions of poorly-counselled genetic testing, please check out my own experience with the topic here.

On a historical front, I would add that there is, indeed, a founding "mother" in the "amino acid club": the amazing Rosalind Franklin, whose imaging of DNR was actually stolen by Watson and Crick. She died without ever getting credit for being the real person to actually identify the structure of DNA -- a travesty that still continues. (Check out the NPR story here, which tries very very hard to make W & C look less slimy.)

Even the Mac "genius" retro ads leave her out, and so do my kids' school textbooks. But Rosalind Franklin deserves infinitely more credit than she's ever gotten. Like many women, much of her brilliance is dismissed by critics through the handy trick of calling her "difficult" (I'm not sure how that negates brilliance, plus, if someone stole my life's work as the world applauded, I'd probably be a tad "difficult" myself...). Her legitimate claim to being the sole identifier of DNA's structure is also somehow refuted through the media's constant mention (if it's mentioned at all) of W&C's blatant act of fraud and outright theft as being merely "research used without her permission" -- a phrase that both confirms that it occurred, but implies she participated in the act. That's a handy verbal trick if you can pull it off, kind of like the scientific equivalent of saying she shouldn't have used such slutty lab equipment. 

I just thought you might enjoy being introduced (if you hadn't been already) to another brilliant woman. Thanks so much for writing such a great piece,

Jan

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