Learning to Love Your Genome

Keith Stewart, MBChB, MBA
Carlson and Nelson Endowed Director, Center for Individualized Medicine, and Vasek and Anna Maria Polak Professor of Cancer Research, Mayo Clinic in Scottsdale, Arizona

The daily circus of recent world events has left me wondering whether it is truly plausible that I share a genome with the other half of the population, or whether my alienation could be explained by a heavy burden of Neanderthal DNA or excessive cilantro hypersensitivity (it’s a thing – look it up). To explore this hypothesis, I had my genome sequenced.

Proving that this is an emerging obsession, I did it serially, in various formats, hidden like a secret bottle of gin from an unsuspecting family. Truthfully, only a small part of the Stewart blueprint was analyzed and reported at any one time, perhaps feeding my craven need to indulge more.

The first foray involved a $2,900 whole-exome sequencing from which I learned I am a carrier of four heritable diseases (for anyone who cares or is brave enough to marry my children): Niemann-Pick disease type C, galactosemia, hemochromatosis, and spinal muscular atrophy. I was reassured that I did not carry a particularly noxious mutation that has plagued a branch of my immediate family for the past 50 years. I also learned that, if my pharmacogenome is to be believed, I should take higher doses of warfarin, lower my doses of statins, and pretty much forget about using antidepressants.

Admittedly, like a CIA operative, I was initially underwhelmed by the paucity of data. But on reflection, what the genome did not reveal proved to be more interesting. I tested negative for 1,596 other known conditions, including genetically based cancer and neurodegenerative predispositions. My relief is tempered, though, by the hard-to-ignore clinical zinger that, in the past few years, I have become utterly unable to recall anyone’s name three minutes after being introduced.

Still, I felt perky about my “negative” result and settled on the possibility – or perhaps the alternative fact – that I had reduced the cost of my future health care by avoiding the need for repeat genetic testing, making drug adverse events less likely, and allowing more informed future family planning (probably best if no one forwards this latter conclusion to my wife).

So, what if such testing were routine and we all participated? Would these conclusions be generalizable? Even in my own iron-overloaded, lipid-accumulating, metabolic minefield of a genome, the logic for hematologists to embrace such a path reveals itself when we consider the possibilities of identifying and reducing the disease burden of global plagues such as sickle cell anemia, thalassemia, hemophilia, and cancer.

Inspired to learn more, I have mainlined genomic testing for the past three months. A venture into ancestry confirmed I am resolutely Scottish (go figure) and, thus, can blame a lack of more “exotic” DNA for my refusal to dance at weddings. I hold out hope that the pending results from my $149 National Geographic Genographic DNA Ancestry Kit will reveal some Genghis Khan or caveman lineage – explaining my misanthropy.

Next came whole-genome sequencing – this time for $999. I should have quit while I was ahead. I opened the latest electronic report on a grey day in January, in an airport hotel in Brussels (think “Manchester by the Sea” dubbed in Flemish). Failing to read the small print, I slowly focused on the word “Alzheimer.” This resulted in a really awful, most unpleasant, distinctly uncomfortable 15 minutes, until I realized that the words “typical risk” were on the right side of the screen, just out of sight on the mobile app.

Recent data show that around 3 percent of the average adult population have an unsuspected inherited and medically actionable genetic finding, while 80 to 90 percent are carriers of inherited disease, and pretty much everyone has clinically relevant information in their pharmacogenome.

My own experiences aside, the rapidity of progress in genome sequencing is astonishing. It is easy to forget that only 15 years ago, no human genomes were yet sequenced. Now, genetic prognostication and targetable mutations are routinely used in treating blood cancers.

At our own clinic, families with rare diseases have whole exomes sequenced each week with clinical diagnostic intent, healthy individuals are counseled on the role of predictive genomics, and pharmacogenomic alerts fire in the electronic health record on a daily basis. A rapid genome-sequencing program in the neonatal unit is active, and individualized medicine clinics for bone marrow failure syndromes, inherited cancer, hyperlipidemia, arrhythmia, peripheral neuropathy, inflammatory bowel disease, and pediatric liver disease are up and running. Genomics-based diagnostics are being built for inherited bleeding, myeloma drug resistance, and leukemia gene fusions. Plans are afoot to offer a low-cost, medically relevant genomic screen to any interested patient, and a deep dive into the uncharted territory of the circulating tumor DNA atlas is under way.

All of which suggests that you may soon need a crash course on the molecular basis of asparagus odor detection, wet ear wax, and photic sneeze reflex – all of which were reported to me in my genome journey. In case you are still dying of curiosity, I am indeed genetically overly sensitized to the bitter taste of cilantro, I have a trait associated with a longer index finger (but surprisingly not middle), and I can now understand why I hate the sound of people chewing: It’s called “misophonia,” for the poorly informed. The wonders of the genome indeed.

The content of the Editor’s Corner is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated.

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