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Genetic Linkage

Good and Potentially Bad about FDA's Greenlighting of 23andMe Direct-to-Consumer BRCA Mutation Tests

News that consumers will soon be able to purchase a genetic test for three BRCA mutations may seem like déjà vu. That's because it is.

This is the second time that direct-to-consumer genetic-testing company 23andMe has offered screening for the mutations linked to breast cancer. The difference now from when it was yanked off the market in 2013? FDA approval.

That's huge. Read More 
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DNA Testing Kits as Holiday Gifts Can Bring Surprises

The text you type here will appear directly below the image
Lately people have been sending me their direct-to-consumer (DTC) genetic testing results for help with interpretation. Although companies like 23andMe and ancestry.com do a pretty decent job of explaining findings, people not familiar with genetics might be confused. And they can be so upset, or scared of the science, that they forget that human behavior lies behind some disturbing information.

So it was that Lisa G., not her real name, emailed me recently, asking about the likelihood that a stranger claiming to be her half-brother really was. He’d gotten the idea from a 23andMe test. So as ads for DTC DNA tests ramp up as the holidays approach, I thought I’d relate this simple example of the feelings that findings can evoke. Read More 
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New Guidelines on Testing Kids’ DNA – the Cliff’s Notes Version

Should kids have genetic tests? It depends. (NHGRI)
Exomes are big news. Sequencing of the protein-encoding part of the genome is increasingly solving medical mysteries in children. It began with Nicholas Volker and his recovery from a devastating gastrointestinal disease with a stem cell transplant once his exome sequence revealed his problem. And recent Medscape assignments reveal the trend: 7 of 12 kids’ exomes leading to diagnosis at
Duke University
from May 10, 2012; whole genomes of 5 infants from the neonatal intensive care unit at Children’s Mercy Hospital and Clinics in Kansas City, Missouri from October 3, in under 2 days each, focusing on 600 single-gene diseases; and 300 patients at the Whole Genome Laboratory at the Baylor College of Medicine, with 300 more waiting -- 85% of them kids, from November 9, 2012. (You have to sign in to Medscape; it’s free.)

But wait.

Before we all run out to get our exomes and/or genomes sequenced, Read More 
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Genetic Testing: Carrier Confusion & Generation Reversal

A breast cancer cell. (Natl Cancer Inst)
In the usual trajectory of passing on genetic information, the older tell the younger, when the time is right. Typically, a patient has a genetic test because family history, ethnic group, or some other clue suggests to an astute practitioner an increased risk of something specific.

If a test reveals a mutation that could cause a disease, then the patient and perhaps her partner discuss how, when and what to tell their children – in the best of circumstances, with the help of a genetic counselor. Read More 
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My New View of DTC Genetic Testing

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“Are you still collecting stories about DTC testing? I've got one for you!” my grad student L.W. e-mailed a few days ago. Little did I know her family's experience would change my mind about direct-to-consumer genetic testing.

L.W. had taken my online course “Genethics” in 2008 for the master’s program at the Alden March Bioethics Institute of Albany Medical College. Read More 
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A Medical Manual from 1909

I discovered a treasure at a thrift store. For 89 cents, I bought “The People’s Common Sense Medical Adviser in Plain English or Medicine Simplified,” by Dr. R. V. Pierce, head of The Invalids’ Hotel and Surgical Institute in Buffalo, New York, circa 1909. In these days of WebMD and direct-to-consumer genetic testing, this peek into medical history is quite an eye opener.

The first part of the 1,000-page tome is eerily similar to the human anatomy and physiology textbooks I co-author. Some things don’t change much. The final section unveils an astonishing natural pharmacopeia, from various barks and roots, to pulverized rabbit testicles to cure older men suffering from erectile dysfunction, or perhaps the newly-named “low T.” In between are sections that are just odd.

Chapters cover hygiene, “mother and babe,” marriage, and my personal favorite, “self abuse.” “Statistics show that insanity is frequently caused by masturbation,” admonishes Dr. P., and it can be deadly. He rails against “criminal abortion,” which is “secretly practiced by women who desire to rid themselves of the evidence of immorality, and by those in wedlock who wish to avoid the care and responsibility of rearing offspring.” And the good doctor has ideas about race that echo back to Darwin. While genetic researchers today marvel at the diverse genomes of the Koisan of Namibia, Dr. P. equates them to baboons.

The Medical Adviser is just as telling for what it omits – cancer, for example – from a time when tuberculosis (“consumption”), smallpox, and various fevers were of far more concern. It teems with terms probably not uttered in decades, and new to me: erysipelas, quinsy, scrofula, and of course spermatorrhea, about which the esteemed author obsesses (more on that soon).

The book is festooned with marvelous illustrations and page after page of testimonials. Sexism is entrenched. While names and photographs accompany the musings of women with “female weakness,” “womb trouble,” and “nervous collapse,” complaints from men with the aforementioned spermatorrhea (“seminal weakness,” aka premature ejaculation, thanks to self abuse) are identified only by case numbers.

I think Dr. P. could have used a female co-author. Read More 
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Genetic Incidentalomas

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. Read More 
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I'm a DES Daughter

Early June marks the 30th anniversary of the reporting of the first AIDS cases, but it’s also an older medical anniversary – recognition that the drug diethylstilbestrol (DES) derailed development of the reproductive systems of a huge cohort of fetuses. I was one.

My mom, like millions of others, was handed “a vitamin” while pregnant with me in 1954, which in those days of medical paternalism, she never questioned. And so when I became a teenager, I began to drip, and was hauled off to the gyno. The verdict: Adenosis. The label: DES daughter. It was scary.

As an endocrine disrupter before the term was coined, DES, among other things, played havoc with the boundaries between tissues of the cervix, which prevented glands from vanishing on schedule. With the hormonal onslaught of adolescence, the errant glands went into overdrive. Fortunately, I didn’t have the otherwise rare cancer whose sudden appearance led to identifying the problem, as with AIDS. I also escaped the trademark DES small uterus, and my husband, a DES son, escaped XY-related problems. But my mom did die of breast cancer – another legacy of the “vitamin” thought to protect against pregnancy loss. And so far the DES Follow-up Study on the third generation – my three daughters – has revealed only a slight increase in ovarian cancer risk that is likely a statistical fluke awaiting larger numbers.

Pregnancy paternalism took years to dissipate. In 1981, my ob clearly knew something was amiss, but he said nothing. And so we were shocked at the on-time birth of daughter #1, who weighed less than the scraggliest chicken at the supermarket.

Then in the middle '80s I began providing genetic counseling at CareNet Medical Group in Schenectady, NY, founded by a wonderful ob/gyn, Hong Kyu Cheon, whose mother had been a midwife in Korea. When he retired, he handed the practice over to his daughter and daughter-in-law. Today CareNet is run by women. It's not that an XY ob/gyn can't be competent or caring, but there is something comforting, given what happened to my mother, about a woman-run practice.

And how things have changed! Patients now come into doctors offices already very informed, even naming specific drugs thanks to all the TV ads. My genetic counseling patients come armed with printouts describing their risks and possible tests, and sometimes even direct-to-consumer genetic test results. It is hard to imagine my mother's time, when she was expected to happily take anything the white-coated authority figure handed out.  Read More 
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Blaming Genes in the Workplace

Think it’s a great idea to send off a spit sample to see which future health conditions lurk in your DNA? In the U.S., the Genetic Information Nondiscrimination Act (GINA) prevents employers from using that information  Read More 
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Beauty Genes and Celebrities

I love to roam among the posters at scientific meetings in search of research tidbits that the media miss. I just found a great one at the American Society of Human Genetics conference that is certain to have profound implications for celebrities.

Among the many posters showing  Read More 
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