Category Archives: Robert Resta

Don’t Look Now

At the bus stop the other day I saw a young man who had no nose. No proboscis, no nasal hypoplasia, no midline facial cleft, no Voldemort nasal slits. Just a deep hole, the circumference of a quarter, in the center of his face. The shock was heightened by encountering him in the clear daylight of a beautiful afternoon, outside of the normalizing context of a genetics clinic.

My mind sorted through possible etiologies. A freebasing accident gone horrifically wrong? A congenital anomaly syndrome whose name was lost in the cobwebs of my brain? A developmental process gone awry? The product of a new teratogen? An extreme case of self-mutilating psychopathology?

My fellow commuters in waiting were either staring directly at him, or, like me, struggling to disguise our rudeness by trying to simultaneously gaze at and just past him. I rationalized my behavior by telling myself that I was doing what any reasonable geneticist would do – trying to fit him into a Dave Smith pigeonhole. But, truth be told, I was gawking at him.

Name That Syndrome. It is a game that geneticists often play when we have the opportunity to observe the parade of humanity in all of its terribly wonderful variety. That exotically gorgeous woman with the ice blue eyes and gray forelock sitting at the bar? I bet she has Waardenburg syndrome. That overly friendly young boy with the starburst iris trying to make friends with every angry airline passenger aggravated by the flight delay? Only a kid with Williams syndrome could have that much faith in the goodness of humanity. That overweight blind child with post axial polydactyly clinging to her bedraggled mother, the weary pair standing on a rush hour bus because nobody had the decency to offer them a seat? I hope her pediatrician had the savvy to diagnose Bardet-Biedl syndrome. And that guy waiting to board the plane who has wide-set eyes, a depressed nasal bridge, a smooth philtrum, and mild syndactyly – he must have something. I wonder if the airport’s facial recognition security software has Gorlin’s Syndromes of the Head and Neck programmed into it?

Context matters. Within the confines of the clinic, it is entirely appropriate for a genetic professional to intensely examine every square centimeter of a patient’s body. But once we step out of the front doors of our medical towers and into the streets, we lose the mantle of medical authority that grants us the social privilege of staring closely at other human beings to look for differences subtle and profound that stray from the norm (of course, variation is the norm).

Separation of personal and professional life is a complex, challenging, and ongoing process. We often have a hard time finding the Off button for our clinical instincts. Like clerics and cops, geneticists can feel like they are never off duty. I struggle with this nearly every day, dancing a tango where I am vying with myself for the lead.

I do my best to justify the social crassness of Name That Syndrome by re-framing it as clinical curiosity.  But it’s not polite to stare; Mom is right once again. On the streets they are not clinical puzzles. They are people with beating hearts who are trying to scratch out a decent life in a hard world. They deserve respect and dignity, not freak stares. If we lose sight of this, we become poorer clinicians and lesser people.

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It’s All About Me

Now that FDA and FTC are cracking down on online genetic testing there are fewer major players in the revolutionary new field of Perfectly Useless Genetic Screening (PUGS). So I thought that I could fill this void by re-branding GeeKnowType, my previous foray into artisanal personalized genetic testing. And voila! The RestaEZ  Gene Panels™ were conceived.

The basic principle behind the RestaEZ Gene Panels™ is that if somebody, somewhere says something is genetic – especially if the source is the Internet –  then enough consumers, er, patients, will believe it and I will offer a genetic test for it.

Here is a  sample of some of the valuable medical information you will obtain from my RestaEZ Gene Panels™:

Restassured – The prenatal test that uses circulating free placental DNA that will assure you that your unborn baby is not gay, obese, gluten-sensitive, or unable to get into the finest college or preschool. Of course, I have nothing against overweight gay men who can’t even go out for pizza with his friends and who barely graduated high school, but, well, you know, parents should have a choice about these things.

UnderAResta – Worried that your adorable baby may be the next Baby Face Nelson? Then insist that your child’s pediatrician screen your baby for XYY, CTNNA2, and MAOA. A portion of the fee is donated to the Restatution Fund, which will pay any legal fees and bail on the outside chance that a random socioeconomic factor might influence your genetically normal child to break the law and affect the subsequent verdict and sentencing.

Restaurateur - Interested in a career as a chef but not sure if you have the palate for it? This panel  - which includes  TAS2R38, TAS1R2TAS1R3, PKD2L1, and PKD1L3  genes – will let you know if you are a supertaster or if you may as well be eating cardboard or truffles for all you can tell. Order this panel and I will throw in polycystic kidney disease testing at no extra cost.

RestaLess Legs Do you think you may have wanderlust but can’t stay in one place long enough to find out? Are you losing sleep because you think that your partner may up and leave you out of the blue and leave you singing the blues? Then DRD4 analysis is what you need. Important – please leave a forwarding address so the results can be sent to you.

RestaLess Eggs - Are you paranoid that your hot new girlfriend will all of a sudden “find herself pregnant,” trap you into  marriage, and ruin your otherwise excellent relationship and sex life? Then have her take the test for The Mom Gene when she asks if you think you two should move in together. No more fretting about lifetime sentences, umm, I mean, commitments.

PRestaDigitation – Whatever happened to The Vapors, Neursasthenia, Hysteria, and all those other diseases that were rampant in the 19th and early 20th century? Well, let me assure you that they are still with us but because doctors could never cure them they instead sold us the line that these were imaginary disorders and magically made them disappear by snapping their fingers and declaring them obsolete. I can  just as easily wave my hands and make these maladies suddenly re-appear in near epidemic numbers; all I have to do is utilize social media to recruit people who think they are afflicted with these serious disorders. Although no genetic markers are yet available for these conditions, I am sure that if I run enough genome wide association studies I will find some linked anonymous markers. This will allow sufferers to receive personalized medical care, such as the water cure, magnotherapy, electrotherapy, uterine massage, and yogurt based enemas provided by spas, asylums, sanatoria, and other major medical centers.

I strongly recommend that anyone seriously interested in their genetic make-up include in their order the RestaTheResults Option. At little extra cost – only 50 cents per nucleotide - you will have access to every single genetic variant in your personal genome, including benign polymorphisms, synonymous variants, and every variant in your non-coding DNA. Because it’s your DNA, damn it, and you have the constitutional and God-given right to know your entire genetic blueprint and the government has no business withholding it from you.

I declare no conflict of interest when it comes to RestaEZ Gene Panels™. Sure, I make money off of the tests but that is beside the point. I am a good person, well-intentioned, guided by sound ethical principles, and I am only trying to make people’s lives better.

 

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NIPS SPIN

Advertising is the art of making whole lies out of half truths. ~Edgar A. Shoaff

Every few years a new screening technology comes zooming down the prenatal pike, sometimes arriving more quickly than we might like. First there was maternal age, with the magical age of 35 as the cut-off. Low maternal serum AFP arrived in the 1980s and the OB community embraced it virtually overnight when ACOG’s Committee on Professional Liability issued a statement that practitioners could be held legally liable if they had not offered this screen to a patient who had given birth to a child with Down syndrome. This was followed in short order by the Triple Screen, The Quad Screen, nuchal thickening, Integrated Screening, etc., each one a statistical notch above its predecessor. The latest iteration – cell-free fetal DNA or Non-Invasive Prenatal Screening (NIPS)  - stands head and shoulders above the rest. Two of our colleagues have already discussed the limitations and strengths of NIPS here on The DNA Exchange.*

NIPS is big, as in global big. One lab makes its brochure available in more 20 languages, from Afrikaans to Xhosa (the pregnancy gods must be crazy, dropping pamphlets out of The Cloud). Tens of millions of women around the world are likely to undergo NIPS in the near future. And pregnant women are a “renewable resource” –  a whole new batch pops up every day and many women will have two, three, or more children. Competition for market share among labs is stiff and there is little incentive to dissuade women from undergoing prenatal screening. It’s not that labs coerce women to undergo screening, advocate eugenic agendas, or run roughshod over personal autonomy. All labs would support a woman’s right to decline prenatal screening and Lord knows they stay away from the abortion discussion. But if enough women decline, then there is no incentive to offer the screen. The companies have something to sell and will spin their product to attract customers.

Which brings me to the subtly misleading implications of the name Non-Invasive Prenatal Screening. Sure, NIPS is non-invasive. But so is ultrasound, AFP, HCG, etc. All of these screening tests are non-invasive and therefore do not carry a direct risk of fetal loss. NIPS  is no different from the rest in that sense. It is superior to other screens in terms of having a very low first positive rates, high positive predictive value, and high sensitivity. But NIPS is still an alternative to other screening tests, not to amniocentesis or CVS.

Yet the websites of companies that offer NIPS communicate a different message that subtly suggests that NIPS is in fact an alternative to amniocentesis/CVS instead of an alternative to, say, the Integrated Screen:

First we thought the PC was a calculator. Then we found out how to turn numbers into letters with ASCII – and we thought it was a typewriter. Then we discovered graphics, and we thought it was a television. With the World Wide Web, we’ve realized it’s a brochure. ~Douglas Adams

The suggestion that NIPS is a diagnostic test is further reinforced by reassuring text in large, appealing fonts – Comprehensive, Accurate, Trustworthy, and, my personal favorite, No Confusion. Such wording conflates screening tests with diagnostic tests. Who could resist a test that boasts to be >99% accurate, especially when combined with images of smiling, beautiful parents and babies so cute that you wish your touch screen would allow you to hug them? It is easy to see why parents might be confused and some genetic counselors feel that 75% of their patients may think that NIPS is diagnostic. Yes, the labs also offer comparison to other screens, information about the conditions being screened for, links to disability focused websites, and acknowledge the role of diagnostic testing. But information does not sell products; images and impressions do.

http://en.wikipedia.org/wiki/The_Treachery_of_Images

The Treachery of Images by René Magritte

NIPS is a pretty good screening tool that can help patients decide if they want to proceed to diagnostic testing such as amniocentesis or CVS. However, the first step in the process of considering any testing should be a soul-searching and difficult discussion between parents and with their care providers about views on disability, parenthood, expectations for their children, and beliefs about pregnancy termination (I can’t prove it, but I am pretty sure that discussion is not taking place anywhere near as frequently as it should). For parents who feel it is important to know the chromosomal status of their baby, the next step is to outline the pros and cons of screening tests, emphasizing that a screen only provides a probability that a child may have a particular chromosomal disorder. The risk estimate provided by the screening test may help parents decide if they wish to undergo diagnostic testing.

One might counter that labs are commercial entities engaging in good old American advertising, which everybody knows is not exactly a strictly honest business. But prenatal screening is not like trying to sell Coke vs. Pepsi or Ford vs. Toyota or Chia Pet vs., well, whatever it is that Chia Pets are in competition with. We are talking about babies, our deepest hopes and dreams, and the core values that define our humanity. This demands a higher standard and this is where genetic counselors need to work with their laboratory employers to elevate the discussion.

 


* Missing from much of the professional  discussion about NIPS has been the viewpoint of people with disabilities, their families, and their advocates. As Rachel Adams points out, the Down syndrome community in particular might feel particularly targeted by a test named Maternit21 – but that thorny topic is for another day.

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A Mixed Verdict

A recent $50 million dollar jury verdict in a “wrongful birth” lawsuit in the Seattle area* has caught the attention of genetic counselors, hospitals, patient advocates, and legal experts. The ruling in this case may have both positive and negative implications for the genetic counseling profession. Let me be clear up front – I am not passing judgement on the verdict, the medical providers, the parents, the quality of care, or the laboratory. This case is very complicated and no doubt many details were not publicly reported. Although I know some of the parties involved, I was not directly connected to the case and I have no insider knowledge. Indeed, I did not know about the case until it hit the news.

In 2007 a woman underwent chorionic villus sampling (CVS) because her husband was a known carrier of a very subtle 2;9 translocation. The institution where the procedure had been performed had no genetic counselor working on the day the CVS was performed, contrary to departmental guidelines for complex cases. Somehow the details of the translocation were not clearly communicated to the cytogenetics laboratory. The fetus had an unbalanced translocation that was erroneously reported out as a normal karyotype. The couple continued the pregnancy to term and the misdiagnosis was detected after the child was born. In 2010 the couple sued the hospital, the laboratory, and the physician who performed the CVS. The physician and the plaintiffs entered into a “High/Low” agreement  in which the defendant agrees to pay a minimum recovery in return for the plaintiff’s agreement to accept a maximum amount regardless of the outcome of the trial. The medical center and the laboratory  were held equally responsible for the $50 million payout, with half the money going to a Guardian ad Litem for the child to pay for his medical care and other expenses and half going to the parents.

The core argument of the plaintiff’s lawyer was that the error would likely have been prevented if a genetic counselor had overseen the patient’s prenatal testing to assure that the critical information about the translocation was clearly communicated to the laboratory. The medical center had reduced the genetic counseling staff despite pleas from the maternal fetal medicine specialists and in the face of growing patient volumes and increasing net revenue. Lawyers for the plaintiff further claimed that the medical center and laboratory did not follow Error Prevention and Quality Management Policies and that the misdiagnosis was the result of a systemic failure. These arguments were important to the extraordinarily large size of the award; the missed diagnosis was attributed to “true negligence” rather than a one-time human error.

The outcome of this case can be beneficial in several ways for the genetic counseling profession. The jury acknowledged the critical role that genetic counselors serve in the delivery of medical care. For genetic counselors trying to justify their positions and salaries can now also argue that their institution’s legal vulnerability can be dramatically reduced by having an adequately staffed genetic counseling service. After all, genetic counselors’ salaries are a pittance in the overall hospital budget and pale in the face of multi-million dollar legal damages. Genetic counselors served as expert witnesses for both the plaintiffs and the defendants, further enhancing the profession’s status.

On the other hand, the verdict did little to improve the rocky and complicated relationship between genetic counselors and people with disabilities, their families, and their advocates. From the perspective of many in this group, prenatal diagnosis and selective termination are bright shining examples of society’s intolerance of people with disabilities. Because genetic counselors are integral to the delivery of prenatal diagnosis services, we are criticized for being part of a larger social and systemic bias.

Genetic counselors counter that they do not direct patient’s decisions, only support them. Genetic counselors are all too familiar with the gut-wrenching, emotionally draining process that patients go through when they decide to terminate or continue a pregnancy in which the fetus has a chromosomal imbalance. And in many situations, genetic counselors serve as advocates for people with disabilities and their families. But this defense does not hold water with those who argue that the very existence of prenatal screening is an insult to people with disabilities who, after all, do not see much in direct benefit from NIPS, amniocentesis, CVS, etc. What positive message can someone with disabilities find when half of the fifty million dollar award was for pain and suffering of the parents, and the very justification of the life of someone with disabilities is called into question when he or she is labeled “a wrongful birth?”

For now, we live in a society where women have the hard-earned right to terminate a pregnancy for whatever reason they choose (although the ability to act on that right can be severely hampered by socio-economic status and governmental policies). Genetic counselors line up behind the defense that they nondirectively help women to act on this reproductive freedom. Disability advocates are often avid supporters of reproductive rights too but do not feel that prenatal testing is necessary to the expression of reproductive freedom and point out that society’s negative view of disabilities and unwillingness to allocate appropriate resources further worsens the effects of disabilities. The two sides seem to be at an impasse and the fact that genetic counselors might applaud this court’s decision may only further contribute to this impasse.

We cannot ignore the voice of our critics.  I am not sure what the solution is. Prenatal diagnosis is unlikely to go away unless abortion becomes illegal again. If genetic counselors suddenly decided to pull out of prenatal diagnosis services, I suspect that informed patient decision-making would deteriorate and people with disabilities would lose one of their few potential advocates in the prenatal system.

As a profession and as individuals we need to reach out to our critics and find some common ground, such as the recently developed Open Lines forum where disability scholars, genetic counselors, parents, and people with disabilities can openly and safely discuss their perspectives. Surely the two sides are not as dysfunctional as the US Congress. It will be painful and difficult, but great achievements often require great suffering.

* – King County (Washington) Superior Court Case # 10-2-43289-2, Judgment Record # 13-9-35173-6 & 13-9-33521-8

Note: Some of the information in this posting is based on an article written by the plaintiffs’ lawyer (Gardner T, “Significant verdict in wrongful birth suit” Trial News, January 2014, pp. 9-11).

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TMI?

Genetic testing for single disorders is rapidly going the way of yogh (Ȝ), eth (ð), and thorn *(Þ), those Old English fossil letters of the alphabet. With the advent of massively parallel sequencing and other new testing technologies, multi-gene panels are the wave of the immediate future. Some labs offer testing for 1700 genetic diseases on a single saliva sample. Single gene tests will soon seem as quaintly ancient as The Canterbury Tales.

The eye-blink rapidity of the evolution of genetic testing has made this an exciting time to be a genetic counselor. There is much to be said about multi-gene panels and the technological, scientific, clinical, ethical, and social issues that they raise. Here I want to share a recent experience with a hereditary cancer risk gene panel that made me think about some less discussed issues stemming from gene panels - Will patients  be able to understand this Midas-like wealth of genetic information, integrate it into their health care, and share it with their families? How adequate are current counseling strategies to deal with this complexity? 

My bright and educated patient had been diagnosed with young onset breast cancer, as had several of her first degree relatives.** One of these relatives previously had normal BRCA analysis. No other relatives had been diagnosed with cancer. A multi-gene panel indicated that my patient carried two pathogenic mutations, one in BRCA1 and the other in MUTYH. On the surface, this is not too complicated – a dominant mutation (BRCA) and a recessive condition (MUTYH polyposis) within one sibship, something that a first year genetic counseling student would be able to think through without much difficulty.

Simple. Or so it seemed until the discussion quickly became complex when I started switching back and forth between dominant and recessive inheritance and the different risks to siblings, nieces, and nephews; the need to test the patient’s spouse and potentially her siblings’ spouses for MUTYH mutations; and what further hereditary breast cancer genetic testing might be worth considering for the affected sibling who previously had normal BRCA analysis. It was like trying to focus on two different radio stations that were playing different songs simultaneously.

When a test result indicates a pathogenic mutation, I provide a detailed letter to the patient that serves as a guide to clinical management and to review the implications for the patient’s family. My first go-round with writing the letter for this double mutation patient was a 7 page affair that left my head aching. I eventually settled for two 3+ pages letters, one for each condition, but it still felt unsatisfactory to me. The follow-up took several sessions, a large chunk of administrative time, and multiple phone calls. Because some relatives do not live in the immediate area, it will be difficult to know how well this information will be communicated to the rest of the family.

Think of those female family members who may wind up testing positive for the BRCA1 mutation and carrying two MUTYH mutations. Will they have the drive to undergo annual colonoscopy, annual mammography, annual MRI, monthly self-breast exams, semi-annual physical breast exams, and whatever other screening we might suggest? Or elect to have risk-reducing salpingo-oophorectomy, prophylactic mastectomy, and, if they have a high polyp burden, prophylactic colectomy? That is asking a lot of someone, to say the least. Many patients will follow screening recommendations initially but after five or so years may begin to fall off in their compliance if the demands are too great.

And that is just for a small gene panel. No doubt we will encounter multiplex mutation patients who carry more than just two high risk genetic markers as routine whole genome/exome sequencing comes closer to reality. We cannot expect patients to regularly consult their genomes on a daily or weekly basis, like a genetic I Ching, to guide their life choices.  I suspect what may happen is that patients will focus on a few aspects of one or two diseases depending on their particular circumstances and experiences, and let the rest fall by the wayside. I not uncommonly encounter BRCA positive patients who say “Well I don’t have to worry about ovarian cancer because there is only breast cancer in my family, so there is no need for me to have my ovaries removed.” Even for the most medically sophisticated, highly motivated, and well-educated patients, there is a limit to how much information they can process and act on.

Then there are the possible psychosocial implications and narcissistic threats engendered by carrying not just one but multiple gene mutations, and the familial issues as increasingly complicated information is transmitted across the kinship network. With no family history of colon cancer, the MUTYH results came out of the blue and added another level of psychological complexity by raising concerns about a cancer that had not been part of the family’s prior medical landscape.

Some labs provide excellent educational materials, far better than what most counselors can put together with their limited time and resources. However, these pamphlets and online materials are geared toward explaining a single disorder within a family, not with providing a comprehensive narrative that interweaves the implications of multiple hereditary conditions. We need to develop  better counseling and education techniques to allow patients to effectively utilize complex genetic information and to help patients adhere to a screening strategy with as few financial, practical, scheduling, and emotional barriers as possible. Genetic testing may become relatively inexpensive and widely available, but the social and ancillary medical costs may be where the real expense lies . And that is not even considering the massive problem of maintaining properly curated databases to track, study, and communicate information about variants of uncertain significance.

To some extent, the situation may be analogous to PKU. As thoughtfully discussed in The PKU Paradox by Diane Paul and Jeffrey Brosco, PKU is typically described as a straight-forward mendelian recessive disease that has a remarkably effective simple intervention. PKU has had its share of astonishing success that has provided moral capital for justifying all kinds of genetic testing. Hundreds of millions of babies have been screened for PKU.  However the clinical, ethical, resource utilization, and social issues engendered by PKU screening are anything but simple, far from being resolved, and we are still uncomfortable acknowledging them. And that is for just one relatively uncommon genetic disease. Those problems will be magnified as we test for many conditions, some of which are not so rare.

PKU Cover

Am I sounding an alarm over a non-issue? What are the thoughts  and ideas of our DNA Ex readers?

* – A little bit of language trivia for the curious reader: The letter thorn (Þ), which represents the phoneme “th” (/θ/) as in “there,” survives in modern English in a peculiar role in the names of certain businesses like Ye Olde Clothing Shoppe or Ye Dragon’s Den. The Y in “Ye” is derived from the Early Modern English version of thorn, which was indistinguishable from the letter Y. “Ye” in these names is a modern cutesy way of spelling “The” and “Ye” should be properly pronounced “the” rather than “yee.”

**- Clinical details have been changed to maintain confidentiality.

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Metaphorically Speaking

With more than 30 years of experience, my tenure as a genetic counselor is roughly equal to the age of  the average practicing genetic counselor. It is no exaggeration to say that I entered the field when many of today’s genetic counselors were still zygotes. A few years ago I ran into a patient whom I had counseled during her pregnancy 27 years ago who proudly informed me that the daughter she was pregnant with back then is now a genetic counselor.

Truth be told, I have reached  a point in my career where I question my relevance to the genetic counseling profession. I worry that the issues that concern and stimulate me are irrelevant to the current and future practice of genetic counseling, that I am stuck in a professional time warp where I am fighting yesterday’s battles and fretting about irrelevant ethical and clinical dilemmas. Maybe my work here is done.

Even more concerning is the possibility that younger patients may think that I cannot possibly understand their problems. They are at vastly different points in their life cycles than I. There is little overlap between our cultural reference points and we likely have distinctly different comfort levels with the technological advances of the last 3 decades. Who wants to be counseled by their father?

Photo courtesy of Lizzie Resta

Phone

VHS Tapes For VCR

When I first started out as a counselor, I fretted that I was so much younger than my patients that they would not take me seriously. Now I struggle with how to relate to a 30-year-old female BRCA mutation carrier trying to decide whether she should tell her fiancé about her carrier status, and if should she have a prophylactic mastectomy, which in her mind might render her an “unfit” mother because she would not be able to breast feed. My insecurity has come full circle. Sure, good counseling skills should make those differences irrelevant, but still…..

The potential generation gap between me and my younger patients surfaced recently when I met with a woman whom I had initially met with in the 1990s when she was pregnant and amniocentesis had revealed an apparently balanced de novo translocation.* Because of our past experience together she requested to meet with me again because of her subsequent personal and family history of cancer.

Before we started addressing her current situation she told me that she wanted to let me know how much she had appreciated the counseling I had provided during her pregnancy nearly two decades ago. What she had found particularly helpful was a metaphor I had used to help her grasp the concept of translocations. “Bob, you described chromosomes as essentially being a set of encyclopedias, genes were the words in the encyclopedias, and DNA was the alphabet used to spell the words. A balanced translocation was like a few chapters from Volume 10 had broken off and joined Volume 4, and vice versa. You couldn’t say for sure if a few words or letters were lost as a result of the translocation, but as far as the lab could tell, the encyclopedia had all of the necessary information, just rearranged. The light bulb went on in my head, and I was able to make a decision to continue that pregnancy.” I am not claiming that I broke new counseling ground with this explanation; I suspect that many genetic counselors use some version of it.

She continued “My husband and I liked that imagery so much that we used it when we finally decided to tell our teenage son about his translocation.” After they broke the news to their son about his genomic constitution, the patient said that her son silently contemplated what he had just been told. The parents held their collective breath, anticipating a complicated genetics question or a deep emotional response. Finally, he looked up and asked “An encyclopedia – is that anything like Wikipedia?”

Well, I thought, I wasn’t just being paranoid about my relevance to genetic counseling. Even my Genetics-To-English Dictionary is obsolete. I really do need to think about packing it in as a counselor and taking an administrative position with no patient contact.

Rare First Edition of the Genetics To English Dictionary

After I recovered from that shock, I got to thinking more clearly about their son’s statement. Hey, I thought, maybe I could update my Genetics-To-English Dictionary and appropriate the Wikipedia metaphor to my current work in hereditary cancer. Wikipedia is essentially the genome. It contains a lot of information, but some of that information is inaccurate and needs to be corrected and updated, much as DNA can acquire mutations and needs to be repaired. Mismatch repair proteins, the culprits in Lynch syndrome, are like the anonymous editors who vigilantly proofread Wikipedia, reporting and correcting typos to restore the integrity of the information. When the mismatch repair protein genes are mutated, the proofreaders are less accurate, DNA damage accumulates in the cell and eventually leads to cancer. In Lynch syndrome, the proofreader has a hereditary dyslexia.

Perhaps there still is some hope for me as a genetic counselor. But first I have to figure out how to stop my stupidphone from making that awful chirping sound. At precisely 3:12. AM. Every morning.

* – Some clinical details of this scenario have been changed to maintain confidentiality.

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Caught In The Act

I keep a bowl of chocolates on a table situated between the two chairs that accommodate patients in my office. It is a simple gesture, a small attempt at creating a friendlier environment for conducting the sometimes scary business of genetic counseling. I spread enough bad jujus as part and parcel of my work; I can try to do a little something to offset the negative karma. And it is decent chocolate, not Halloween rejects or forgotten treats that have been lurking in the back of the snack cupboard since the Clinton administration.

Although my chocolate stash has not provided great insight into the psychological complexity of genetic counseling, it has been a surprising and at times amusing source of insight into human behavior on a micro-scale. As they used to say on the old Candid Camera television show, I catch people in the act of being themselves.

Guys, for the most part, walk in, see the chocolate, and say “Hey, great, chocolate!” and then unabashedly help themselves to a few pieces. Many women, however, tend to have a more complicated relationship with chocolate. Here I share a few examples that illustrate this tangled web.

Maybe He Won’t See Me: This is the most common scenario. They want chocolate but do not want to be “caught” eating in front of me, as if somehow it violated social norms or might shape my opinion of them. As we engage in the counseling process, their eyes involuntarily sneak sideways glances at the bowl, the siren call of the miraculously transformed pods of Theobroma cacao too alluring to resist (One patient actually begged a là Odysseus “Please, before I eat it all, tie my hands to the arms of this chair.”). They can get wily too, waiting for an opportunity that distracts my attention, such as when I turn my back to them to complete a test request form or leave the room to photocopy some paperwork, and then sneak a piece or three. Either they quickly unwrap and eat it, hoping that I did not detect the maneuver, or sequester their pilfered pleasure into their purses. If I happen to notice their covert actions, they voluntarily offer an explanation along the lines of “Oh, I just wanted to bring home a piece for my son. He really likes chocolate.” What, like your kid expects a treat every time his mother has a doctor’s appointment?

Get It Away From Me:  Here will power is a serious problem. They sit down and unthinkingly pluck pieces out of the bowl without ever taking their eyes off of me, their uncannily accurate radar guiding them to their personal dark or milk chocolate preference. After a few minutes they realize that they have worked their way through four or five pieces and plead “Please, take this away and hide it in a drawer.” It reminds me of the slyly clever Cookies episode from Arnold Lobel’s delightful Frog and Toad children’s books.

Oh Heck, Why Not?: Like good Christians shunning Satan’s temptations, these patients nobly avoid the chocolate for the duration of the session. But as they prepare to leave, they steal a longing glance at the bowl, torn between desire and decorum. I usually suggest that they take a piece to reward themselves after an emotionally exhausting counseling session or to recover from the physical trauma of their upcoming blood draw. “Oh, I shouldn’t ….. well, alright. I guess I can have one piece since I didn’t get chocolate syrup drizzled on the whip cream on my morning mocha. I will save it for after lunch.” Perhaps in the complicated calculus of calories and diets chocolate has fewer calories after lunch or the mocha counts as Morning Calories and the chocolate as Afternoon Calories.

Calories and Insulin: These patients first pass the chocolate under their noses before popping it into their mouths, like an oenophile sniffing a Premier cru Bordeaux. They savor the pleasure of the silky sweet sensation on their tongues and palates, torn between swallowing and lingering on the moment and sometimes emit a quietly restrained orgasmic “Mmmm.” Then I think back to my review of their medical records and recall multiple appointments at the Diabetes Wellness Program or the Weight Control Clinic, and I feel like a bad clinician who should have planned more carefully for the needs of my patients.

The No Holds Barred Chocolate Addict: Social etiquette is quickly abandoned as these patients unselfconsciously dig into the bowl like Hansel and Gretel in the witch’s cottage. They think nothing of emptying the bowl and leaving only the crumpled wrappings, making it look as if a swarm of locusts had descended on my office. A patient once asked “Do you have any more dark chocolate? My sister just ate the last piece, and I really don’t care for milk chocolate.”

Should Seymour Kessler or Jon Weil reads this piece, no doubt he will roll his eyes and think “For crissakes, Bob, didn’t you learn anything from my teachings? You need to be attending to the profound psychosocial aspects of genetic counseling and the alleviation of human suffering.” Well, Jon and Seymour, I do strive to be a serious and insightful counselor. But sometimes patients – and I – need a piece of chocolate too.

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Questions For The Panel

If you are a genetic counselor engaged in testing for hereditary cancers, I suspect you are as bewildered as I am these days. With so many labs offering BRCA testing post Association for Molecular Pathology v. Myriad Genetics, Inc. it is difficult to know which labs best serve our patients in terms of value, reliability, insurance coverage services, clinical support, and quality assurance. Familiar labs are offering new tests and unfamiliar labs are offering testing at Costco prices. Not to mention various law suits and counter-suits over BRCA testing that make me worry that some judge somewhere is going to tell a lab to put all of its testing on hold, leaving patients’ test results in legal limbo.

But what really has me confused – and not a little bit upset – are the new multi-gene cancer panels.

The advantages of the multi-gene panels are obvious. They are cost-effective. They help avoid pondering “Gee, that family really could have been a Cowden. I really should have run PTEN” into the sleep-disturbed wee hours of the morning. Panels will also probably result in significant syndromology reassessment. If you offer PTEN testing only to families who look like they  have Cowden syndrome,  you lose much of the true clinical variability of the condition. And, with all respect and apologies to Robb Pilarski,  Cowden syndrome is in serious need of re-assessment.

Savvy patients are beginning to demand multi-gene panels because they read about them on the Internet or heard about it at their support groups. And I would not be at all surprised if DTC marketing of gene panels starts to rear its ugly head along side the tadalafil, cyclosporine, ibandronate, and eszopiclone commercials that run during the evening news.

So what’s not to like about  multi-gene panels? Let’s face it – many of us are just plain bored with BRCA testing. Panels all cost about the same price, and not terribly more expensive than just running BRCA1/2. Woe to a clinic that only offers BRCA1/2 testing when their crosstown rival routinely offers multi-gene panels to everyone. And who wants to look like an out-of-it fuddy dud who only offers a test developed in the previous century? Isn’t it great to have a choice to run a 6 gene panel, a 16 gene panel, a 26 gene panel, or a 49 gene panel to suit the needs of patients and clinicians? You just choose the panel that’s right for the patient.

And therein lies the rub. How do I know which panel is right for my patient? Labs offer little in the way of clarification as to why certain genes are included or excluded from a panel. From the clinician’s perspective, it seems like the choices reflect the arbitrary expertise of the lab with certain genes, the economic calculations of a given lab, and the desire to out-gun the other labs – why sail a 6 gun sloop when a 40 gun ship of the line can blow it out of the water? In my darker moments, I think that we sometimes choose a lab because a famous geneticist is affiliated with it or a friend from grad school works there.

If clinicians and the labs are honest about it, most of us have little idea of how to guide patients who have a deleterious mutation in genes like RAD51, GEN1, XRCC2. Sure, most labs provide references that might justify inclusion in the panel. But the labs do not cite contrary articles that suggest the predictive power of the particular gene might be low nor do they mention the paucity of publications on the clinical management implications of many of the genes.

There is also a noticeable absence of information on the demographic, clinical, or family history characteristics that might point to one panel over another. Are mutations in one set of genes more common in Russians, Japanese, or Native Americans? Are weak family histories suggestive of one group of genes and strong family histories indicative of another set of genes? What about age of onset? The tumor’s genetic or pathologic profile? Breast only families? Breast and colon families? Clinicians don’t know and neither do the labs.

A step in the right direction will be the pre-conference symposium on gene panels at the upcoming NSGC Annual Education Conference on October 9th. But that is only small bandage on a gushing artery. Bigger measures are needed, and here I offer a few:

1) The key professional organizations – NSGC, ASCO, SGO, etc. – need to form a joint committee that identifies a minimum set of critical genes that should be included on all breast, ovarian, or whatever cancer panels, à la newborn screening. Labs would be free to include whatever additional tests they would like. A joint panel would prevent each society from recommending its own preferred panel that might result in confusingly different recommendations from other professional organizations. Such a panel must take great pains to avoid any financial or intellectual biases.

2) The genes included on the panels should be rated according to their clinical utility and the strength of the data based on an analysis of peer-reviewed publications.

3) Centralized databases should be established for tracking patient outcomes,  clinical and demographic variables, and variants of uncertain significance. Labs that fail to participate in joint databases should be singled out so that clinicians would have the option not to utilize labs that declined to participate in joint registries. While it is important for labs to stay competitive, fiscally sound, and profitable, we can’t lose sight of the core ethical value that the primary goal of genetic testing is to serve patients, not bottom lines. Failure to share data strangles the tree of patient care at its roots.

4) Lab websites should include a balanced discussion of the pros and cons of why each gene is included in the panel – particularly for those genes that are not recommended by the above suggested joint committee – and a regularly updated link to a Pubmed search for that particular gene, not a simple link to one or two articles.

5) The joint committee could also serve an advisory and educational role to health insurers so that patients have equal access to appropriate testing, regardless of which plans cover them.

No doubt The DNA Exchange’s wise and insightful readership have their own ideas, opinions, and recommendations. Let’s hear about them.

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Freud, Kesey, Campbell, And The Case of A Congenitally Unusual Vagina

Vintery, mintery, cutery, corn,
Apple seed and apple thorn;
Wire, briar, limber lock,
Three geese in a flock.
One flew east,
And one flew west,
And one flew over the cuckoo’s nest.

A recent story about teeth grown from stem cells that were extracted from urine reminded me, in the odd ways that brains make associations, of One Flew Over The Cuckoo’s Nest. I first read Ken Kesey’s novel in the mid-1970s when I was majoring in anthropological folklore at Brooklyn College,  a wannabe Joseph Campbell. Kesey’s novel, viewed through my newfound mythological lens, was ripe with primal imagery and mythological motifs . A decade and a career later, I came across a case report in the British Journal of Obstetrics and Gynaecology of a rare congenital anomaly and in a flash my worlds of mythology and genetic counseling merged. And it all starts with a vagina, or more precisely, a toothed vagina.

Three near universal figures in folklore are Trickster, Hero, and the Vagina Dentata. Trickster takes on many shapes and forms and plays different roles in different cultures. A common story involves Trickster disobeying the social rules to upset cultural norms. One could make the case that Bugs Bunny is the culturally distorted Looney Tunes descendant of Trickster Rabbit. Hero is often the Founding Father or Savior of a culture who must overcome a great obstacle or defeat a horrible monster, not uncommonly with the help of Trickster. The Vagina Dentata figure is a female beast – sometimes called The Terrible Mother –  who is endowed with a toothed vagina with which she emasculates and controls men.

As you might guess, the vagina dentata figure is a frequent target of psychoanalytic theory and feminist critiques. Clearly this goes deep into Freudian territory. Some view it as the mythological re-telling of the conflict between patriarchal and matriarchal societies. Females are portrayed as monsters because the story is told by male victors.

Set in what was then called an asylum  for the insane in Oregon, the plot centers on Randle Patrick McMurphy (better known to many of us as Jack Nicholson), Chief Bromden, and Nurse Ratched, the three geese of the rhyme’s flock. McMurphy/Trickster wreaks havoc by commandeering boats and buses, and generally irritating Nurse Ratched by flaunting her rules that give her absolute control of the inmates. As Nurse Ratched describes McMurphy to a co-worker: Sometimes a manipulator’s own ends are simply the actual disruption of the ward for the sake of disruption.

Chief Bromden is Hero, a big man whose large size is a phallic symbol and inability to speak is a manifestation of his impotence and domination by Nurse Ratched.

Nurse Ratched is the Vagina Dentata. A ratchet wheel is a toothed wheel (okay, the spellings aren’t exactly the same, but give Kesey some literary license here) and cuckoo’s nest is an old slang term for vagina. Chief describes Nurse Ratched’s  monster-like qualities:

She’s going to tear [them] limb from limb, she’s so furious. She’s swelling up, swells till her back’s splitting out of the white uniform and she’s let her arms section out long  enough to wrap around the three of them five, six times. She looks around her with a swivel of her huge head…and she blows up bigger and bigger, big as a tractor….

Later, McMurphy discusses Ratched with another inmate:

Inmate: She’s not some kind of giant monster… bent on sadistically pecking out our eyes.

McMurphy: No, buddy, not that. She ain’t peckin’ at your eyes. That’s not what she’s peckin’ at.

Inmate: Not our eyes? Pray then, where is Miss Ratched pecking, my  friend?

McMurphy: At your balls, buddy, at your everlovin’ balls.

With his slyness and fondness for breaking rules, McMurphy gains Chief’s trust by sharing a pack of gum and gets him speaking again , symbolically restoring Chief’s phallic potency.

Later in the novel, McMurphy recruits some prostitutes to help release the sexual repression of the stuttering Billy Bibbit. Nurse Ratched discovers the shenanigans and humiliates Billy by threatening to tell his mother. Subsequently, the shamed Billy commits suicide for which McMurphy blames Nurse Ratched. Enraged, McMurphy chokes Ratched and ripped her uniform all the way down the front, screaming again when the two nippled circles started from her chest and swelled out and out, bigger than anybody had ever imagined, warm and pink in the light...

McMurphy’s punishment for the assault is lobotomy, the symbolic equivalent of castration for Trickster whose power lies in his wits. Chief, his vitality restored by McMurphy, smothers the lobotomized McMurphy (a half century before Oregon passed its Death With Dignity law), rips a control box off the floor, smashes a window, and escapes to freedom, Hero resurrected.

Of course, this is only one of many ways of reading the novel. Did Kesey have mythological motifs in mind when he formulated the novel? That’s unknowable, but if folklorists are right, mythology is always on our minds. The tales that emerge from writers and storytellers tap into deep subconscious wells. The sexual and power conflicts within our minds and our society play out in our stories; we can’t help but tell these tales.

It is not surprising that congenital anomalies and genetic disorders can play mythological and religious roles that range from sacred to profane. Congenital alterations of the flesh may be transformed into hero or beast. It’s hard to say if an actual toothed vagina is the source of the mythological figure, but even the rarest encounter (although ovarian dermoid cysts not uncommonly contain teeth) with this anomaly would likely have left a deep and lasting impression. As Chief says, “It’s truth even if it didn’t happen.”

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Albatross

Ah! well a-day! what evil looks
Had I from old and young!
Instead of the cross, the Albatross

About my neck was hung.

And till my ghastly tale is told,

This heart within me burns

He went like one that hath been stunned,
And is of sense forlorn:
A sadder and a wiser man,

He rose the morrow morn.

- Excerpts from The Rime of The Ancient Mariner, by Samuel Taylor Coleridge

Eugenics. I can hear the thud as the collective eyes of genetic counselors roll heavily at the mention of the E-word.  That finger has been wagged in our faces ad infinitum. Alright already, we have learned our lesson from this shameful past. That was like more than half a century ago. Do we have to still keep apologizing for something we never did? Enough with the hand-wringing and perseveration. We’ve smoked this one down to the filter.

Well, no, apparently we are not done. As historian of medical genetics Nathaniel Comfort has pointed out in a recent thoughtful Genotopia blog (with an equally thoughtful commentary by Alex Stern, the biographer of our profession), eugenics discussions are back with us. We need to keep having the discussion because apparently we are not sadder and wiser people this morn. Some even think – with great hubris, in my view – that with our supposedly greater wisdom and technological advances, maybe some version of eugenics is not such a bad idea after all.

I am not going to repeat Nathaniel’s and Alex’s arguments here; visit the Genotopia blog and read the originals. What I want to do is to offer a  framework for thinking about the issues raised by these historians and introduce the concept of genetic discrimination into the mix.

Genetic discrimination, in my definition, is discrimination based on a person’s presumed or actual genotype and it’s presumed or actual phenotypic expression. The word discrimination comes from  the Late Latin discriminationem, meaning “to make distinctions” and can have both negative and positive connotations. Racial and gender discrimination that results in suffering and inequity is bad. But a discriminating person is one who shows great taste for fine things. Not to try to dance too many angels and devils on the head of this pin, but perhaps when discrimination has a negative effect, it could be called dyscrimination.

Eugenics, then, can be viewed as a form of negative genetic discrimination, the goal of which is to improve the genetic health (whatever that means) of future generations.

Prenatal diagnosis, the usual aim of eugenic critiques, is not eugenic because it does not try to alter allele frequencies of future generations. Down syndrome is almost never an inherited disorder, and people with Down syndrome rarely reproduce. Prenatal diagnosis is not an attempt at “the self direction of human evolution,” as the 1921 Second International Eugenics Congress defined eugenics.  But from the standpoint of some, prenatal diagnosis is a form of negative genetic discrimination – fetuses are discriminated against because of their genome and the common but inaccurate perception of the Down syndrome phenotype as a backward child with a heart defect but a pleasant personality. Although the insensitive term mongolism is rare these days, the common image of “the Mongol child” has not evolved as much as it should have.

Pre- or early pregnancy screening of parents for mutation carrier status for various genetic conditions, on the other hand, might rightfully come under eugenic criticism since its explicit goal is to improve the genetic health of future generations and to wipe out genetic diseases by preventing the conception of homozygous recessive offspring. Never mind the nonsense spewed forth on some websites; carrier screening usually has very little to do with improving the health and quality of life of babies who are born with genetic conditions. Carrier screening can result in reduced suffering if fewer children are born with life threatening or medically serious disorders but it rarely improves the health of babies who are born with those conditions. Whether this is a “good” or a “bad” form of eugenics, and how commercial laboratories advertise their product, are questions open to healthy debate.

Newborn screening, as it is currently practiced, is not eugenic because its intent is to improve the health of a child by treating the presumed phenotype based on the genotype. Newborn screening could thus be viewed as a positive form of discrimination, albeit one with flaws that we are not comfortable acknowledging . But newborn screening can also be viewed as negative genetic discrimination, depending on the condition being screened for. Some people who are deaf have raised serious concerns about screening newborns for hearing loss.

Genetic screening for adult onset disorders like Lynch syndrome or familial hypercholesterolemia may be positive genetic discrimination. The goal of this screening is to treat the phenotype based on the genotype with the hope of reducing the incidence of serious, life-threatening diseases or to mitigate their effects. Dietary changes, treatment with statins, high risk cancer screening, and surgery are strategies that are offered to people at increased hereditary risk of developing these diseases. Of course, if there were to be widespread preimplantation or prenatal diagnosis for these conditions, then we should rightly raise eugenic questions.

Why make these distinctions? Because the word eugenics has become an angry accusation that ends discussions. The social effects of genetic medicine and genetic counseling should always be open to vigorous scrutiny but the criticism needs to be accurate and sensitive to nuance. Maybe some of what we genetic counselors do is eugenic, and maybe under certain situations, this may not be as terrible as it sounds. And maybe some of what we do is dyscriminatory but not eugenic; we need to understand why it is dyscriminatory so we can do something about it. And maybe lots of what we do is very helpful for many people and not particularly eugenic. To cram all of medical genetics into a eugenic framework prevents any progress from ever being made. The two sides start to resemble Democrats and Republikans in a dysfunctional Congress, never able to engage in meaningful debate. Let’s get this albatross off our necks.

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