Category Archives: Robert Resta

Are We Ready For This?

Recent advances in genetic testing technology have us poised on the brink of a new paradigm of prenatal diagnosis – prenatal screening for all genetic and chromosomal conditions. Okay, not all disorders, but lots. Non-invasive Prenatal Testing (NIPT), whole exome sequencing, and expanded carrier screening are close to being available and affordable to a large proportion of the population. This is the culmination of a trend that began with the introduction of amniocentesis in the late 1960s, followed by ultrasonography, maternal serum screening, microarrays, and cell free placental DNA in maternal serum. From a strictly technical standpoint, each technology, while far from perfect, was an improvement on its predecessors in terms of accuracy, detection, false positive rates, and the range of  detectable genetic conditions.

On the surface, this sounds like progress, and it is, in many ways. These technologies can contribute to the reduction of the incidence genetic conditions, some of which are pretty serious, a long-standing goal of medical genetics since its inception, as Nathaniel Comfort has pointed out. But technological advances often outstrip the ethical and social means with which to appropriately assess, modify, and utilize them in fair, just, and meaningful ways. So I ask these questions of the sage and thoughtful readers of The DNA Exchange: Just because we can perform prenatal screening for nearly everything genetic, should we? Who should be making this decision?

There are many competing and intertwined narratives about the history of prenatal diagnosis. Let me offer one such narrative to provide ethical and historical angles. During the 1970s and early 1980s, amniocentesis was primarily offered to women of “advanced maternal age” because of the well-documented increase in the incidence of trisomy with maternal age. At the time, in the US women 35 and older represented about 5% of the pregnant population, and this group accounted for about 20% of pregnancies with Down syndrome (this statistic has since changed considerably). While such a policy could be viewed as discriminatory and prejudicial against people with disabilities, the goal of the policy did not seem to be the elimination of genetic disability. Rather, the effect and likely the intent of the policy was to level the reproductive playing field for “older” mothers. During the 1970s, women made great strides in expanding their social and economic opportunities and in taking some measure of control over their reproductive lives with birth control and the availability of safe, legal abortion. Women could now readily attend most colleges and graduate schools, had more career opportunities, and did not feel as much social pressure to retire to motherhood after high school. However, one of the perceived obstacles for delayed childbearing was the greater risk of Down syndrome and other trisomies. Amniocentesis removed this perceived obstacle and consequently women felt freer to delay childbearing until such time as they felt that they and their partners were ready.

Over the decades, mission creep worked its way into prenatal screening. With the gradual incorporation of ultrasound and maternal serum screening into most pregnancies, regardless of maternal age, the detection rate for Down syndrome increased, and critics of prenatal diagnosis raised the specter of the theoretical elimination of all people with Down syndrome. While such an outcome never seemed likely for a variety of social, cultural, individual, and economic reasons, that could be viewed as the intent of prenatal screening. But still, aneuploidy represents only a small portion of all genetic and congenital disorders.

But it is a qualitatively different ethical story with universal NIPT and the expanding number of conditions it can screen for, the prospect of carrier screening for hundreds of genetic conditions for all couples, and talk of whole exome screening of fetuses. That is making quite a profound statement to and about people with a wide range of physical and developmental abilities.

We tacitly assume that the majority of pregnant women want such screening at the same time that we offer it to them. Many patients will  assume that because we are offering it, it must be a good thing. Because genetic counselors’ jobs can depend on the offer and uptake of such services, it affects our views and actions in ways that we often cannot fully appreciate or grasp. To some extent, we offer new testing because labs are offering it and because genetic counselors tend to be early adopters of new genetic tests. As much as we like to think that we are objective assessors of genetic technology who always put the best interests of patients first, the complicated human psyche makes for a messier reality. Our perspectives are distorted by being in the center of the storm. Go ahead and disagree with me if you want, but you are by and large wrong. That’s not me trying to sound superior; motivated blindness is a basic foundational principal of human psychology.

Psychological complexity aside, think of this. The medical profession is already doing a less than stellar job of presenting a realistic and unbiased picture of Down syndrome to parents. Remember, too, that more and more prenatal genetic testing happens without the involvement of a board certified genetic counselor and that parents are often not educated about these conditions until after they have received an abnormal test result. Not exactly the best time to seek out and weigh complicated information. Add a few hundred more conditions less common and familiar than Down syndrome, and you can see the makings of a goddamn mess.

So can there ever be an ethical justification for universal prenatal screening of (theoretically) all genetic and chromosomal diseases? Let me offer some suggestions that could serve as a starting point to address this question. One can argue that this framework or one like it should have been in place decades ago. I agree, it should have. I recognize that for people who are opposed to termination of pregnancy under any condition or for some of the staunchest disability advocates, prenatal screening will never be acceptable unless it somehow improves the lives of people with different abilities and their families. But I ask all sides to at least hear me out.

First, many parties should be involved in the discussion about wide scale prenatal testing, à la Cyprus and thalassemia screening. Prospective users, clinicians, labs, ethicists, religious leaders, legal experts, legislators, and most especially the community of people who are affected directly by the conditions in question (let me add “and others” since no doubt I am forgetting some important stakeholders). You will never get everyone to agree on all of the details, but there should be at least broad consensus about the most critical issues among the majority.

Second, more resources need to be devoted to improving the lives of people with genetic conditions and their families. Every newborn should  be able to live full, rewarding, loving, and enjoyable lives as much as humanly possible. This involves large-scale medical, technological, and social innovations and changes. Improving the social attitudes toward disability is a long, slow, frustrating journey but that should not deter us.

Third, related to the above, prenatal genetic testing should also offer some benefit people with the conditions in questions and their families, other than letting them have the same option as everyone else to terminate pregnancies. Right now, people with disabilities and their families get essentially zero benefit from prenatal screening. Or more accurately, very little research has been done to show any benefits.

Fourth, any new technology or test needs to be vetted by those who do not have a vested professional, financial, or personal interest in the technology or test. Intellectual, research, and financial conflicts of interest have ways of distorting our views in subtle ways that we are incapable of appreciating. This is extraordinarily difficult for us to understand and acknowledge (vide supra motivated blindness).

Fifth, better resources need to be developed for parents to become educated about the medical implications of genetic diagnoses, the range of developmental outcomes, the resources available to manage the condition, and the impact on families, particularly in lower socio-economic populations.

Sixth, this information needs to be provided to parents before they decide to enter the cascade of prenatal screening, not after they receive an abnormal test result. Parents have to carefully decide which if any condition(s) is important to their reproductive and family planning.

If all of these recommendations are in place, this will allow parents to make informed choices about whether or not they wish to go down the prenatal screening pathway and for which conditions. For parents who would never consider a termination under any conditions, they should have the option of screening only for those conditions for which prenatal knowledge can help the child and family, with better medical, psychological, or adaptational outcomes. For parents who have carefully weighed these issues and feel that there are certain conditions that they will choose to avoid if they can, then they should be supported in their decisions with safe, legal, and non-judgmental abortion services. For parents who are not interested in prenatal screening, they should be supported in their decision rather than being made to feel like they are sub-standard parents.

We can ignore my plea, just sit back and see what happens. But this would be a big mistake. Although genetic counselors obviously cannot address this issue by themselves, we are in the ideal position to take the lead in organizing, coordinating, and spearheading the discussion. We owe it to ourselves and to our patients.



Filed under Robert Resta

No Great Shakes

Cooties. That dread disease for which there is no effective vaccination. A microbe resistant to all known antibiotics and antivirals. A fourth biological domain – archaea, bacteria, eukarya, and cootia. Cootiensis trumpii, in formal Linnaean taxonomy, is the sole representative of this branch of life. A highly contagious cause of a wide range of medical, social, and psychological ills. The Dreaded Lurgi, to our UK colleagues and Spike Milligan fans. Etymologically, cootie may be derived from kutu, a term for a biting insect in the Austronesian language family, attesting to its pandemic nature. Cooties appear to thrive in certain foods, icky substances like mystery spills on hospital floors, and dropped food not picked up for a few dangerous seconds too long. In the sometimes cruel world of childhood, an unfortunate socially awkward child may be super-infected. During my pre-pubescent years, I was fairly certain that most girls my age were cootie hosts. My sisters sure thought I was a cootie reservoir.


Two virulent strains of Cootiensis trumpii, viewed through an electron microscope.

Cooties may be as old as humanity. Some paleoanthropologists believe that the hand impressions common in many Paleolithic caves actually represent ritual attempts to purify the hands of cooties acquired by the ancestors of modern humans after they interacted with Neanderthals and Denisovans, who in fact may have been wiped out by a devastating cootie plague rather than having been out-competed by our early ancestors (Okay, I admit I just made that up about paleocooties and early humans. But nowadays it is apparently okay to make up facts, just as long as they serve one’s agenda.).

Paleolithic cootie purification rituals?

Paleolithic cootie purification rituals?

All of which brings me to how I greet patients at my cancer genetics clinic. About a decade ago it dawned on me that many of my patients are immunocompromised from their cancer treatment. The last thing they need is to acquire an infectious disease from me. Handshakes have long been known to be a source of microbe transfer between people. So I decided that I would stop shaking hands with my patients when I greeted them in the waiting room. After all, we are supposed to make them healthier, not sicker.

No, I don’t know the likelihood of passing along infectious disease cooties via handshake in an outpatient setting but it is probably not trivial. Yes, I use a hand gel sanitizer but many people use them inadequately. Besides, I bet all that hand sanitizing is selecting for super-resistant cootie strains. Evolution is far more resourceful and clever than we can ever hope to be. Soap and water may be more effective than alcohol gels in eliminating microbes but, honestly, how many of us will sing “Happy Birthday” twice while thoroughly soaping up between genetic counseling sessions? No, I am not a germophobe. Regular exposure to microbial organisms is a good way of keeping my immune system cocked and loaded. Yes, my hospital has policies on minimizing contagion in out-patient settings. For example, the plants in my office must be a minimum distance from patients.

The potential cootie host in my office.

Which is why it strikes me as odd that guidelines do not include a hand-shaking ban; my guess is that hand clasping is at least as likely a source of nosocomial infection as the big old plant in my office. On top of that, many employees come in to work when they are sick with some crud, trying to be conscientious, not inconvenience co-workers, and not screw up patient schedules. “Oh, it’s just a cold and I am past the infectious stage, I am sure” they will unconvincingly say between coughing fits. The road to an office-wide flu epidemic is paved with their good intentions. And not uncommonly there are unstated conflicting tensions between hospital policies encouraging employees to use their sick days and the attitudes of mid-level management who seem to view sick days as abuse of a privilege bestowed by God and only to be used when you are near death or beyond.

I recognize the social importance of the handshake in establishing a trusting relationship between strangers. So I have replaced it with a simple wave and a pleasant smile, which is probably at least as socially effective and friendly as a handshake. Some patients look at me quizzically when I state my no handshaking policy. However, the vast majority become very appreciative of the policy once I explain its basis and most people say “That’s a good idea. I wonder why most healthcare providers don’t do it?” Good question. I think it actually enhances the trust between provider and patient, and communicates that I care about them far more concretely than those hospital advertising slogans that proclaim patients always come first. And for patients who still think I am peculiar after my explanation, well, tough noogies, as we used to say when I was a kid (extreme situations called for the more forceful “Tough noogies on your boogies!”).

Call me old-fashioned, but other forms of greeting, like the fist bump or its two-knuckle modified version called a cruise tap, seem inappropriate in the hospital setting and still involve some degree of skin-to-skin contact. Wearing gloves to shake hands would be just plain old wrong. There are other greetings that do not involve skin contact – the wai in Thailand, eyebrow flashing, sticking out your tongue (Tibet), the Japanese bow, the namaskar of India, the  jumping greeting dance of the Maasai, or particularly among men in Western cultures, that barely perceptible slightly angled up-tilt of the head between two bro’s who sort of recognize each other. But unless you work primarily with specialized patient populations, the regular use of such greetings will probably only lead to awkward misunderstandings between clinicians and patients.


Inspector Clouseau (wanting to know if your dog bites) and Professor Quincy Adams Wagstaff (addressing the faculty of Huxley College) were both frequent users of the flashed eyebrow greeting.

I admit that it felt odd when I first started my no-handshake policy. I sometimes held my hands behind my back to fight the instinctive urge to shake hands. Deeply embedded cultural practices don’t disappear overnight. But after a few months, it became quite natural and I found myself recoiling in concerned surprise when I would see other providers shaking hands with patients. I have even begun minimizing handshaking outside of work; there is always “that bug that’s going around” that I prefer to avoid if I can. The no-handshake policy should not be limited to the cancer clinic. We need to minimize the risk that any patient will get sick from a visit to a medical office, whether or not they might be immunocompromised. No one deserves the cooties!


Thanks yet again to Emily Singh for help with graphics


Filed under Robert Resta

What Is Genetic Counseling?

Until recently, I have felt pretty comfortable calling myself a genetic counselor. I have a graduate degree in genetic counseling, passed a long and difficult certification exam, and I am licensed by the great state of Washington to practice genetic counseling. It’s on my business card, the directory of my office building, and it is my official job title. I have been providing genetic counseling to patients for 33 years. I had not lost a wink of sleep worrying over what to call myself until about two years ago when I started to develop a nagging identity crisis when, on this very web site, my fellow DNA Ex’er Allie Janson Hazell suggested that maybe it is time to re-think if we should be calling ourselves genetic counselors. It was a minor itch at first. But now it’s grown into a persistent problem that I can’t stop trying to scratch, like the mysterious treatment-resistant, psychologically rooted foot disease that afflicted the John Turturro character in the recent HBO mini-series The Night Of.

But let me pose the question differently than Allie did. Why give up a good and beloved name? And I don’t even want to begin to think about the bureaucratic nightmare of rewriting state licensure laws. Instead, maybe, just maybe, it is time to debate whether we should redefine genetic counseling and the genetic counselor’s scope of practice. After all, genetic counseling is what genetic counselors do. If many of the daily activities of genetic counselors are not captured by the current definition of genetic counseling, then perhaps it is time to rethink it.

I acknowledge some personal resistance and intellectual conflict of interest – fellow DNA Ex’er Michelle Strecker and I were part of the National Society of Genetic Counseling Task Force that wrote the modern definition of genetic counseling in 2oo5 and published in 2006 (the first formal definition was published by the American Society of Human Genetics in 1975 ):

Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.

• Education about inheritance, testing, management, prevention, resources and research.

• Counseling to promote informed choices and adaptation to the risk or condition.



I like that definition, with its integration of clinical, educational, and, most critically, psychological aspects of genetic counseling. I am not sure I want to see it relegated to a historical footnote. Paradoxically, it could be that I am subconsciously trying to unconvince myself about the need for a new definition as much I am trying to convince the blog’s readership that it is time to consider updating it.

But I have to admit that maybe the modern definition is not so modern anymore. Genetic testing has become, in some instances, downright cheap. Everybody and their cousins are offering genetic testing. You can even obtain genetic testing, for all intents and purposes, without the involvement of a physician, genetic counselor, or any other health care provider. Roughly one in five genetic counselors works in a laboratory setting. Genetic counselors work as test interpreters, policy advisors, genetic ancestry specialists, insurance advisers, laboratory managers, account managers, sales staff, mutation database curators, laboratory liaisons, report signers, educators, and researchers. There are probably genetic counselors who are performing activities that I can’t even think of or grasp. Although for now we are still largely anchored in the clinic, we are drifting on a professional tide away from it. The definition probably still reflects the activities of many genetic counselors, but it also may not capture what a lot of genetic counselors do in their practice.

Here is the scope of practice for genetic counselors from the website of the National Society of Genetic Counselors (a more detailed listing of genetic counseling competencies can be found at the Accreditation Council For Genetic Counseling):

Genetic Counselor Scope of Practice:

a) obtain and evaluate individual, family, and medical histories to determine genetic risk for genetic/medical conditions and diseases in a patient, his/her offspring, and other family members;

b) discuss the features, natural history, means of diagnosis, genetic and environmental factors, and management of risk for genetic/medical conditions and diseases;

c) identify and coordinate genetic laboratory tests and other diagnostic studies as appropriate for the genetic assessment;

d) integrate genetic laboratory test results and other diagnostic studies with personal and family medical history to assess and communicate risk factors for genetic/medical conditions and diseases;

e) explain the clinical implications of genetic laboratory tests and other diagnostic studies and their results;

f) evaluate the client’s or family’s responses to the condition or risk of recurrence and provide client-centered counseling and anticipatory guidance;

g) identify and utilize community resources that provide medical, educational, financial, and psychosocial support and advocacy; and

h) provide written documentation of medical, genetic, and counseling information for families and health care professionals.

Some of the core questions and issues are, as I see them:

  1. Do the definition of genetic counseling and the scope of practice accurately reflect what goes on in clinics and in other work settings?
  2. Should the definition be broadened such that the very act of genetic counseling incorporates some of the newer activities of genetic counselors? This would suggest that the definition of genetic counseling could include some practices that are not involved with direct patient interaction.
  3. Is the definition still adequate but the scope of practice needs to be reworked? Or is the scope of practice adequate but the definition needs some sprucing up?
  4. How do we not lose sight of the psychological component to genetic counseling?
  5. Distinguishing between genetic counselors (roughly equal to the scope of practice) and genetic counseling (roughly equal to the definition).
  6. Remembering that genetic counseling ≠ genetic testing.
  7. Any definition will have an implicit ethos that needs to be carefully considered. The current definition is clearly centered on the psychological and physical well-being of patients.

Perhaps it is time to create another task force to address these questions and issues. I second Allie Janson Hazell’s suggestion that any such group should be international in scope; North America does not have a monopoly on genetic counseling. Of course, that could lead to an ungodly large committee; Resta’s Rule Of Committees is that a committee’s effectiveness is inversely proportional to its size. Decades of experience have taught me that the maximal effective committee size is five (no, I did not arrive at that number by a rigorous scientific process; it’s just a natural fact revealed to me in a trance one day).

I suggest a tiered process. A small task force, ideally international, investigates these questions and issues, and if the definition and/or scope of practice are found wanting, then they draft a new definition and/or scope of practice. This would then be passed on to a larger committee consisting of several representatives of the major international genetic counseling organizations, who could then choose whether to pass it on to their larger membership for comment.

The task force should include a clinical person, a lab person, and two or three other genetic counselor specialties. Grizzled veterans like me should be kept off this committee. We may unknowingly be too caught up in the old vision, too self-convinced that dammit, we do genetic counseling the right way. This project needs counselors who are early mid-career to late mid-career, the group who are the natural successors to us silverbacks, ancient shamans, and village elder wise women.

The scope of practice does not have to be particularly terse. But the definition should not be too wordy; think of how convoluted and awkward the old ASHG genetic counseling definition was. The current definition is about the right length, and, practically speaking, the definition can stand on the first sentence alone without the bullet points below it. I think that it is a tough act to follow, but sometimes the show must go on.

Oh, and while they are at it, they really should consider changing the wording to the more grammatically correct genetics counselor and genetics counseling. And let me interject another curmudgeonly opinion. I think that there are valid points made by both sides of the “Are they patients or are they clients?” debate, and I personally go back and forth freely. But I pray to God that we never use the phrase “consumers of genomic medicine.” I don’t care what you tell me about the business side of genetics and medicine; we should never label people as primarily income generating entities.

What do the Good Readers of The DNA Exchange think about this? Complete the very unscientific poll below, and share your thoughts in the Comments section.

The NSGC Annual Education Conference – only 2 weeks away – will be an ideal venue to further this discussion. And speaking of the AEC, note the announcement just below the poll about an opportunity to meet some of your favorite DNA Exchange bloggers at the upcoming Annual Education Conference in Seattle.



GCs Got Talent! A Genetic Counseling Talent Show/Benefit For The Genetic Support Foundation At The NSGC Annual Education Conference in Seattle Friday, September 30 at 8:00 PM

An Evening of Music, Comedy, Dance, Storytelling, Arts and Crafts As Performed By Our Very Own Genetic Counseling Colleagues

Meet Some of Your Favorite DNA Exchange Bloggers, Judges Laura Hercher & Michelle Strecker, And The Evening’s Emcee, Yours Truly, Kool Papa Bob!



 Illustrations by genetic counselor Dena Goldberg – “Dena DNA

Do you have a good story to tell or a talent to put on display? We would love to hear from you. There are still a few slots available. Story tellers and performers should email to learn more.


For more information about the event, and ticketing, visit

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Filed under Robert Resta

Miracles, Monsters, And Do-Re-Mi: A Variant Cultural History of The Word “Mutation”

None of us can cast stones for we are all fellow mutants together.

– Herman Muller (1950)

Until relatively recently, mutations were thought to be uncommon events that irregularly popped up around the genome, save for a few hotspots here and there. Unless exposed to a mutagen, DNA was conceptualized as a fairly stable molecule and the individual genome tolerated only a limited amount of variation. But large-scale DNA sequencing has demonstrated that gene mutations are pretty much the norm rather than the occasional exception. For example, a recent as yet unpublished study by Craig Ventner’s team of 10,545 deeply sequenced  human genomes found that each genome contributes on average 8,579 novel variants and uncovered more than 150 million variants in the coding and non-coding regions. If you run a complex genetic test and you don’t find a mutation of some sort, then there is probably something wrong with your sequencing technology. Of course, not all gene mutations are bad. Some are disease associated, some may confer biological advantage, some are neutral, and some are difficult to pin down. Differentiating among the good, the bad, and the neither-good-nor-bad has become a bête noire for anyone faced with interpreting the clinical significance of genetic test results for patients, especially when classifications differ among labs.

Although the word mutation carries some potently negative connotations, its definition implies objective scientific neutrality – “An alteration in the nucleotide sequence of DNA,” in its simplest form. But of necessity this is only a recent, post-Watson and Crick wording that itself has mutated over the centuries and that has often had some not-so-neutral musical, psychological, biological, pop culture, sociological, and religious ramifications. A hop, skip, and a jump through the history of the word reveals the richness and variety of its usage – as well as its darker sides.

According to the Oxford English Dictionary, one of the earliest recorded occurrences of the word goes back seven centuries to – who else? – Chaucer who used it in the sense of a change or alteration and whose Middle English rendered it as mutaycouns (“mutaycouns of fortune” from his translation of The Consolation of Philosophy by the Roman philosopher Boethius). Shakespeare used it similarly when, in King Lear, Edgar cries that the misfortunes of fate shorten our lives “World, World, O World! But that thy strange mutations make us hate thee, Life would not yield to age.”

Mutation was also used to describe the key Catholic belief in the transubstantiation of bread and wine into the body and blood of Jesus Christ during the sacrament of Communion. In the 1426 translation by John Lydgate of the French Cistercian monk Guilaume de Deguileville’s Pilgrimage of the Life of Man, a popular devotional book of the Middle Ages, we read about “That marvelous mutacion, Bred into flesshe, wyn into blood.”  This “marvelous mutacion” is a critical distinction between Protestant and Catholic theology, two religions that seemed to be at war with each other for most of the Middle Ages. Catholics believed that the Eucharist wafer dipped in wine transubstantiates into the actual body and blood of Christ whereas Protestants viewed it as a symbolic and ritual re-enactment of the Last Supper. Presaging future genetic connections between monsters and mutations, Martin Luther referred to transubstantiation as “a monstrous word for a monstrous idea.” During my Catholic school years, I remember joyously singing “Eat His Body, Drink His Blood, and we’ll sing a song of love. Allelu-Allelu-Alleluia!” Leonard Cohen does not have a thing over the Catholic hymnal.

Musically, mutation is the exchange of one syllable for another in an ascending note scale, as in solmization, i.e., associating a musical note with a human sound. Think do-re-mi-fa-so-la-ti-do. Mutation is also used in music to describe changes in singing voice that occur with age and gender, particularly the change that occur in boys’ voices as they transition to puberty, much to the chagrin of many choirmasters of Medieval Europe’s churches (a curiously coincidental link between religion and mutation). Choir boys were faced with a Sophie’s Choice of either genital mutilation or mutation.

Mutation also bridges musical and genetic definitions when DNA sequences are transformed into musical notes. For a couple of hundred bucks you can upload your 23andMe DNA sequence and have it translated into a piano solo, dance music, or a fully scored orchestral work. It’s a little bit funny, but the thing is what I really mean is that it gives new meaning to Elton John and Bernie Taupin’s 1970 hit single Your Song. As a leading candidate for the award of The World’s Worst Dancer, my daughters shudder to think what my DNA would sound like if it were translated into dance music and performed in public. No doubt it would contain many nonsense mutations although my daughters would hope it contains a very early premature stop codon. In a darkly comic coincidence that bridges modern music, Herman Muller’s above quote, and DNA, the musician Frank Zappa named his official fan club United Mutations, supposedly after reading his weird fan mail (think of how unusual the mail must have been if Zappa found it strange). And in another odd connection between mutation’s musical and biological connections, Zappa sounded like Darwin when he proclaimed “Without deviation from the norm, progress is not possible.”

The earliest reference I could find to the use of the word mutation in the context of evolution was in the 1869 publication Die Formenreihe des Ammonites subradiatus by Wilhelm Heinrich Waagen, a German paleontologist and geologist (no doubt somebody used the word before Waagen; there is always somebody else who was “really the first”). Based on his observations of fossil ammonites in the Punjabi Salt Range, Waagen proposed that evolution occurred slowly through minute mutations in a definite direction and that could be observed by careful examination of successive fossil strata, resulting in the eventual emergence of new species (though I think  he was thinking of mutations as anatomic rather than strictly genetic phenomena). Waagen was a devout Catholic who opposed Darwin’s evolutionary model and who tried to reconcile the fossil record with Genesis, suggesting that new species arose through new acts of divine creation

Mutation in its more modern sense arose with the re-discovery of Mendel’s work by de Vries, Correns, and Tschermak-Seysenegg and the flowering of modern genetics and evolutionary theory in 1900. de Vries in particular emphasized the importance of mutations to evolution in his magnum opus The Mutation Theory (1901-03). Gene mutations were now understood to be the engine that drove evolutionary change and chromosomes were thought to somehow carry genes. But the physical nature of mutations remained a mystery that was not resolved until the early 1950s when Alfred Hershey and Martha Chase identified DNA as the “hereditary material” and Watson and Crick famously resolved the structure and self-replicating mechanism of DNA.

Mutations could be adaptive or non-adaptive, though the presumption was that most mutations were evolutionary dead-ends and natural selection genetically purified the population (one can see the natural jump to eugenic ideologies). Creatures that were very different from their contemporaries presumably from underlying gene mutations were sometimes called, in the vocabulary of Richard Goldschmidt, “Hopeful Monsters,” evolutionary opportunities for saltatory speciation through chromosomal level mutations (Hopeful Monster and Hopeful Monsters are also the names of two different musical bands, as well as the title of 1990 novel by Nicholas Moseley). Others thought that hopeful monsters were only hopeful ideas and that speciation occurred through a more gradual dynamic balancing of winnowing and selection of small effect mutations.

Early 20th century eugenicists took the notion that mutations were largely negative and ran with it down some dark ethical alleyways. The “defective germ plasm” of immigrants from anywhere other than certain parts of northern and western Europe, people dwelling in the lower socio-economic rungs, the feeble-minded, and other undesirables made them genetic threats to the hereditarily healthy population. The solution to avoid becoming awash in defective germ plasm was to coercively or non-coercively discourage such genetic riff-raff from producing offspring. Eugenicists also encouraged genetically desirable people to have more offspring but such genetic hopefuls were not said to carry good mutations, just good genes.

The early 1930s saw the introduction of the far more neutral term allele, derived from allelomorph, which was itself introduced in 1902 by William Bateson, who also gave us the word “genetics.” Essentially alleles were versions of the same gene that differed on a DNA level. Although allele is in genetic publications, it has never really entered into the wider public vocabulary and discussion around genetic variation.

The geneticist Herman Muller had a career-long interest in genetic mutations, starting with his work with Drosophila in Thomas Hunt Morgan’s Fly Room at Columbia University and continuing with his Nobel-winning work on radiation induced mutations. His work, perhaps more than any other, was critical in the development of the idea that mutations were primarily harmful. In his influential 1950 American Journal of Human Genetics paper “Our Load of Mutations,” he viewed mutations as a “load” that the human species had to bear. However, he thought that most mutations were only slightly disadvantageous, and that each of us carries 8 slightly harmful mutations. Each mutation carried a selective disadvantage of 2.5%, and thus on average each person has a 20% chance of death or reproductive inefficiency as a result, under the assumption that humans were still living in the Neolithic. Muller worried that the comforts of the modern world allowed more maladaptive mutations to survive and increase, and that environmental exposure to ionizing radiation increased the frequency of  new mutations. This problem could be ameliorated by reducing the amount of man-made ionizing radiation and discouraging reproduction among those who carried the most mutations, “only” 3.5% of the population in his reckoning. Theodosius Dobzhansky served as a counter-point to Muller, arguing that variation was mostly adaptive and we should embrace the social and genetic diversity brought about by mutations (Muller’s paper and his disagreements with Dobzhansky are thoughtfully discussed in historian of biology Diane Paul’s 1987 paper “Our Load of Mutations” Revisited and is my primary source here).

Thus until about 60 years ago, with a few exceptions, mutations were largely viewed as having negative effects, while recognizing that some portion must be positive to allow adaptation and evolution to occur. Other than synonymous mutations in which the amino acid sequence is not altered, the notion that a mutation could have no phenotypic effect was not seriously discussed because mutations could only be inferred by their phenotypic effects. But in the 1960s, Motoo Kimura, among others, suggested that, based on studies of protein evolution, the rate of nucleotide substitutions was so high that it was difficult to believe they all had a positive or negative phenotypic effect. He felt that most mutations were neutral, that is, they have no measurable phenotypic effect and genetic variations among populations were largely the result of genetic drift, influenced by population size and dynamics. Mutations are like algae floating in the gene pool, pulled by the stochastic and unpredictable tides of populations

In Pop Culture, public fear of mutation arose in the context of the post World War II threat of nuclear war and the potential subsequent widespread exposure to ionizing radiation. Mutants in the public conception were typically monsters or super-humans with special powers that could be a blessing and/or a curse. Godzilla, The X-Men, the backwoods Southerners of  Deliverance, certain zombies (though apparently there are some finely nuanced arguments about the distinction between mutants and zombies), Spiderman, and the Hulk all owe their unique characteristics to mutations induced by radiation or inbreeding. For the most part, you don’t want to be these creatures. While it would be pretty cool to web-sling through the upper reaches of Manhattan’s skyscrapers, hulk-out to frighten off bad guys, or maybe even level a city or two, the message is almost always that being a mutant comes with the Faustian price of giving up the soul of your humanity. In conversation, to label someone a mutant is to suggest that they are very different, and usually in not such a good way. Even when used in a sort of positive context to describe super-athletes who seem to function on a different level than their competitors such as LeBron James, Diana Taurasi, Babe Didrikson Zaharias, Babe Ruth, Wayne Gretzky, Florence Joyner, Michael Phelps, or Diana Nyad, its use suggests that they are a different species from the rest of us, “freaks of nature” (ironically echoing the centuries old terminology “sports of nature” to describe biological specimens whose anatomy deviated significantly from the species type).

Not surprisingly, for many patients in genetics clinics, discovering that they carry a mutation, even in a recessive form, can be a narcissistic ego blow and affect desirability as a mate. If you carry a mutation you are implicitly a mutant. Connotations of the word mutation contribute to fears of having children with disabilities. Currently in medical genetics, and probably for the better, mutation is falling out of favor and there is a trend to replace it with a more neutral, or least less negative, terminology. Mutations are now described as variants that are categorized by qualifiers – benign polymorphism, uncertain significance, deleterious/pathogenic, etc. Although this nicely delineates the multiple effects and uncertainties of mutations, it doesn’t necessarily suggest that carrying a mutation is a good or normal state of affairs. And carrying a pathogenic variant, even a likely pathogenic variant, usually doesn’t make you feel too good about yourself when you wake up each morning and look at yourself in the mirror.

Mutations also cause much fretting and hand-wringing on the societal level. Witness the controversy around genetically modified organisms and worries that Frankenstein-like plants or animals will take over the environment like some real-life mutation, er, variant, of Day of The Triffids. Even CRISPR-Cas9 and other gene editing systems, which are intended to fix mutations, are criticized because of fears that they may unknowingly induce undesirable mutations in non-targeted parts of the genome.

At the end of the day, mutations are part of our biological identity. They are literally etched into our DNA, although we would be ignorant of the existence of most of them in the absence of DNA sequencing technology. None of us are Wild Types and all of us are Wild Types. We should embrace mutations, not reject them (well, at least most of them). Mutation is the norm for life, not the exception. Despite their typical neutrality, fear of mutations has been used to justify religious wars, castration of pre-pubescent boys, sterilization of the “unfit,” and to engender deep-rooted psychological fears in parents and in societies. Muller and Zappa were both right – we are all mutants and we should be united. But it turns out that being a mutant is usually not such a bad thing.

For an excellent short review of the concept of mutations in the history of biology, see Mutation: The History of An Idea From Darwin To Genomics by Elof Axel Carlson, Cold Spring Harbor Laboratory Press, 2011. Once again thanks to Emily Singh for help with graphics. 


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Who Decides?

The past decade has seen an evolution in the way that new genetic tests become incorporated into clinical practice. Historically, genetic tests such as amniocentesis, CVS, AFP screening, newborn screening, and ethnic-based carrier screening were introduced after undergoing government-funded studies conducted by academic and clinical institutions. This research was typically supplemented by exploration of the ethical and socio-economic issues generated by new technologies and engaging the principal players in the at-risk community in open discussion. This may have resulted in a slower clinical integration of novel technologies but the net result was better patient care because the technology’s strengths, limits, and ethical and socio-economic implications were more clearly defined before the testing was offered routinely. Not to say that this approach was perfect. Recall the problems that arose when sickle cell carrier screening was introduced only to become entangled in the thorn-bush of racial politics and racial history.

Commercial interests played less of a role in such decisions in part because the tests generated lower profits due to their labor-intensiveness (think about the time spent in counting chromosomes and hand cutting and pasting karyotypes or running Southern blots), had limited target populations due to the rarity of most genetic disorders, and could be costly. There just weren’t that many large-scale genetic testing labs out there.

Now, however, genetic testing is cheaper, more profitable, less labor-intensive, and has a wider proposed target population – every pregnant woman, many people with cancer or who are at hereditary risk (maybe only 10% of breast cancer patients are appropriate candidates for hereditary testing but most of those patients have a lot of relatives), every woman, and, as with the aim of some direct to consumer (DTC) tests, everyone. Genetic labs pop up left and right, merge, expand, are bought out, and otherwise engage in business. Twenty years ago, trying to find a lab to run a genetic test could involve hours of detective work and secret word of mouth sources. Now labs are knocking on our doors cajoling and pleading for our patients’ samples. While most labs are deeply concerned about patients and are well-intentioned, they are also equally concerned about profits. Money-making, after all, is why businesses exist so it is no surprise that labs have started to take a more active role in introducing new genetic tests. This is not a phenomenon peculiar to genetics. It has been going on in medical care for decades, and genetics is just starting to catch up. It is also reflective of the growing trend in the health care industry to refer to patients as consumers of medical care and to implement customer service based patient care models.

Several genetic tests come to mind here – expanded carrier screening, offering noninvasive prenatal testing (NIPT*) to low risk pregnant women, multigene cancer panels, and SNP-based DTC testing. These tests worked their way into patient care after aggressive sales tactics and questionable advertising claims helped amplify the demand. This was further driven by competition between clinics to offer the latest and greatest tests to their patients, the general eagerness of genetic counselors to seek genetic answers for their patients, and patient word-of-mouth networks. About the only counter-balance has been a reluctance on the part of health insurers to cover new and unproven testing. Most of my patients want that new genetic test but only if their insurance company covers it, although low-cost labs like Color Genomics are challenging this limitation.

To some degree, patients can benefit from these tests but not necessarily to the extent that one might think. 23andMe states that their product should not be used for clinical decision-making – at least for now – while at the same time offering “wellness reports” and “genetic snapshots of your health.” This sounds to me like clever ad copy to deflect regulatory concerns about health claims while at the same time suggesting that the product is an important aspect of everyone’s medical care. Supporters of expanded carrier screening acknowledge its limitations in terms of  studies on net health benefits and cost effectiveness but still offer the test routinely and subtly suggest that the test is standard when they claim that they work directly with a network of over 6,000 health care professionals. NIPT may soon become an appropriate test for all pregnant women, but this conclusion should be driven by independent studies conducted outside of the commercial sector. Multigene cancer panels have shown some benefits, but not nearly as much as many clinicians had hoped for.

I am grateful for the valuable contributions that labs have made to patient care. Quicker turn around times, incredible help with verifying insurance coverage, and highly knowledgeable genetic counseling staff who happily share time and considerable expertise in interpreting complicated results. 23andMe provides far better patient education materials than any single genetic counselor or clinical institution or professional organization could ever hope to create. And 23andMe was several steps ahead of everyone in facilitating patient connections to researchers and each other as well as when the company made raw data available to consumers. I never anticipated that patients would have wanted such level of detail. Along those lines, note the recent complaint filed wit the Office of Civil Rights against Myriad in which several patients assert that their HIPAA rights were violated because they claimed that Myriad would not share all of the genetic variants that were detected, including those that are considered benign or clinically insignificant. Clearly I am still time-stuck in the era when couples were ecstatic to receive a karyotype of their unborn baby and I can’t remember a single patient requesting records of all their amniotic fluid metaphase spreads and cell counts.

Of course, introducing new tests before they are ready for prime time is just part and parcel of living in a market driven society. The context is much larger than the genetics niche or even medical care in general. Labs and competitive clinics should not be faulted for engaging in behavior that is widely condoned elsewhere. Nor should all blame be placed squarely on the shoulders of labs. Everyone needs to be engaged in this process. It is not just the buck dancer’s choice, my friend. Labs can put the brakes on new tests a bit. Clinicians and labs need to form better relationships while tests are in development. Labs need to step back while independently funded research verifies claims of accuracy. Governments need to step up funding for such research. Clinics need to fend off marketing pressures to prematurely offer the newest tests to patients. Communities need to be involved in the process. We all need to work harder to dispel the myth that genetics is destiny and that DNA is the blueprint for our humanity. Labs need to be fully transparent with their data even if it means sacrificing some basic business principles of corporate secrecy.

The explosive growth of lab positions for  patient-focused genetic counselors – roughly 20% of genetic counselors are employed by labs, according to the 2016 Professional Status Survey of the National Society of Genetic Counselors – can help implement a wiser policy on test development and introduction into medical care. Of course, as I have mentioned previously (ad nauseam, according to some) genetic counselors will need better training to navigate the murky, complex waters of conflict of interest.

Labs, clinicians, and patients need to recognize that market forces don’t have to be the only engine that drives policies on test development and introduction into clinical practice. We are talking peoples’ lives here, not trying to outmaneuver Pepsico’s Cheetos in the market niche for snacks that you can’t seem to stop eating, even when your hands and mouth turn that peculiarly unnatural orange color (did you know that there are 21 different types of Cheetos on the market? Cheetos Sweetos, however, has been discontinued.). Innovation can be wonderful, exciting, and improve medical care. Let’s just do it wisely.


  • – actually it would be more accurate to say that the P in NIPT stands for placenta. It is not really cell free fetal DNA; it’s cell free placental DNA.


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Appearances Are Important

About two months ago a story about conflict of interest in the Boston Globe caused a bit of a kerfuffle in the genetic counseling community. The article reported on the experiences of some pregnant women who felt that financial conflict of interest on the part of a few genetic counselors had resulted in the patients being given misinformation about the results of their non-invasive prenatal testing (NIPT). The counselors mentioned in the study had either received speaking fees from the lab where the testing had been performed or was an employee of a lab.

In my reading, the source of the patients’ understandable frustrations stemmed not so much from conflicts of interest on the part of the genetic counselors as it did from misunderstandings on the part of the patients and their physicians about the distinction between the false positive rate and the positive predictive value of NIPT. These two very different statistical measures can easily be confused with one another and this confusion has haunted maternal serum screening since AFP screening for spina bifida was introduced in the early 1980s (we sometimes used to darkly joke that the A in AFP stood for Anxiety and the F stood for an impolite word that would be familiar to Boston Red Sox fans when they describe their nemesis Bucky Dent). Providers and patients often incorrectly interpret a false positive rate of, say, 0.2% to mean that a positive test indicates a 99.8% probability the baby will be affected with the disorder in question. Who would not be anxious if they were convinced that there was over a 99% chance that their baby has a potentially serious health condition?

I am sure that the genetic counselors in the story understood the distinction between positive predictive value and false positive rates, and tried very hard to convey this to the patients. These counselors are well-respected and highly ethical colleagues. Really, they could have been any of us. We all have been in these counselors’ shoes and we were all feeling their pain – as well as the patients’ pain – when we read the story. Did some blind spot on the part of the genetic counselors not allow them to see how their counseling may have been influenced by an unacknowledged conflict of interest? Perhaps, and that is a point worth considering seriously. But as every genetic counselor knows, the anxiety and emotional fragility of couples faced with threatening information, particularly during pregnancy, usually dominate genetic counseling sessions and can result in patients coming away with a less than perfect comprehension of statistical fine points. We humans are emotional creatures, not Vulcans.

I think that the evidence for overt financial conflict of interest on the part of these genetic counselors was not strong. The counselors were certainly not exploiting these patients “for personal advantage, profit, or interest,” in the words of the Code of Ethics of the National Society of Genetic Counselors (NSGC). My guess is that the concern about conflict of interest arose from at least one of the patients not finding out about the counselor’s relationship with the lab until afterwards (from the article it is not clear if at the time of genetic counseling the patient was aware of the counselor’s financial ties to the lab but it seems that she learned about it only later).

And therein lies a critical point about conflict of interest – the appearance of financial conflict of interest can be just as corrosive as actual conflict of interest. Grumble though we may about the article, by bringing this to our attention, the reporter, Beth Daley, performed an important service for genetic counselors and our patients and we should be thankful for it. Public trust in our professional skills and judgement can be seriously compromised if patients perceive us to have a financial conflict of interest. Unless we openly and honestly confront conflict of interest in all its many forms, rather than deny its existence or ignore its potential, problems and misconceptions stemming from the appearance of conflict of interest will only worsen. And, possibly, a more blatant financial conflict of interest scandal may one day rear its ugly head (it would be astonishingly naive to believe that “It can’t happen here.”).

So how can the NSGC and individual genetic counselors help reduce the appearance of conflict of interest? We should be in the vanguard of addressing financial conflict of interest and demonstrate that we take it seriously. To this end, I have one concrete suggestion – the on-line NSGC directory of genetic counselors should include voluntarily provided information about the financial relationships of genetic counselors with any company other than their employers. And the directory should also clearly state who the employer is in situations where genetic counselors are employed by labs but working in hospitals and providers’ offices. While we are at it, maybe the American Board of Genetic Counseling should also consider doing this with its directory of certified genetic counselors. The Affordable Care Act requires this of physicians but for now the law does not apply to genetic counselors.

I am guessing that this suggestion might not immediately sit well with some of us. But once you get past your initial reaction and think about it a bit more clearly, it is a simple and powerful idea. It is also consistent with Section 1 of the NSGC Code of Ethics, which states that genetic counselors should:

Acknowledge and disclose circumstances that may result in a real or perceived conflict of interest.
Avoid relationships and activities that interfere with professional judgment or objectivity.

Actions are more powerful than words. Voluntarily including this information in the NSGC directory demonstrates that genetic counselors recognize that conflict of interest is a real problem and that we are not sitting around waiting to do something only if some federal law eventually requires us to do so. It allows patients to learn beforehand about a genetic counselor’s financial ties and gives patients the opportunity to discuss it openly with counselors. Or, if patients are so inclined, they can seek an alternative counselor or a second opinion.

Transparency is always the best policy – for us and for our patients.


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Everyone’s Worst Nightmare

The story that I tell here is, I know, a one-sided tale. It is also the source of pending litigation. A friend of a parent of the child reached out to me to ask me to share the story with the genetics community with the hope that some good could come out of a terrible experience, and did so with the approval of the parent’s lawyers. I obtained the details from publicly available records. I am not passing judgment on who was right, who was wrong, who did what, and who didn’t do what; the lawsuit will rule on that. I have had no involvement with the care of the patient or the subsequent legal wrangling, nor do I have any particular expertise about the disorder in question. For months I have struggled with whether the DNA Exchange is the appropriate venue for this, but ultimately decided that the family’s voice needs to be heard. I have largely anonymized the story because, really, specific names and diseases do not matter. What matters is that steps need to be taken to help ensure that other patients, families, providers, and laboratories do not repeat this sad tale.

The child was born about a decade ago, the product of an uncomplicated, happy, and desired pregnancy. At a few months of age, the child developed seizures after receiving a routine vaccination and went on to experience ongoing seizures of differing types. Various diagnoses were entertained particularly mitochondrial diseases and treatment included standard anti-seizure medications. A number of specialists were involved with the child’s care, including geneticists. Early on in the work-up genetic testing identified a mutation in a gene linked to a disorder that would explain the child’s seizures, a finding which the lab interpreted as a variant of unknown significance (VUS). Based on available literature at the time, there was some reason to believe that the variant might be a pathogenic mutation – it had been reported in affected patients –  but determining the clinical significance of a gene mutation is a problem that continues to plague genetic testing today.

Now here is where the story gets complicated and fuzzy, and to me where the tragedy starts to unfold. Apparently, the physician who ordered the test decided that the genetic test result was inadequate to help establish a definitive diagnosis, and pursued other diagnostic possibilities. As far as can be gleaned from the records, the genetic test results were not shared with the family although some of the treating physicians had considered the diagnosis on clinical grounds. The child continued to be treated with medications that, unfortunately, worsen the seizures for the condition that the child was ultimately diagnosed with – a condition caused by mutations in the gene in which the VUS was found. Sadly, the child died a few months shy of 3 years old from intractable seizures likely related to the contraindicated seizure medications.

The family did not find out about the genetic test results until about 7 years after the child died and only then after a parent requested the results. A few months later, the lab produced a revised report that reclassified the variant as a disease-associated mutation. Curiously, the report does not contain a revision date nor does it include the reasoning or data that led to the revised interpretation.

On one level, this story tells the genetics community nothing it did not already know – interpreting the clinical significance of a VUS is a terribly complicated and at times subjective affair. There is no single gold standard that can be used to determine clinical significance, which involves complex statistical, genetic, and biological analysis. Two equally capable labs can look at the same set of data and come up with diametrically opposite conclusions. Articles address the frequency of variants in genetic testing and differences in interpretation, along with providing an idea of the scope of the problem. But statistics are not stories. Stories convey the human impact of statistics and the urgency of the problem. As the saying goes, one death is a tragedy; a million deaths is a statistic (attributed to, of all people, Joseph Stalin).

Public databases such as ClinVar are starting to address this problem but they are still in their infancy. Indeed, a recent check of ClinVar revealed only one entry for the variant in question and the entry doesn’t even classify the variant. As human genome testing is ordered at exponentially increasing rates, the need for a uniform approach to genetic test interpretation and data-sharing is beyond pressingly critical. Restrictive gene patents and data hoarding may be good for business but they are not good for patient care. Lots of money will be made through genetic testing; some portion of those profits need to be channeled to funding well-curated freely available databases ( a database that is not well-curated is useless, and potentially harmful). Perhaps there could be tax breaks for labs that share data and government funding could favor research projects utilizing labs that share variant data.

But this story highlights other potential weaknesses in the genetic testing process. Parents and patients need to have pre-test genetic counseling so they are clearly informed when genetic testing is ordered. Results need to be explained to patients, even if they are uncertain. This is no mean feat, especially when a patient is going through an extensive work-up and many tests of all varieties are being ordered. Results have to be clearly available in medical records so all providers can have ready access to them, and patients should always have a copy of their test report made available to them along with an explanatory letter. A letter to the family summarizing the results could have prevented a lot of anguish for this family. There must be good mechanisms in place to regularly update test interpretations and for those updated interpretations to be communicated clearly and without delay to providers and patients. Patients should be encouraged to actively participate in seeking more information about their genetic test results and to enroll in centralized databases such as PROMPT. Maybe labs should allow a random sample of their report interpretations to be audited by an unbiased third party such as the College of American Pathologists to assure adherence to test interpretation guidelines. This could be a voluntary program but labs may be eager to participate as a selling point of their commitment to accuracy. Governments and insurers must allot the funds and resources for all this to take place.

The outcome here was the worst possible for everybody – most especially the patient and the patient’s family, but also no lab and no care provider ever wants something like this to happen to a patient. It haunts us all. If any good can come out of this, then this story will inspire us to work with greater urgency and cooperation to create workable solutions. Our patients deserve no less than the very best.

This posting is dedicated to the memory of the child whose all-too-short life is discussed here.


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