Tag Archives: whole genome sequencing

A Diagnosis Is Not The End Of The Odyssey

by Robert Resta, Jennifer A. Sullivan, Allyn McConkie-Rosell

Allyn McConkie-Rosell, Ph.D., CGC, is a Professor in the Division of Medical Genetics at Duke University Medical Center. Jennifer A. Sullivan, MS, CGC is a
Senior Genetic Counselor in the Division of Medical Genetics at Duke University Medical Center. Robert Resta, MS, CGC, is a genetic counselor at Swedish Medical Center in Seattle and a frequent contributor to The DNA Exchange.

The Diagnostic Odyssey – that meandering, lengthy, and frustrating quest for a diagnosis. Genetic counselors, medical geneticists, and patients with rare disorders and their families are achingly familiar with it. The allusion to Homer’s Odyssey is apt. Odysseus’s decade of wanderings are replete with perils, disappointment, love, wonder, whimsical gods, adventure, and frustration. Surely some specialist somewhere in the world can tell me what condition my child has been born with, and I will brave the wine dark seas for as long as I must to find that expert! Genetic testing technologies like whole exome/genome sequencing have shortened the quest for many patients, though perhaps not as often as one would have hoped.

The label Diagnostic Odyssey suggests that the diagnosis is the end of the odyssey. And therein lies the problem. Many families and patients discover that a diagnosis does not necessarily allow them to settle down happily with Penelope in the kingdom of Ithaca. A successful diagnostic workup may be the end of the odyssey for clinicians, but for patients and families the diagnostic quest is just one phase in the life cycle of genetic disorders.

A diagnosis may answer some questions such as cause and recurrence risk, but it can also create a whole new set of issues. For patients diagnosed with ultra-rare conditions, families may be faced with frustration from a lack of available knowledge about treatment or prognosis. Even if medical interventions are possible, finding and accessing those resources, and getting health insurers to pay for them, can be a major undertaking. Or a condition’s rarity may make it impossible to form an effective patient/family community to provide advocacy and support. The diagnostic odyssey may result in some patients feeling like diagnostic oddities.

If a newly diagnosed syndrome turns out to be untreatable or life-shortening, parents may lose all hope and descend into existential despair. A non-diagnosis at least holds the glimmer of a chance for a treatment or cure out there somewhere. Patients who have a diagnosis changed from a previous incorrect diagnosis may lose the sense of identity and support supplied by the disease community that they had been involved with for years.

The label Diagnostic Odyssey focuses on one medical aspect of a condition. Clinicians can take much-deserved professional satisfaction in having finally solved a long-standing mystery. But for many families, living with a genetic condition is not a temporally demarcated event and, above all, not only a medical experience. Patients will also still need to implement strategies and solutions to the social, educational, lifestyle, and psychological ramifications of the disorder. It is an ongoing journey, one that continues to unfold as patients age and develop new symptoms, family structures evolve over time, medical treatment advances, and sociocultural changes re-shape attitudes toward inclusivity and the availability of resources. A genetic condition, named or not, will continually present new challenges throughout the entire life of a patient.

We do not mean to imply that a diagnosis is unimportant. We recognize the emotional and potential medical value of finally “putting a name on it.” But the name just points the ship in a new direction to unexplored regions with different threats, problems, and rewards.

Perhaps the Diagnostic Odyssey label needs to be retired or renamed to more accurately reflect its role in the process of living with, and adapting to, genetic conditions. So we turn to the Good Readers of The DNA Exchange to offer their suggestions – what do you think?


Genetic Counselor Talent Show Friday, November 16th

Are you attending the 2018 Annual Education Conference of the National Society of Genetic Counselors in Atlanta next week? Worried that days of  PowerPoint presentations and polite applause will make you forget what fun is? Want to have a blast one evening and see your genetic counseling colleagues in a very different light? Then attend the Genetic Support Foundation’s GC’s Got Talent  2018 genetic counselor talent show on Friday evening November 16th. Cancel all your other evening plans for Friday, November 16th. Trust me – there will be nothing even close for entertainment. With Yours Truly, Bob Resta, as Master of Ceremonies, how could anything beat it? Can you dance, sing, or play an instrument? Are you a Slam Poet? Then show off your talents to your colleagues! Or, if like me, you have Zero Talent, then join me as part of the Story Telling Crew. I have a goofy and weird story to tell. But we all also have poignant, tragic, comic – or all of the above – tales to tell. If I can do it, then you can do it. If you wish to impress your colleagues with your talent, send an email to info@geneticsupport.org to sign up. Show up et regarder les bon temps rouler.

For more information, visit: https://geneticsupportfoundation.org/gc2018

 

 

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Do I Really Have To Tell Them? Duty To Recontact And Variants of Unknown Significance

Duty to recontact (DTR) is one of those principles that on Mondays, Wednesdays, and Fridays I feel should be an unquestioned standard of care. On Tuesdays, Thursdays, and Saturdays, the practical part of me prefers to sweep it under the ethical rug (on Sundays, I give it a break and enjoy a wee bevvy of single malt Scotch). The devil lies in the details of time, effort, unremunerated cost, and frustration involved with trying to notify patients of significant re-interpretations of test results or the availability of new testing technologies. A recent systematic review of DTR by Ellen Otten and her Netherlandish colleagues concluded that, broadly speaking, patients value being recontacted whereas clinicians feel that DTR is desirable but impractical.

I was surprised to learn that the American College of Medical Genetics is the only professional organization that has issued a formal statement in support of DTR, initially in 1999, with an update in 2013 specifically addressing clinical exome sequencing and clinical genome sequencing (Readers, please let me know if I am mistaken). I am not aware of case-law or legislation that mandates DTR, but I would feel awfully uncomfortable if a law suit were brought against me for failure to recontact a patient. It is hard to ignore something that carries the label “duty.”

In a previous posting I suggested that  labs should refrain from reporting variants of unknown significance (VUS) because VUS should virtually never be used to guide clinical practice, and that labs should track VUS and alert clinicians to significant reclassifications. That blogpost generated interesting discussion on all sides of the issue. Collaborative databases such as ClinVar and PROMPT may help sort out the clinical relevance of human genetic variation, and to some extent relieve individual labs of part of the burden of dealing with VUS. But these efforts will only further the importance of clear and reasonable DTR guidelines. We are in this to improve the lives of our patients, and if advances in genetic knowledge are not used to help clinical care, then we have a  failure on our hands.

As a first step, let me offer some suggestions toward establishing reasonable DTR guidelines:

  1. The primary – but not exclusive – responsibility of monitoring and reclassifying variants should lie with the original testing laboratory or whichever corporate entity might one day buy out the lab.  However, transparent sharing and curating of data among labs – such as with PROMPT and ClinVar – is critical and should be supported by government funding and built into the cost of testing. Classifying variants is enormously complex and the final word requires more than just a few smart people at a single lab rendering their opinions.VUS scale
  2. Labs should make good faith efforts to contact ordering clinicians – not patients – when a variant is reclassified. The clinician is responsible for integrating the test results into patient care. If the clinician is not reachable or no longer affiliated with the same institution or practice, then the original ordering facility should be notified. If efforts to re-contact clinical personnel fail, labs might then consider contacting patients directly, though this could be left up to individual lab policy. If all attempts to recontact fail, well so be it, but should be fully documented. If clinicians do not want to take on the responsibility of DTR, then, quite frankly, they should not engage in the practice of ordering genetic testing and should refer their patients to geneticists or other clinicians who are willing to assume this task.
  3. DTR should be limited to situations where the reclassification of a VUS has direct clinical impact. Thus, there should be no DTR if a VUS is “down-graded” to a polymorphism or a benign allele. In my experience, the vast majority of VUS are down-graded. Alerting patients to every variant and then notifying them months or years later that the VUS was clinically irrelevant is not the best use of resources and manpower. However, DTR becomes critical if a VUS is “up-graded” to Suspected Pathogenic or Pathogenic, or – the more painful phone call to make – if a Suspected or Pathogenic allele is “down-graded” to a polymorphism (“Uh, that salpingo-oopphorectomy and mastectomy, well, maybe they weren’t so necessary after all.”).
  4. There should a “statute of limitations” on how many years out from the testing date that DTR would apply. My daughter suggested 7 years from the time of the original interpretation; she tells me that this is consistent with the length of time that care providers are legally required to keep patient records. I might be persuaded in favor of five years, in light of the mobility of clinicians and patients, the inevitable business cycle of lab acquisitions/mergers/closures, and advances in genetic testing that will rapidly make today’s cutting edge techniques look as elegantly primitive as Clovis point technology.

    iClovis

    iClovis

  5. When undergoing genetic testing, patients should fill out a form with their contact information. Patients should be actively involved in their medical care and this brings with it an obligation for patients to inform clinicians of contact information, along with details of who and how to contact if the patient becomes deceased, mentally incompetent, or otherwise unreachable.  Ideally clinics would contact patients every two years or so to update contact information. While this is theoretically straight-forward with electronic medical records (EMR), most EMR are far less flexible and surprisingly less able to allow such seemingly straight-forward database functions. Getting your IS department to extract individualized reports, mail merges, and data analysis from the EMR is almost as difficult getting the US Congress to pass meaningful legislation. And, to add another layer to participation in their own care, patients should be permitted viewing access to online VUS databases, which should be made user-friendly. It may not be what every patient wants, but it should be available for those who wish to pursue it. In this area, we could learn a lot from direct to consumer genetic testing labs, which are light years ahead of us in designing easy to use, highly informative, up to date websites and creating on-line communities.

Some of you will support a few of these proposals and think that others are about as good an idea as Discount Colonoscopy. But if we don’t do something then nothing will ever get done. What are your thoughts?

 

Once again, thanks to Emily Singh for doing the hard work on the graphics (really, isn’t iClovis très cool?).

 

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VARIATIONS IN A MINOR KEY: SOME THOUGHTS ON PRENATAL TESTING IN AN ERA OF WHOLE GENOME SEQUENCING

James Watson is many things – geneticist, Nobel laureate, agent provocateur – but in the realm of psychiatry he is first and foremost the parent of a son with schizophrenia.  So when he spoke in 2007 at the World Congress of Psychiatric Genetics, it was as a family member, albeit a family member with an unusually good grasp of the science.  And it was as a family member that he exhorted the scientists in the audience to keep up the good work, so that “someday we could identify those individuals destined to suffer from mental illness in utero, and weed them out.”

How often do you hear an audible gasp in the midst of a plenary talk?  The dismay and the indignation were palpable.  Researchers throughout the day interrupted their talks on GWAS to express in the strongest possible language that the goal of their work was to understand the pathophysiology of the disease and perhaps to aid in diagnosis – not to provide pre-symptomatic risk  assessment and not – no, never – not to be used prenatally.

“But if this is what families want,” I asked one speaker later that day.  “How do you propose to restrict testing, once the means to test is available?”

“They can’t,” he replied.  “They must not.”

Ah.  Of course.  They must not – I will pass that along.

Five years later, it is not GWAS but whole exome sequencing and whole genome sequencing providing all the buzz at conferences.  Solving the diagnostic odyssey!  Revolutionizing cancer treatment!  Ushering in an era of personalized medicine!  It’s very exciting.  Prenatal testing is rarely mentioned, and then only in passing – while prognosticators sing happy songs of a not-so-far-off day when every baby will be sequenced at birth.

Sequenced at birth?  Will it even be necessary?  Maybe Mom and Dad have baby’s DNA already, on a hard drive or a memory stick or downloaded onto their cell phones along with the ultrasound pics.

This is not the genome sequencing story you are seeing in the papers or the blogs.  It’s not what researchers are excited about.  The ones we hear are all about science journalists getting their DNA decoded and setting off on odysseys of self-discovery that involve hours of consultation with clinical and academic superstars who donate their time. We hear about kids with strange constellations of symptoms finding answers after years of disappointment.  Those are heartwarming tales: anecdotal and difficult to imagine at scale, but hopeful and exciting nonetheless.  But there is another theme playing, in a minor key, and I hear it faintly, hidden beneath the violins and the trumpets.

I hear it, an unspoken question, when we debate the utility of genomic information.  What does to mean to say that information is actionable? (Prevention? Treatment? Cure?  Prenatally, there is only Yes or No.)  Can patients handle uncertainty?  (And what will we lose, when pregnancies are terminated just to be on the safe side?)  Doesn’t everyone have the right to know what is in their own DNA? (The information is available – why not use it?  What could possibly go wrong?)

Whatever tests are available postnatally will find their way into prenatal use.  The gateway technologies – PGD, cell-free fetal DNA testing – are in place. And there is no use saying, “they can’t, they won’t, they shouldn’t” because they can and they will – and sometimes they should.  There will be good uses too: success stories and disasters averted.  A blanket “no” is not an option, and granting anyone authority to pick and choose which uses are worthwhile vests altogether too much power in the hands of any one person, or profession, or bureaucratic entity.

The same tests can be done before or after birth, but the experience is entirely different.  Uncertainty after birth is an opportunity.  The least useful information is that which will absolutely come true, no matter what you do.  Uncertainty before birth is a crisis.  Anyone who has ever discussed a variant of uncertain significance with a pregnant mother can tell you that.  But what are the chances there will be developmental delay?  Are you certain that the heart will be affected? How sure are you that this means anything?  Not nearly sure enough.  Please understand that.

In general, notions of genetic determinism increase the likelihood that genomic testing will have negative consequences.  Fatalistic attitudes about the power of genes could lead people to overestimate the meaning of elevated risks and underestimate the meaning of reduced risks.  Anxiety, stress, missed mammograms – you have heard this before.  Shrug.  People are grown ups.  They will figure this out.  Information is power.

But we are in a whole new universe trying to reconcile underpowered and often misunderstood predictive testing in the context of prenatal use.  So please, in telling tales of all the wonderful things that genome sequencing will do, save space for a mention of what it cannot do.  Make sure they understand that there are great wide cracks in our crystal ball.  Do not oversell the value of genotype in the absence of phenotype.  Remember that in the end neither researchers nor physicians nor genetic counselors will dictate how this new technology will be used.  Others will make that call, and we will be in the choir, singing songs of praise laced with sorrow.

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As a Genetic Counselor, Would You Go Public With Your Genome?

A Canadian version of the Personal Genome Project (PGP) was launched earlier this month. This is an initiative that, for one key reason, is likely to have a rippling effect for the genetic counseling profession. Modelled after and in collaboration with George Church and his group at Harvard, the project aims to recruit 100,000 volunteers to have their whole genome sequenced and posted publicly online for the advancement of research. As someone who has followed the US Personal Genome Project from the outset, I’m thrilled that Canadians will now be able to participate in this important research.

So why is the Canadian version of this project so important for genetic counselors specifically? Because the first participant (whom the media has aptly named Canuck One) to bravely volunteer to “bare her genomic soul” and forgo any form of anonymity while doing it, is a genetic counselor. Jill  Davies and her involvement with PGP-Canada was profiled in The Globe & Mail (one of Canada’s largest national newspapers) earlier this month.

Globe and Mail PGP-1

In full disclosure, Jill Davies is a close colleague and friend (and also a previous guest contributor to The DNA Exchange). The Medcan Clinic genetics program has been involved in the PGP-Canada project from the outset, and therefore it is no coincidence that Jill happens to be participant number 1. But it is also precisely the fact that she is a genetic counselor that the PGP team was keen to have Jill step up to the plate. Who knows the potential implications—clinical, ethical, legal and social—of whole genome sequencing better than a GC? Beyond immersing herself into her work (quite literally), Jill’s participation will undoubtedly help raise awareness of the genetic counseling profession, which is something that I think should be celebrated.

Not surprisingly, with the potential to have my own whole genome sequenced hitting closer to home, I’ve been thinking a lot about whether this is something I would go through with, and if not—why?

The Globe & Mail has done an excellent job in asking the general public this very same question. In conjunction with the official start of the PGP-Canada project, the newspaper launched a widespread interactive media series — The DNA Dilemma—running from December 8 to December 22. This is one of the biggest and most comprehensive genomics-related media series I’ve seen. It is really worth the look at the articles and commentary. They have even developed a genomics game: Win, Lose or Genome?

By far the most interesting component to the series for me is the Infographic-type Poll on whether people would choose to have their genomes sequenced. Of the 1000+ respondents so far, a whopping 80% say they would have sequencing, and 70% believe the benefits outweigh the risks (you can filter the results based on age, gender, location etc). As a genetic counselor I find these numbers fascinating (and surprisingly high).

Globe and Mail Poll

My hunch is that if we polled GCs specifically, this number would be lower. There are so many interesting questions about why this might be—is it because we are more informed? Is it because we are a self-selected group who are more attuned (and potentially concerned about) the ethical issues associated with genetics to begin with? If I had the skills to create such a beautifully intricate poll as the one above I would, but I’ll have to make do with the standard DNA Exchange poll to test my theory. So—what do you say? Would you participate in the PGP?

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What Genetic Counselors are Talking About

Last week, I attended the National Society of Genetic Counselors (NSGC) Annual Education Conference in Boston. Although I attended talks on a variety of subjects, where possible I chose sessions focused on new genomics technologies and associated issues. There were some common threads tying these discussions together beyond ‘genomics’ itself. Here’s a quick summary of some of the things I observed and learned.

1. Secondary, Ancillary, Incidental – Oh my!

It is no surprise that discussions around the use of Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) universally include the question of what to do with the “extra” data—those pieces of information we weren’t looking for, but happened to find. What was surprising are the differences in the terminology we use to describe these extra pieces of data. Jessica Everett, a GC from the University of Michigan Mi-OncoSeq project explained that confusion over this terminology lead her team to decide that they would universally refer to an incidental finding as an unintended piece of information that “falls into your lap” and a secondary finding is extra information you end up finding out, but have to look for.

There are likely some official definitions and designations that already exist here. But it is apparent that we as a GC community currently don’t have a consensus on the nomenclature around this issue.

2. GCs don’t need new skills, but rather need to apply our skills in new ways.

This type of thinking is music to my ears—I love the challenge of applying our skills in new and unique ways. The GC role in pharmacogenomic testing specifically was a sub-theme here. I heard multiple genetic counselors who work in the realm of pharmacogenomic testing say that while they initially believed their role with patients undergoing testing for pharmacogenomic purposes would be minimal, the applicability of our traditional skills and opportunity to provide value to both patients and physicians was far greater than they anticipated. 

3. “Scalability” of the Genomic counseling session

The sheer volume of information and amount of time required to consent patients for WES/WGS technologies was routinely cited as a barrier to genetic counseling in the genomic era. In some cases, GCs plan for a 2+ hour pre-test counseling session, and in most cases there are multiple visits or contacts before testing is initiated. There was also alot of discussion about how best to inform patients about the various types of information that can be learned through genome sequencing technologies. Bioethicist Scott Kim (also from the Mi-OncoSeq project) made a good case for a ‘flexible default’ model for informed consent in these situations.

Consistently GCs commented that when asked ‘do you want to know everything?’ patients and research participants will almost always reply ‘yes– of course I want to know everything!’ However, the use of specific scenarios or examples seems to be required in order to elicit a more meaningful discussion about potential results, and what information patients will decide to opt out of receiving. (This is a topic I’ve previously written about.)

4. Collaboration

Although this may be the least exciting or surprising underlying theme, it is likely the most important. Almost every lecture concluded with a slide highlighting the importance of a collaborative and multidisciplinary approach to genomic testing.

As always, I’d love to hear about others’ reactions and impressions from this year’s AEC. Please feel free to share, below.

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