番茄社区

In the not-too-distant past, the focus for medical geneticists was diagnosis.

"More than 90% of it was [identifying], 'What does this child have?' Because that's what parents wanted to know," Max Muenke, MD, CEO of the American College of Medical Genetics and Genomics (ACMG), told 番茄社区.

Now, genetics touches nearly every medical specialty, either via screening programs or treatments targeted to specific diseases. Ob/Gyns counsel women with BRCA mutations on breast and ovarian cancer risk. Neurologic conditions like spinal muscular atrophy and Duchenne muscular dystrophy have seen novel therapies come to market in recent years. And cancer drugs are tailored to tumors with specific mutations.

is starting in Nashville this week. Muenke and ACMG President Marc Williams, MD, spoke with 番茄社区 in advance of the meeting. Following is an edited transcript of that conversation.

Who does ACMG represent?

Muenke: We're the only professional membership organization that represents the entire field of medical genetics and genomics. The field consists of a set of professionals who have one goal, and that is optimal patient care.

Three groups of professionals work in this field. You have board-certified medical geneticists, board-certified laboratory geneticists, and genetic counselors.

Our goal is to help diagnose children and adults from pre-conception to birth, through childhood to adulthood, to the aging population, who have disorders that have some genetic component.

What resources do you offer practicing physicians?

Muenke: ACMG houses the . [On the website], you can see the map of the U.S. and you can see, for instance, that Arizona has 42 conditions that are screened for, or that New York state has 62, or that Arkansas has 32. You can also see what conditions are being screened.

This is a contract that we have had with the NIH, or the Eunice Kennedy Shriver National Institute of Child Health and Human Development, for over a decade.

Then we have practice resources. Our are specifically made for the practicing clinician. These are made for the family physician, the internist, the pediatrician. So, if the family physician gets a diagnosis back, and they're like, "Oh my gosh, I heard this at some point in medical school," they can go to the ACT sheets. You'll find in one page all that needs to be done right now, and when you have to refer the patient.

Who specializes in medical genetics and genomics?

Williams: It's really changed over the years. When I started, it was fairly limited to those individuals who were primarily interested in rare disease. Those of us in pediatrics, for instance, trained in a specialty, either in dysmorphology or metabolic disease.

However, as our knowledge has increased, we have individuals from many specialties who have done additional training in genetics to focus on specialty-specific genetic diseases. We have joint training programs in pediatrics and genetics, internal medicine and genetics, and neurology and genetics. We also have joint training programs that are beginning to be developed in ophthalmology and genetics.

The American Board of Medical 番茄社区 (ABMS) has designated us as a primary medical specialty. So we are, in some ways, primary care clinicians, even though our focus is on disorders that are more specialized.

Because of the way that fellowships were developed, it used to be that people would do a primary residency, like pediatrics or Ob/Gyn, and then would do genetics. Now we're developing these joint training programs so that you can do pediatrics and genetics at the same time, and then come out with eligibility for both boards.

Last year, ACMG released its . Why focus on screening for congenital anomalies or intellectual disability?

Muenke: Instead of a geneticist thinking whether it could be various syndromes, and ordering one test after the other, now we strongly recommend that exome/genome sequencing is the first- or second-tier test for patients with congenital anomalies and intellectual disability.

Having this stamp of approval of the American College of Medical Genetics and Genomics has an impact on payers. Instead of paying $200 for one test and finding out it was negative, then doing another test for $500, and another test for $300, now we do one test that costs $800, and that's it.

Williams: This was actually the culmination of 10 years of work by the board of the College and working groups. We identified the need a decade ago to use best practices for development of evidence-based guidelines. Up to that point, we've been relying on the consensus process. While expert opinion and consensus is a level of evidence, it's probably at the lowest level of evidence, and it's inherently at risk for bias.

So, we developed a process by which we can move to systematic evidence reviews conducted by the College that would then inform the development of evidence-based guidelines. Now, this is a time- and resource-intensive process. It's not something that you can slap together just with volunteers. So we needed a strategy to be able to develop resources that would support that.

Through our foundation, which is the charitable fundraising arm for the College, we initiated dedicated fundraising to support the development of evidence-based guidelines. We were able to use that mechanism to accrue resources that we could then use to hire a methodologist, access literature, develop the key questions that would inform a guideline, and then follow the protocol that was laid out by the National Academy of Medicine on how to develop a best practice for an evidence-based guideline.

The second piece of that is the how-do-you-decide-what-to-do question. That's where we have a topic committee that reviews submissions from an open nomination process. Anyone can nominate a topic for consideration of an evidence-based guideline. This topic review committee then reviews these topics -- along with our methodologist who does a preliminary review of the evidence -- to make a determination as to whether there is sufficient evidence to justify moving forward with the guideline. We use that prioritization process to identify those topics that seem best suited for development of an evidence-based guideline.

We're now at the point where we have a couple of additional guidelines that are under development. We hope to be able to increase our resources through the fundraising activities so that we can do more of these and also make the nomination process more robust.

ACMG also recently pioneered a . What's known about this gene variant and its risk for breast/ovarian cancer development?

Williams: The evidence seems to indicate that PALB2 probably has relatively equivalent risks for breast cancer development as BRCA2. If you have a variant in BRCA2, it seems to confer a somewhat lower risk than the BRCA1 variant does. PALB2 seems to be more equivalent to BRCA2, but still would meet that threshold of being very high risk compared to the general population.

There are a couple of other genes that are associated with breast cancer predisposition that are currently under review by the College that may also, if they meet that evidentiary threshold, be added to our recommendations in terms of what should be tested for in somebody where you suspect hereditary breast or ovarian cancer.

This is where having a foot in the discovery space, as well as a foot in the clinical space, is really important for the College because we're that interface that hopefully will facilitate the translation of new findings into best practices of clinical care to improve health outcomes.

What does the future of genetic medicine look like?

Williams: One of our committees is the therapeutics committee, which is dedicated to looking at therapeutic interventions to treat genetic disease. That can be very broad. It can be things like enzyme replacement therapy for storage diseases. It can be the treatments that are being used now to approach disorders like spinal muscular atrophy, certain types of cystic fibrosis variants, and Duchenne muscular dystrophy. Ultimately, it will probably include CRISPR.

We have that structure in place to evaluate new therapeutic interventions. But I think the key role of the College is to say, when does this meet a threshold that it looks like it's going to provide value when compared to other interventions? And what are potential harms that could accrue from using a therapy of this type that people need to be aware of before it moves into clinical practice?

So when we talk about something like CRISPR, there's clearly a lot of opportunity for that, at least in theory, to treat genetic disease. We're very excited about that, but we also recognize, particularly when it's applied to the germline, that there's risk for off-target problems that could lead to other types of medical issues down the road and could impact outcomes.

We also have our ethical, legal, and social issues committee that is specifically tasked to deal with all of the other issues that could result from an intervention like CRISPR.

Muenke: From a historical perspective, there was a time when more than 90% of the task of a medical geneticist was diagnosis: what does this child have? Because that's what the parents wanted to know.

I think the field now is changing to include not just management, but treatment. We are an organization that has a heavy emphasis on what comes next. I think diagnosing either by clinical means or by exome or genome sequencing will allow not just a management of counseling and providing care for a family, but eventually, in some diseases, providing a cure.

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