Next Generation Carrier Screening for Genetic Diseases


Speaker 1 (00:00):

Welcome to the Contemporary OB/GYN podcast series, brought to you by Quest Diagnostics. Now, here's your host for this podcast, Scott Kober.

Scott Kober (00:11):

Thank you and welcome to this podcast. My name is Scott Kober with Contemporary OB/GYN. Today, we'll be talking about next-generation carrier screening for genetic diseases. I'm happy to be joined today by Jim Warren, a genetic counselor at Quest Diagnostics, to talk about some of the key issues for practicing OB/GYN to be mindful of. Welcome, Jim, and thank you so much for joining me today.

Jim Waurin (00:36):

Thanks for having me.

Scott Kober (00:37):

Jim, why is carrier screening important for pregnant couples or couples trying to get pregnant?

Jim Waurin (00:43):

The OB/GYN in laboratory communities have been performing carrier screening since healthcare providers started screening the African-American population for sickle cell disease and the Ashkenazi Jewish population for Tay-Sachs disease way back in the 1970s. Once we found the gene for cystic fibrosis, or CF, in the late '90s, we started screening for CF in the European population as well. The reason that carrier screening was initially offered for those diseases was twofold.

Jim Waurin (01:15):

Biochemical or genetic changes defining carrier status had been well-defined and they are common autosomal recessive disorders. What recessive means is that it takes two copies of a non-working gene to produce a child with a disease, one each from the mom and dad. For these diseases, carriers are asymptomatic, so they would not otherwise be aware of their status until they had an affected child.

Jim Waurin (01:42):

The prevalence of these disorders is quite high in their respective populations. For instance, if you are an Ashkenazi Jew, you have an approximately 1 in 29 chance of being a carrier of Tay-Sachs disease. If you are not Jewish, but are of European descent, you have a far lesser chance, approximately 1 in 300. If you are an African-American, you have an approximately 1 in 13 chance of being a carrier for sickle cell disease. If you are a Northern European, you have approximately a 1 in 25 chance of being a carrier for CF. Because these disorders carry a high risk for couples in those demographics and are quite severe if they are indeed inherited by a child, it is quite important to perform carrier screening for them.

Jim Waurin (02:34):

Over time, we've learned that there are other severe diseases that newborns are at risk of inheriting from Mom and Dad, and thanks to next-generation sequencing, we can now offer screening for additional conditions.

Scott Kober (02:47):

What do professional organizations currently say about the use of carrier screening panels?

Jim Waurin (02:53):

The American College of Obstetricians and Gynecologists as well as the American College of Medical Genetics and Genomics both have come out with statements saying that all patients should be offered pan-ethnic carrier screening that involves diseases beyond sickle cell, Tay-Sachs, and CS. ACOG recommendations state that expanded carrier screening panels should include disorders with a carrier frequency of at least 1 in a 100. Those disorders are all covered in Quest next-generation sequencing panel. In addition, various Jewish organizations have put together a list of approximately 10 conditions with high rates of carrier frequency in the Ashkenazi Jewish population for which screening should be considered. These conditions with carrier frequencies up to about 1 in 125 are included on Quest panel as well.

Scott Kober (03:52):

Is there any data showing roughly what percentage of pregnant couples are screened for genetic diseases, whether that's in the general population or one of these specific genetic groups at higher risk of carrier frequency?

Jim Waurin (04:05):

Our market analysis suggests that up to 50% of couples are screened before or during pregnancy, which of course means that up to half of them are not. It would seem that we have a significant amount of work to do, and by we, we mean the healthcare industry, providers, and the genetics community.

Scott Kober (04:25):

How do the current commercially available carrier screening panels differ?

Jim Waurin (04:29):

They usually differ in two ways. They differ in their size, meaning how many disorders are included within the panel, and they differ in their analytic methodology.

Jim Waurin (04:40):

Let's start with the first one. As I mentioned earlier, ACOG picked a cutoff of carrier frequency of 1 in 100 as its recommended prevalence for including conditions in a carrier screening panel. If you extrapolate the math, it is equivalent to a birth frequency of about 1 in 40,000, which is a reasonably high prevalence. There are some carrier screening panels that include disorders with carrier frequencies of 1 in 200, 1 in 250, and even 1 in 500. If you do the math on that, that translates to disease frequencies of about 1 in 100,000 or 1 in 500,000. If you consider that there are approximately 3.7 million births per year in the United States, that's a very small number of cases.

Jim Waurin (05:32):

For some of these extremely rare cases, it may be that the couple both turn out to be carriers for a disorder, in which case they do have a one in four chance of having a child with a disorder. But then there might not be a lab available that has the ability to perform a diagnostic test for the pregnancy, either via CVS, [inaudible 00:05:57], or amniocentesis. That really isn't helpful to the couple and likely will cause unnecessary concern. That's one of the reasons why all of the testing for diseases currently on our Quest panels have been validated on prenatal samples as well as blood.

Jim Waurin (06:15):

Now, what about the analytic methodology up for these panels? There are generally two methods involved in next-gen sequencing. Some laboratories use targeted gene sequencing because you can identify the genetic mutations that are most common in a given population and therefore configure your tests to look for particular hot spots. Other laboratories choose to sequence the entire gene. The problem with that approach is that you risk getting an answer back showing a variant in a specific gene that may or may not cause the disease in question, so you run the risk of giving physicians and patients information that they won't know what to do with. Whereas, if you are just focusing on targeted mutations in a gene, there is literature showing that if a child has this specific sequence, the phenotype can include A, B, C, and D.

Scott Kober (07:12):

I would think that you would want to do everything you can to put the mind of the already nervous mom, especially the first-time mom, at ease instead of overburdening her with information that may or may not be relevant.

Jim Waurin (07:24):

That's exactly right, Scott. I've been in this field for a long time and there are a couple of gems rules of laboratory medicine that I've come up with. One of those rules is, don't ask a question or order a test if you don't know what to do with the answer. If you have a large panel of tests and you get an answer back that doesn't help you deal with the patient, what good have you done? Another rule is don't increase the patient's anxiety with a test result if you don't have a way to alleviate that anxiety. If you order a test that comes back with a positive result and there is nothing you can do or offer based on that result, all you have done is increase the anxiety of the patient. In the case of the pregnant mom, they already have enough to worry about.

Scott Kober (08:11):

Is it typically any more difficult to get the father of the child to participate in carrier screening than the mother?

Jim Waurin (08:17):

It varies. There are generally two ways that a clinician will order expanded carrier screening. The first one is to do both partners at the same time, so couples testing. If a clinician has the availability and the couple is willing, he or she has them both in his office, draws tubes of blood, sends them both off at the same time, and they get answers back at the same time. End of discussion. The other way is to do testing sequentially. Since, obviously, the OB/GYN is going to see the mom happens all the time, it is sometimes easier to order carrier screening just for her first. If she comes back negative for everything on the panel, then you don't need to do the dad since all of these disorders are autosomal recessive. If the mom comes back as a carrier for the disease on the panel, then the clinician needs to have the father tested.

Scott Kober (09:15):

For the OB/GYN practice that is considering either bringing on a new carrier screening panel or perhaps replacing the one that they currently use, what are the key components that they should consider when making that decision?

Jim Waurin (09:27):

What they should do is to look at the list of disorders covered within the screening panel. Every laboratory that offers a next-generation carrier screening platform publishes the list of conditions that are covered within their panel. Panels can be of different sizes, from something less than 100 diseases to over 300. The point here would be to pick a panel that fits both the healthcare provider's and the patient's needs.

Jim Waurin (09:54):

Quest started out by launching a panel of 22 diseases. We learned, however, that there were many more that we could screen for and thus offer more to expect in patients. Moving forward, our panel options will come in several flavors, if you will, thus being able to accommodate both the patient and physician needs. We find patients and providers like having options.

Jim Waurin (10:20):

The second question involves the methodology the lab uses and the way they report a result. Is the clinician going to receive an answer that finds a variance of unknown significance, or are they going to receive an answer where either they or someone else can counsel the pregnant family on a clear phenotype for which risk has been identified? Quest Diagnostics looks closely at hot spots and doesn't report out variance of unknown significance.

Jim Waurin (10:51):

Lastly, they should ask if the laboratory has the ability to do something about the prenatal diagnostic version of the diseases they are testing for. That's probably the most important thing, because what are you going to do with a positive result if you can't provide a CVS or amniocentesis for the couple?

Scott Kober (11:12):

Are most commercially available carrier screening panels covered by insurance, or are they typically out-of-pocket expenses for the patient?

Jim Waurin (11:20):

To the best of my knowledge, they are typically covered by insurance. Once ACOG put out their recommendations, most insurance companies fell in line behind that guidance. There are some laboratories, including Quest, who have a policy that, whatever cost insurance does not cover, your patient will only be responsible for up to a certain cap, often about $300.

Scott Kober (11:43):

Jim, as we're wrapping things up, if you could come up with two or three key bullet points that you would want our audience to take from today's conversation, what would those be?

Jim Waurin (11:53):

Two things. First, every patient should be afforded the opportunity to have carrier screening, and second, diseases on the carrier screening panel should be appropriate for testing and followup work, meaning that they should have the ability to have followup diagnostic testing done in case of a positive result in Mom and Dad. Quest recently expanded our carrier screening portfolio to include medically responsible options designed with guidelines and the patient needs in mind. Learn more at [ 00:12:27].

Scott Kober (12:28):

Well, great. I think this has really been a terrific discussion about some of the core issues surrounding next-generation carrier screening for genetic diseases. Thank you so much for joining me today, Jim.

Jim Waurin (12:40):

Thank you for having me.

Speaker 1 (12:42):

Thank you for joining us today. You've been listening to the Contemporary OB/GYN podcast series XX. This podcast is brought to you by Quest Advanced Women's Health.


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