Andres Reig:
In terms of expanded carrier screening, can you tell us a little bit what it is? Give us a brief introduction.
Jason Franasiak:
Sure. So carrier screening is a type of genetic test and it can tell you whether or not you’re a carrier for a particular gene of a known genetic disorder. So when it’s done before pregnancy, you can figure out your chances of having a child with that genetic disorder. So for example, if both parents are carriers of a recessive gene, there’s a 25% chance that their child will get a gene from each parent and be affected by that disorder. There’s a 50% chance that the child would be a carrier of the disorder, just like the parents. So for expanded carrier screening, many disorders are screened for utilizing a single sample. This type of screening is done typically without regard to race or ethnicity, and companies that offer expanded carrier screening create their own panels of disorders to test for. Some of these panels test for more than 100 different disorders in a single sample. Typically the panels will focus on severe disorders, which affect a person’s quality of life, typically, from an early age.
Andres Reig:
Where did this come from, the idea of doing expanded carrier screening? Can you tell us a little bit of how this started and how it’s evolved?
Jason Franasiak:
Sure. So expanded carrier screening or carrier screening in general, concurrent with the development of prenatal screening programs in the 1970s, came about as community-based carrier screening programs. These were developed in populations with increased incidents of specific genetic diseases. Carrier screening programs were implemented in patients that were already pregnant.
Jason Franasiak:
The first carrier screening program was really for Tay-Sachs disease, and it was made possible of the discovery of the underlying biochemical deficit. Over a five-year period of time in the early 70s, Tay-Sachs carrier screening programs were implemented in Jewish communities in more than 50 cities. Several factors contributed to this process, including a high rate of carriers in the Jewish population, advocacy on the part of scientists and clinicians who were deeply involved with high-risk families, and the existence within the Jewish community of organizations willing to help coordinate or lead testing programs.
Jason Franasiak:
These Tay-Sachs disease carrier screening programs served as models for other screening programs in the Mediterranean region to identify beta thalassemia carriers. These programs like the Tay-Sachs disease were community-based, focused on genetic disease with increased prevalence, and resulted in dramatic reductions in bursts of children affected by the disease. This, of course, was through pregnancy termination. As with Tay-Sachs disease, carrier screening received strong community support and incorporated access to genetic counseling, prenatal diagnosis for at-risk couples, and abortion services.
Jason Franasiak:
It wasn’t until after 1989, with the identification of the gene associated with cystic fibrosis, that cystic fibrosis screening became available in the late 1990s. The professional consensus was that it should be offered to all individuals or couples seeking prenatal or preconception care. Subsequently, several professional guidances came out which resulted in support of pan-ethnic cystic fibrosis screening. This move has been motivated in part by the difficulty assigning individuals to a single ethnic determination based upon ancestry-based screening. I think we’ll talk a little bit more about the difficulty in assigning single ethnicities in a moment.
Jason Franasiak:
Through the past decade, it’s becoming increasingly common to offer carrier screening to the general preconception and prenatal populations. For example, in parts of the world, pan-ethnic screening is commonly offered for hemoglobin occupies and thalassemias, and it’s recently been recommended that conditions such as spinal muscular atrophy and Fragile X syndrome be screened for.
Jason Franasiak:
It’s important to note that although most carrier screening programs have been focusing on identifying carrier couples for prenatal diagnosis and the option of pregnancy termination, there has been increased efforts made to offer carrier screening before pregnancy. This pre-conception testing offers couples a wider range of reproductive options if they want to avoid the birth of a child who’s affected. They can choose not to have children, or they can choose sperm donation, or in vitro fertilization with either egg donation or pre-implantation genetic testing.
Andres Reig:
It’s so interesting, so originally it was a little more of something we do when patients are pregnant or just recently pregnant and now it’s evolving to something more of a test to see who’s a carrier in order to do something about it before we get pregnant.
Jason Franasiak:
That’s absolutely right, Andres. So the main thing that it was originally developed for was determining whether or not one of the ongoing pregnancies might’ve been affected by the disease, and really the only option was pregnancy termination. There has been movement towards doing this ante-natally, or before pregnancy, and thus, placing patients in risk categories before they even conceive.
Andres Reig:
Excellent. So that’s about the when we should do this and how that has changed a little bit. The other important question is who should have this and what the sequence or the stepwise approach should be? Many places do expanded carrier screening on the female patient, and then if the female patient tests positive for something, then we test the male patient, understanding that obviously if the female patient is not a carrier for anything, then there’s no point in testing the second person. What is your thought on that? Do you think we should test the female partner first and then the male partner, or rather both at the same time?
Jason Franasiak:
That’s a very good question. So first off, it’s important to note that there’s a fairly widespread consensus now amongst professional societies and most experts who think that carrier screening offered preconception allows more options than does during screening during pregnancy. Additionally, as noted, these screenings can take place either sequentially, screen the female partner and then screen the male partner if the female is positive, or it can occur concurrently together. With the increased utilization of expanded carrier screening panels, these panels test for more than 100 disease states and so it’s quite frequent that the female will test positive for some mutation and thus require male testing. This will occur in roughly 25 or 35% of cases and this increases with the increasing number of mutations tested for any given panel. Thus, it’s often a bit more straightforward to screen for both concomitantly.
Andres Reig:
You mentioned this panels often test for more than 100 diseases, I’m assuming obviously a lot more mutations than diseases, what conditions or what are some of the most common conditions that this tests for?
Jason Franasiak:
So it really does depend a bit on the panel that’s utilized. Our panel will test for various conditions, and they’re related to all organ systems in the body, including cardiovascular conditions, endocrine conditions, hematologic disorders, hepatic conditions, immuno deficiencies, metabolic disorders, neurologic disorders, pulmonary disorders, renal disorders, and skeletal disorders. The conditions that are included in the panels typically meet a certain type of inclusion criteria being either early, onset, and severe, or onset in childhood and progressively severe, or those that are amenable to early detection for treatment can improve the lifetime management of the disease.
Andres Reig:
In 2016, you published a paper in genetics in medicine that was titled Expanded Carrier Screening in an Infertile Population: How Often is Clinical Decision Making Affected? I know it’s been four years, I don’t know how much you remember about that paper.
Jason Franasiak:
Well, I do remember that paper well. One of the things that we found was that we do in fact see that there are couples who end up being tested positive for the disease, it’s not a vast number, but we want to anticipate that. But what we did find was that in doing expanded carrier screening panels on the couple, we identify carrier states for both members of the couple at which they would have a one in four chance of having a child affected by the disease. And that allows for, because this is all done prenatally and prior to treatment, it allows for us to involve pre-implantation genetic testing for monogenic diseases. We’re able to select embryos, which are not affected by the disease for transfer and thus prevent the birth of a child who is affected by the disease.
Andres Reig:
On that paper, you also wrote a little bit about the role of race and ethnicity in terms of selecting the patients. I know a lot goes into selecting who the best candidate is, you also mentioned on that paper, if I remember correctly, that’s I think .21% of times the result affects clinical decision-making or basically we would need to test about one in 450 couples to actually affect clinical decision-making. So clearly a lot goes into selecting the right patient population to test or choosing who we do this on. But what do you think is the role of race and ethnicity into guiding testing in a population that is becoming, as you say, in your paper more and more racially mixed?
Jason Franasiak:
Yeah. So Andres historically, race and ethnicity were utilized to guide testing, and because genetic mutations were more prevalent in certain communities, this goes back to Tay-Sachs in the Jewish community initially. However, as the world’s population has become more genetically mixed, many of these race and ethnic backgrounds are not holding as true as they did when we were less genetically mixed. So there is evidence from several studies published now that self-reported ethnicity did not match geographic ancestry in nearly one in five individuals thus, expanded carrier screening, which is done regardless of race and ethnicity, may be better at identifying risks of genetic conditions in the diverse populations that we have in our current society.
Andres Reig:
That’s true. I think you’re right, a lot of people identify as a race that may not correspond with their genetic ancestry, like you’re saying, which is actually what would put them at risk of the disease.
Andres Reig:
We also were mentioning before that some of these panels cover more than 100 diseases, some of them cover some diseases, some cover others, what is the difference for the physician? What is the difference between the different available options, the different labs?
Jason Franasiak:
Yeah, so the panels vary pretty widely. They can include as few as about 40 mutations or conditions to more than 1500 mutations or conditions. Most of the providers and most panels will offer somewhere between one and 300 conditions. So in most cases, screening is going to be offered through a physician moderated model where the physician has to order the test and the company can market the test directly to the public, but it requires it to be ordered by a physician. Selection of the disorders on the panel is generally based upon gene frequency and it includes pathogenic variance within a disorder that contribute to the highest detection of carriers. The American college of OB/GYN provides some guidance. This is based upon its well-established approach of selection of disburse, which were evaluated on the newborn screen. This approach considers carrier frequency and prevalence of the disorders, well-defined disorders known to have detrimental effects on the quality of life and disorders with early onset or available intervention. So typically, including adult onset disorders or conditions for which the natural history is not known or poorly established or disorders that occur in very small frequency is discouraged.
Andres Reig:
For these tests that all these different labs offer, what is the technique used today? What do they actually do when they get the sample? Does this differ from some companies to others and how should that be? How should that affect what the physician does and how they interpret the results?
Jason Franasiak:
Yeah. So one of the primary techniques which is utilized is next generation sequencing, and this has really revolutionized genetic screening and genetic testing in general. So next generation sequencing typically refers to a non-Sanger-based high-throughput DNA sequencing technology. This is where millions or billions of DNA strands can be sequenced in parallel yielding much more throughput and minimizing the need for fragment cloning methods, which are often used in the Sanger sequencing genomes. This overall significantly decreases the amount of time needed and the cost required in order to perform these studies.
Andres Reig:
You had mentioned before that most of these tests have to be ordered by a physician, and it’s also important to note, obviously that they should also be interpreted by a physician to help the patient understand what this means and what the significance of it may be. What is your view on interpreting those results?
Jason Franasiak:
Yeah. Andres, all of these results should be interpreted by a healthcare provider, oftentimes the ordering physician, however many times, given the immense amount of information and the progressively increasing complexity of the results of these tests, genetic counselors, who specialize in the communication of these results, may also be utilized. They oftentimes have a bit more time to delve into the significant number of results that these carrier screenings provide to patients.
Andres Reig:
That’s true, the genetic counselors are very, very helpful in this situation. Now, let’s say some of those results are indeed abnormal, what do we do if some of these results are abnormal? How do we counsel these patients?
Jason Franasiak:
Perfect. Well, if the carrier screening is done before you become pregnant, you have several options available. You can choose in vitro fertilization with donor eggs or donor sperm in order to become pregnant. And with this option, the embryo can be tested before it’s transferred into the uterus. You can also choose not to become pregnant. If you have carrier screening after you’ve become pregnant, your options are a bit more limited. In either case a genetic counselor, your OB/GYN, and other healthcare professionals can help explain the risk of having a child with the disorder. One of the things that I think is important is that with doing the testing ante-atally, it does give the option to utilize the patient and partner’s own gametes, their own eggs and own sperm, and undergo pre-implantation genetic testing.
Andres Reig:
That’s right. Of course, that’s one of the main options and potentially, one of the main reasons we would do the expanded carrier screening. Assuming, like we said, some result is abnormal and we decide to go the route of IVF with pre-implantation genetic testing, what is the difference between expanded carrier screening and pre-implantation genetic testing?
Jason Franasiak:
So the carrier screening really looks at the parents themselves, those are the individuals that are producing the gametes, the egg and the sperm, and looks at their risk of passing on a genetic mutation to their children. Pre-implantation genetic testing has to do with testing of the embryos that the egg and the sperm create. There’s really two main forms of PGT, there’s PGT-A, or PGT for Aneuploidy, and PGT-M, or PGT for monogenic diseases. PGT-M determines whether or not you have a genetically heritable mutation, which can be passed onto your child. PGT-M was previously called PG-D, and it looks for the specific mutations in a single gene and is offered to families who have a known genetic mutation, and that’s important. And that’s why expanded carrier screening is important because you cannot perform PGT-M without knowing first what you’re looking for. So you can’t perform PGT-M on any of the inherited mutations or genes, which are out there. It has to be for a specific one or two genetic mutations.
Jason Franasiak:
The risk for this may have been discovered through routine expanded carrier screening. This PG-M is different than PGT-A. PGT-A, or PGT for Aneuploidy, determines whether chromosomal abnormalities exist in the embryos and impacts the chance of successful embryo implantation. This was previously called PG-S or pre-implementation genetic screening, and it looks for extra or missing chromosomes, which can result in miscarriage or in chromosomal issues like down syndrome. Both of the tests are done typically in conjunction with in vitro fertilization, but not everybody needs both tests. So PGT-A can be utilized to improve the chances that an embryo will implant and decrease the chance of miscarriage and can be performed without any a priori testing on the parents. PGT-M is for monogenic diseases and tests for a particular disease that the embryo may or may not have and does require a priori testing of the parents, the egg and the sperm source, again, typically with the expanded carrier screening. Both of them occur by removing about 10 placental cells from the trophectoderm of the embryo and sending that for genetic analysis.
Andres Reig:
It’s quite amazing, actually, what we can do and how far things have come that we are able to detect somebody who’s a carrier before they even get pregnant and then if they do want to get pregnant, we’re able to detect that in the embryo and select the right embryo, so to speak, or to maneuver a way around it in several ways to avoid having an affected child. With all of this that we see, how far we’ve come so far, what do you think is next in the field, in the arena of pre-conceptional and pre-gestational screening?
Jason Franasiak:
Yeah. So I think first and foremost, as genetic conditions evolve, so as more and more genes are identified as causative factors for diseases, and the treatments for these diseases improve, there will be additional disorders that will meet criteria to be added to expand the carrier panels. The state of the art treatment at present involves IVF with PGT-M to allow for embryos, which are not affected, to be transferred. In the future, I think that we may be able to actually alter the genetic code with genome editing tools, such as CRISPR-Cas9, there’s been an awful lot of this in the news and media of late, and I think that we’re still some time away from this. I think that there are some additional molecular techniques that need to be squared away before this becomes ready for prime time and I think that there are some additional ethical components regarding genetic editing and gene editing, which need to be hashed out prior to utilizing this. But I do think that genome editing is coming in the coming years.
Andres Reig:
It shows great potential. It’s very, very promising. Thank you so much for joining us today, Dr. Franasiak. It was a pleasure having you.
Jason Franasiak:
It was a pleasure to be here. Thanks so much.
Andres Reig:
Thank you. Will you be back?
Jason Franasiak:
I sure will.
Andres Reig:
This has been another episode of FertiliPod by IVIRMA. Thank you so much for listening. Tune in next week for more research and topic discussions on all things reproductive medicine. See you next week.
