Genetics: Is Expanded Carrier Screening the Standard of Care?

Hannah Green, a genetic counselor at NYU, discusses the benefits and limitations of expanded carrier screening, highlighting its impact on clinical practice and patient care.

Hi everyone, my name is Hannah Green. I'm a genetic counselor practicing out of NYU Langone Fertility Centre. Depending on the circumstances, more can sometimes be better.

The more genes we test for, the more likely we are to identify increased instances of genetic risk. However, there are some faults, and I'd like to talk about some of those today. I'm taking the stance that expanded carrier screening can be a powerful tool in arming clinicians and patients with potentially life-changing information, but to call it the standard of care is a bit of a stretch.

As we start to expand our panels, we're testing for conditions that are incredibly rare across the general population, and for variants for which sensitivity, specificity, and predictive values are based on ethnic-specific populations. The outcome is that patients are receiving positive results with little information regarding actual clinical risk. So just some background information.

Carrier screening, whether it be expanded or not, is genetic testing performed on an individual that doesn't have an overt phenotype for a condition, but who may carry a variance in a gene associated with that condition. So for instance, a Tay-Sachs carrier doesn't have Tay-Sachs disease, but if his or her partner also carries Tay-Sachs, their offspring is at increased risk for the condition itself. The American Congress of Obstetricians and Gynecologists, or ACOG for short, recommends that all individuals at least be offered expanded carrier screening, but that pursuing a more targeted approach is acceptable too.

At a minimum, all individuals should be offered testing for cystic fibrosis, spinal muscular atrophy, the hemoglobinopathies, and the thalassemias, regardless of ethnic background. As for Fragile X, according to ACOG at least, only some females should be tested for the condition, depending on family history or a personal history of primary ovarian insufficiency. However, despite that recommendation, it is common practice for all people to be tested for Fragile X, or at least all females that is.

When we're talking about targeted carrier screening, it's kind of like the next tier up. So rather than just testing for those standards, we can target a carrier screen to someone's ethnicity or family history. So for instance, if an Ashkenazi Jewish individual comes into the clinic, we can be testing them for conditions that are prevalent within that community, like Tay-Sachs for instance.

When we're talking about expanded carrier screening, we are taking a pan-ethnic approach without regard for family history or ancestry. In other words, we are testing everyone for the same conditions. Historically, an expanded panel has anywhere from about 100 to 1,000 genes on it.

There is really no rule set in stone about how many conditions need to be on that panel. There are recommendations put forth by various bodies, but at the end of the day, it really is up to the labs to decide. Proponents of expanded carrier screening argue that testing everyone for as many genes as possible can identify more at-risk couples in an increasingly diverse world, and that expanded carrier screening doesn't rely on a patient having an accurate knowledge of family history and ancestry, all of which is true.

As I was saying before, though, there are faults. We'll talk about some of those now. Fault number one, we call expanded carrier screening pan-ethnic, but it doesn't necessarily serve all ethnicities equally.

We often market this test as a way to reduce reproductive risk for all of these extra conditions we're testing for, and that might be true for some ethnicities more than others. We know that clinical sensitivity is not uniform across the board. Carrier screening is designed to pick up likely pathogenic and pathogenic variants, ones that are well known we know cause disease.

Variants of unknown significance, or variants for which we lack sufficient data to classify at this time, even if detected, will go unreported, which means that someone will come back negative for that condition even if they carry a VUS. A major issue in the world of genetics is that we've not studied minorities to the same extent that we've studied non-Hispanic white individuals, which means that we are much more likely to detect these variants that we cannot classify in individuals of diverse ancestral and ethnic backgrounds. I should mention that this issue isn't inherent to expanded carrier screening.

This exists in the world of carrier screening as well, but it is exacerbated as we start to test for more conditions and for genes that are even more rare to carry in the general population. So let's take an example. We have a white non-Hispanic individual who carries a pathogenic variant in CFTR, the gene that causes cystic fibrosis.

That individual has their testing, they come back positive, pretty straightforward. We have an East Asian individual that also carries a pathogenic variant in CFTR. The difference is that at the time of testing, we don't know that individual's variant to be pathogenic.

It's considered a VUS. So what happens is that that person has testing, and they come back negative. In this sense, analytical detection has been the same.

The test has picked up the pathogenic variant in the white individual and the VUS in the East Asian individual. However, the clinical sensitivity is what's different here. Clinical sensitivity is a test's ability to call out a positive result on someone who is truly carrying a pathogenic variant.

So by calling expanded carrier screening pan-ethnic, is that really the case? Are we being a bit misleading? It's something interesting to think about. Fault number two, variants can be reclassified at inopportune times. I've been working with a couple recently.

Prior to coming to NYU, they found that they were a carrier couple of a recessive condition. They came to our fertility center. The sole purpose of doing IVF was for PGTM to test their embryos for this condition.

They create embryos, they transfer an unaffected embryo, they have a child who's unaffected, great. They come back for baby number two a few years later. At the time, we can offer them a more expanded panel, which we do.

They pursue it. We're sending testing with a new lab at this time, so the reports come back. One partner's a carrier, the other one is negative.

So now the couple's panicking. The only reason they did IVF is because they were both carriers. So I look into this more.

It turns out that the former lab we're using obviously considers this pathogenic. It was called out. The current lab considers it benign, entirely different.

Depending on which lab we choose to believe at this point, this couple either has five embryos that are usable or one. As you can tell, these variants can be reclassified at really difficult times, and it can be hard to know how to proceed from there. Fault number three, are we impairing patients' freedom of choice because of the undue pressure on individual choice? We know that the goal of carrier screening, according to ACOG at least, is to provide patients with meaningful information to allow them to make pregnancy-related decisions or pre-pregnancy planning decisions.

Meaningful, according to ACOG, is a condition has to have a carrier frequency of greater than 1 in 100, the condition has to have a well-defined phenotype, and it has to have a detrimental effect on quality of life. I can say for sure that many of the conditions I counsel on don't fit this criteria. So recently I've been meeting with a lot of individuals.

They are carrier couples for low penetrance, mild variants associated with later onset of features for hearing loss genes. So what happens is I meet with these couples and I say, okay, yes, 25% risk to each of your embryos. However, if that embryo and that eventual child is in the 25%, they're likely going to be asymptomatic.

If they do have symptoms, it likely won't be until adulthood. And if they do have those symptoms in adulthood, it will likely be mild. So what do we do with this information? Do these patients do PGTM? As we test for more genes associated with these mild features with later ages of onset, are we unintentionally cornering patients into intervention because they feel guilty otherwise? And I get this a lot.

I have people say, well, I'd feel like a bad mother. I'd feel like a bad father if I didn't do this. That's problematic.

At what point do we stop offering these increasingly expanded panels when this could be the result? Fault number four, patients are going into testing not prepared to find out information about their own health. Of the 556 conditions we test females for at NYU, 111 of them have what we call manifesting carrier features. A manifesting carrier is someone who carries a genetic condition, a recessive one, rather than having the full-blown condition, which we wouldn't expect from a carrier.

They might have mild features of that condition. As we start to expand our panels, we could be adding on these genes that are giving patients information about their own health. So how do we manage these expectations up front? In a perfect world, we have pretest counseling for all.

There are about 4,000 genetic counselors in the country. That's one for every 82,000 people. What that means is that a lot of pretest counseling is falling into the hands of REIs and OBs.

And herein lies issue number two, REIs and OBs are busy. So at NYU, we send about 250 to 300 carrier screens a month. Imagine counseling all of that up front.

Additionally, there are many surveys that suggest that most non-genetics providers don't even feel comfortable doing that pretest counseling or post-test counseling for that matter. We technically cover our counseling bases by providing these consent forms. We say, hey, read this consent form.

If you want to continue, great. If not, here's a waiver. This does imply an opt-out approach, meaning that unless you tell us otherwise, this testing is automatically being sent.

Should we be having, should we be taking this opt-out approach to something as nuanced as expanded carrier screening? Another thing to think about. I'd like to wrap up with a case that I think encompasses a lot of the, a lot of the faults that I've just explained quite nicely. So we had a couple come to us, but before they were at NYU, they did carrier screening through their OBGYN.

The male patient was found to be a carrier of cystic fibrosis. The female was negative. The female patient was found to be a carrier of Lee syndrome, which is a central nervous system condition.

The male was negative. They're counseled low risk, less than 1% chance that their child has either condition. They have their first baby.

The baby has both conditions. So what happens here? When we're talking about the cystic fibrosis, yes, we knew that the male was a carrier. We actually found that the female carried a VUS.

The technology did pick that up at the time, but as I talked about before, it's not, the purpose of carrier screening is not to call out VUSs. It's to call out likely pathogenic and pathogenic results. So they were a carrier couple the whole time.

We just didn't know. Talking about Lee syndrome now, yes, the female patient was a carrier. So what happens on the male's end? It turns out that the male was a carrier of a pathogenic variant, not a VUS.

So why wasn't that called out? At the time, the lab that was testing that gene, they were not using the technology required to pick up that mutation. The male had a common, a founder Ashkenazi Jewish mutation. It's a deletion, which does require different technology to pick up at times.

So, you know, we go into this thinking that we're testing everyone for all of these conditions, negative means negative, great news. There's a lot of nuances to this. When we're talking about a standard of care, what standard is insinuating is that everyone's getting the same level or quality of testing.

In order for us to say that expanded carrier screening is actually the standard, we need to be transparent about some of the loopholes and rework our approach to this pre-test counseling and post-test counseling for that matter. Thank you very much.