Kerri Breslin had just turned 30; she and her husband, David, were ready to start their family. Both in great health, the Los Angeles-based couple didn’t expect to have any trouble getting pregnant. Breslin stopped taking birth control pills and, just for safe measure, paid a visit to her gynecologist.
Given Breslin’s ethnic background — half Irish and half Ashkenazi Jewish — her doctor recommended that she pursue carrier screening for roughly 100 genetic diseases, some of which are more common among people of Ashkenazi Jewish heritage, others more common among the Irish. Because these are recessive conditions, the doctor explained, carrier status is only a risk factor — a far cry from a high likelihood of having an affected child. Carrier mutations for most autosomal recessive conditions (those not related to the sex chromosomes) are only a concern if both the prospective mother and father are carriers for the same condition. This was highly unlikely, Breslin thought, since her Puerto Rican husband was neither Jewish nor Irish. In the unlikely event that the two were carrying gene mutations for the same condition, however, they’d have a one in four chance of conceiving a child with that condition.
“I honestly didn’t think twice about the test,” Breslin recalls. “I didn’t think we would test positive for anything. I just thought, ‘The doctor recommended it, so we’ll do it.’ ”
It’s standard practice for OB-GYNs to offer some type of optional preconception or prenatal carrier screening. The minimum number of conditions for which a doctor might recommend screening would be two to six, depending on the couple’s collective ethnicities and whose guidelines the doctor follows. Organizations including the American College of Obstetricians and Gynecologists, the American College of Medical Genetics and Genomics, and the National Society of Genetic Counselors make recommendations. But Breslin’s doctor offered much more than these recommendations.
Expanded carrier screening (ECS) uses genotyping or gene sequencing to determine whether an individual is a carrier for a panel of recessive genetic disorders. Depending on the lab, that panel can screen for approximately 100 to 300 conditions. Like traditional carrier screening, ECS screens for conditions that could significantly shorten a child’s life or greatly compromise quality of life through physical and cognitive impairment. But ECS can also screen for mutations for conditions that vary greatly in their severity, age of onset, and treatability. Some of the conditions are so uncommon that doctors aren’t entirely sure how the disease would manifest in a child born with them, much less how to counsel a couple faced with this risk. Nevertheless, ECS, which is both relatively cheap and simple, has the potential to redefine family planning.
“We have proof that carrier screening can lower the incidence of some of these conditions,” says Robert Green, a medical geneticist at Brigham and Women’s Hospital and a professor at Harvard Medical School. “Expanded carrier screening is a surprisingly untapped, low-hanging fruit in genomic medicine that I believe eventually everyone will have the choice to get.”
Standard guidelines recommend screening for only a handful of conditions. However, the American College of Obstetricians and Gynecologists (ACOG) recently said in a statement that ECS was an acceptable testing method, on par with traditional screening. The organization has previously acknowledged that expanded screening, which costs about $350 out-of-pocket, may be cheaper than the more limited conventional screening, which can run up to $1,000.
Standard guidelines recommend screening for autosomal recessive conditions like cystic fibrosis and sickle cell disease, as well as for X-linked conditions, though in a more limited way. For example, according to ACOG’s guidelines, “Fragile X premutation carrier screening is recommended for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome.”
Conditions like fragile X syndrome and hemophilia are caused by mutations on the X chromosome. Because females have two X chromosomes, they are more likely to be unaffected carriers of X-linked recessive conditions (although they too can sometimes be affected). That’s because they have the mutation on one X chromosome and a normally functioning gene on the other. Males, who, with rare exceptions, only have one X chromosome, will typically either have the condition or not — they do not have a second, fully functional X chromosome to fall back on.
If we assume that a woman is a carrier of an X-linked recessive condition, then male offspring of a female carrier have a 50 percent chance of being affected. Female offspring of a female carrier have a 50 percent chance of being a carrier. All female offspring of an affected male will be carriers; however, male offspring of affected males will not be affected (they will instead receive their father’s Y chromosome — not his X).
Minimum standard guidelines say that OB-GYNs should offer all women carrier screening for spinal muscular atrophy and cystic fibrosis, both of which follow autosomal recessive inheritance. Screening for hemoglo-binopathies, such as sickle cell disease (another autosomal recessive condition), should also be offered. Fragile X screening should be offered to women and their partners with a confirmed or suspected family history of the syndrome. Tay-Sachs screening should be offered to women and their partners if they are of Ashkenazi Jewish, French Canadian, or Cajun heritage, as well as to anyone with a family history of the condition.
What Are the Odds?
At her doctor’s recommendation, Breslin decided to be screened for many more than the top six conditions. Before she underwent the genetic test, her doctor explained that broader screening means increased chances of testing positive for something. Consider a white woman, who is neither Hispanic nor Ashkenazi Jewish and who accepts the standard recommended screenings for spinal muscular atrophy and cystic fibrosis. The chances that she carries the former are one in 40 to one in 60; the chances that she carries the latter, one in 25.
But in a study of 346,790 people who, regardless of their ethnicity, underwent ECS for up to 94 severe or profound conditions, one in three were found to be carriers of at least one condition. The study, published in the Journal of the American Medical Association, was based on DNA collected by Counsyl, a commercial lab that offers the screening.
As the number of disorders included on testing panels increases, so do the chances that an individual carries at least one of those conditions. In a study of 1,301 people screened for 368 conditions, 56 percent were found to be carriers of at least one.
“I’ve seen patients carry [risk variants for] four or five conditions,” says Janice Edwards, a certified genetic counselor and director of the Genetic Counseling Program at the University of South Carolina School of Medicine. “If they weren’t prepared for that — especially for a strange-sounding condition with an unfamiliar name — it can be pretty anxiety-provoking.”
That said, after both partners are tested, the odds that the couple carries recessive mutations for the same severe or profound condition are 1.5 percent. The purpose of ECS is to help identify those couples who are carriers of the same condition.
Understanding the odds, Breslin underwent a blood-screening test. Two weeks later, she learned that she was a carrier for congenital glycosylation disorder type 1a (CGD1A). A devastating condition, it takes the lives of 20 percent of babies born with it within the first year, often due to infections, liver problems, or heart disease. Those who live past the first year can have severe physical and cognitive impairment. Unable to live independently, many people with CGD1A cannot speak and may require a feeding tube. They are typically wheelchair-bound.
Still, Breslin was not terribly concerned. The sooner her husband got tested, the sooner they would learn that he was not a carrier and they could start their family. But David tested positive, too. Incredulous, the couple got tested a second time. After all, Breslin reasoned, with a condition so rare, “the odds that the test results were wrong were greater than the odds that we would both be carriers for this.” But the second set of tests yielded the same results.
“We were devastated. We just thought it would be so easy for us to have a family,” she says.
Shifting the Burden
Though it brought terrible news, ECS spared Breslin and her husband the heartache of having a baby with a severe genetic disorder. The standard guidelines wouldn’t have prevented that — no recommendations include screening for CGD1A.
Proponents of expanded screening support it, in part, for this reason. “It allows you to check everybody for everything instead of picking and choosing based on reported ancestry,” Edwards says. “We are all human, and anyone can be carriers for any of these mutations.”
The data support this argument. When all prospective parents get tested for the same conditions, regardless of their ethnicity, “We are finding that a fair number of these conditions exist outside of the ethnicities that they’d long been associated with, such as Tay-Sachs, which has been associated with Ashkenazi Jewish people and French Canadians ,” says Gabriel Lazarin, a certified genetic counselor. Lazarin co-authored the study of 346,790 people who underwent expanded screening at Counsyl, where he is vice president of medical affairs.
If current trends are any indication, screening couples for carrier status reduces the incidence of babies born with the condition. Doctors began screening Ashkenazi Jewish couples for Tay-Sachs mutations in 1971. Today, arguably because of ethnicity-specific screening, non-Jewish parents are more likely to have a baby with Tay-Sachs disease than those who identify as Ashkenazi.
Expanded screening could also offer more accurate risk assessment for people of multiple ethnicities or unknown family background.
Expanded screening, according to Counsyl’s study, detects significantly greater fetal risk in all major U.S. ethnic and racial groups than standard guidelines do. The researchers used algorithms to model the number of fetuses that would be affected by conditions their hypothetical parents carried. Among white Northern European couples, for example, ECS predicted that 159 fetuses in 100,000 would have genetic disorders. Standard guidelines, which recommend screening Northern Europeans for spinal muscular atrophy and cystic fibrosis only, would have predicted only 55 affected fetuses.
Couples like Breslin and her husband who undergo screening before conception have more options than those who screen after. First, they could simply proceed as planned: conceive naturally and bank on the 75 percent chance that their child will not have CGD1A. Between the 11th and 13th week of pregnancy, the doctor can perform chorionic villus sampling (CVS) by taking a sample of cells from the placenta, via transcervical ultrasound, to be tested for disease. If the test is positive, couples can then decide whether to proceed with the pregnancy.
In some cases, a prenatal diagnosis can guide care in the first days of life and change the baby’s prognosis. Wilson’s disease, for example, doesn’t develop until adolescence, at which point the child has irreversible organ damage. However, if parents knew, then “they could act very early to change their child’s diet, and when that happens, it’s well known that a person with [Wilson’s] disease lives a completely normal life,” says Lazarin.
That would not have been the case for a baby with CGD1A.
“We both agreed that if the child were affected, we would want to terminate,” says Breslin. “But at the same time, I didn’t know if I could ever come back from that emotionally, so we didn’t want to be faced with that choice.”
The best chance of ensuring that a biological child will not have the condition prior to pregnancy is through in vitro fertilization (IVF), followed by a process called preimplantation genetic diagnosis (PGD). The PGD process allows each embryo to be tested for the condition before implantation; doctors then implant only the healthy embryos.
Prospective parents can also use a sperm or egg donor or adopt.
Breslin and her husband very much wanted a biological child. But they were unprepared to face either the possibility of terminating or the cost of IVF/PGD, which can run up to $12,000 per round of IVF and $3,000 to $6,000 for PGD. So they decided to put their family plans on hold.
The Risk of Knowing
Ellen Castrucci wanted no part of the tough decisions Breslin and her husband were facing. When the Rockville, Maryland-based instructional designer was pregnant with her first child, she wasn’t even sure she wanted the standard cystic fibrosis screening. Then her doctor offered the whole shebang: the chance to learn her carrier status for dozens and dozens of conditions.
Ellen’s husband, Brian, an epidemiologist and a data junkie, was enthusiastic about ECS. But Ellen couldn’t help but think about what they would have to do with that data.
“Once you have it,” she says, “you have to make a decision, and I didn’t want to live with however many months of stress and anxiety while I was pregnant, worried that I had made the wrong decision.”
Ultimately, she opted out of all screening. Today, she has two healthy children, a 7-year-old son and a 6-year-old daughter.
Undoubtedly, the tension is higher when screening takes place after conception. “This is a sensitive subject, especially since one of the actions you might take based on screening is prenatal diagnosis that could ultimately lead to termination,” says Green. Carrier screening’s link to termination, Green speculates, could be why it isn’t yet standard protocol.
Ellen says she wouldn’t have wanted the screening prior to conception either. At any point in time, the results could still elicit some tough choices, ranging from whether to trust the tests, to going for more tests, to how and whether she would have a family at all.
The distress brought about by waiting for test results and weighing all the what-ifs puts an unnecessary burden on couples during an already stressful time, says Wayne Grody, a medical geneticist and the director of the Clinical Genomics Center at UCLA Medical Center.
“Your spouse is unlikely to come back with the same really rare disease trait that you have, but it’s going to cause some anxiety for three weeks, while you’re waiting for the results,” he says. “It puts an emotional burden on the couple when, in most cases, there is no risk to the fetus.”
Of course no test can 100 percent guarantee a good outcome. “We all carry variants in debilitating genes, even if the screen comes back negative,” says Edwards. “No test is going to pick up everything. We can reduce risk, but we can’t rule risk out entirely.” Screening can show a couple just how slim their chances of conceiving a child with a genetic disorder are, but everyone has residual risk, whether from a testing error, mutations not detected by screening, or mutations not yet known to be harmful.
Furthermore, no two screening panels rule out the same risks. While there’s overlap in the panels of conditions for which each commercial lab screens, no two companies — among them Counsyl, Good Start Genetics, and GenePeeks, to name a few — test for the exact same ones. Thus two different screening panels could easily give the same couple different levels of assurance or anxiety about their risk. For some couples, this uncertainty might be reason enough to opt out of any testing. For others, it’s motivation to learn as much as they can.
Non-invasive prenatal testing (NIPT), which collects the DNA of both mother and fetus through a maternal blood sample, can screen for the increased chance for certain chromosomal anomalies, but not for single-gene conditions like CGD1A. The test began as a Down syndrome screening, but now screens for risk of trisomy 13 and trisomy 18, among others. If the test finds increased risk, prospective parents can decide whether to get the riskier, but more accurate and invasive, amniocentesis or CVS. Some say NIPT will one day be used for more subtle anomalies, like single-gene conditions.
“It’s very personal, and it should be up to the patient,” Edwards says. “It depends on the kind of information you personally would like to have for your reproductive future.”
Breslin credits the genetic counselors at the screening lab, who continued to counsel her for a couple of years after the positive test result, for her solid understanding of her family’s risks and their implications.
Access to a genetic counselor could make or break a patient’s experience with ECS, but unfortunately, many hospitals do not have a genetic counselor on staff. In a small study of women who tested positive after carrier screening, only half received their results from a genetic counselor. The rest received them by letter, email, or phone from any number of healthcare providers. Those who got their results from a genetic counselor had a much greater understanding of their risk and appropriate next steps.
Potentially powerful data could be useless or even harmful if misunderstood. Too often, the task of interpreting it falls to ill-prepared OB-GYNs and family doctors. “That opens the door to misunderstanding and potentially a liability risk, because of all the uncertainty involved,” says Green.
There is a clear need for standardized pre- and post-screening education. “Without good education behind it, expanded carrier screening could create a lot of anxiety for people, including physicians,” says Edwards. “They’re getting their patient’s positive result back for a condition they’ve never heard of, and without good educational resources, they may feel like they’ve been caught flat-footed.”
A Family is Born
Breslin and her husband were coming to terms with their decision to wait when they got a surprise. Breslin was pregnant.
“We wanted to be happy, but we were so nervous,” she says.
Knowing they might not carry the baby to term, Breslin and her husband kept the news to themselves until she was far enough along for prenatal diagnosis through CVS. “We told the doctor we didn’t even want to know the sex unless the baby was fine,” Breslin recalls.
The only lab that tested for CGD1A was across the country in Atlanta, where the test was held up for weeks because of a winter storm. The delay lasted into Breslin’s second trimester. “My doctor had already told us she wouldn’t be willing to perform the termination after the first trimester. I’d have to go somewhere else.”
She waited and worried — until her doctor called to tell her she was having a healthy girl. Today, Logan is “a healthy, crazy, two-and-a-half-year-old,” says Breslin.
About a year after she was born, Breslin and her husband started to get baby fever and decided they were ready to try IVF followed by preimplantation genetic diagnosis. The process resulted in one viable embryo that, last February, was born — a little boy named Sebastian.