Imagine you are an expectant parent. Just a couple of months into your pregnancy, you opt for an easy genetic screen. A result comes back: the fetus is likely missing a chunk of DNA at site 11.2 on the long arm of the 22nd chromosome—a variant associated with serious medical and developmental issues.
You go online and learn that at least 1 in 4,000 people have this “22q11.2” microdeletion, but the true figure may be much higher. You read about 22q11.2 deletion syndrome’s 180-plus symptoms, including heart malformations, hypocalcemia, intellectual disability, autism and schizophrenia. You discover the bewildering treatment guidelines, the specialist clinics scattered throughout the country, and the vibrant patient advocacy movement spearheaded by the International 22q11.2 Foundation.
Yet the same pathogenic variant—a genetic change or “mutation” known to cause disease—has been found in people with much milder symptoms, and some who barely seem affected at all. No one can give you solid risk factors because our knowledge of 22q11.2 deletion syndrome (also known as DiGeorge syndrome) is riddled with “ascertainment bias”: only people with telltale problems are likely to be tested for it.
Confronted with such profound uncertainty, what do you do? Follow up with traditional diagnostic testing, with its invasiveness, discomfort and small risk of miscarriage? And if the result is confirmed, do you abort the pregnancy?
This sort of dilemma is becoming commonplace due to a revolutionary noninvasive prenatal screening technology, known as NIPT or NIPS, that can detect genetic variants as early as nine weeks into pregnancy using a simple blood sample from the mother. NIPT platforms screen millions of tiny fragments of circulating DNA that are no longer encased in cells; they are free-floating. Most of these “cell-free DNA” (cfDNA) fragments come from the mother, but some will come from the fetus as well. NIPT platforms count cfDNA from different segments of the genome to detect variants in the fetus. If, for example, there are fewer cfDNA segments from the 22q11.2 region relative to others, the fetus will be flagged as “high-risk” for the 22q11.2 deletion syndrome.
In short, it is a screen for risk of a disease rather than a diagnostic tool, but NIPT avoids the unpleasantness of invasive tests such as amniocentesis, and the risk that tests carry. It is also covered by major insurers.
Prenatal screening is big business. The annual market for NIPT is already around $4 billion dollars and is growing rapidly; like other prenatal genetic tests, it is not regulated in the US
NIPT has already helped millions of families, including mine, rule out several serious genetic disorders early in pregnancy, while allowing many others to make informed reproductive decisions when the screens detect a variant.
As a front-page article published in the New York Times Recently outlined, NIPT is becoming a routine part of prenatal care even though most fetuses who screen positive for rare conditions do not have the variant in question. Like many other screens, NIPT often subjects patients to an agonizing wait until further diagnostic testing sorts the true versus false positives. To be clear, only invasive tests like amniocentesis that analyze DNA taken directly from fetal cells can confirm a prenatal genetic diagnosis. As a recent recommendation from the Food and Drug Administration belatedly averred, NIPT companies and health care providers should be upfront about that.
But this question of false positives only scratches the surface of the myriad dilemmas unleashed by cutting-edge prenatal screening technologies such as NIPT and preimplantation genetic diagnosis (PGD)—a process in which embryo a lab-fertilized is screened for genetic disorders before being implanted into a womb.
So, what about the families whose positive NIPT or PGD result is confirmed by later diagnostic testing? They are the ones who must then make the life-altering decision to either continue or abort a pregnancy. What does this revolution in prenatal screening mean for them, for groups affected by genetic disorders, and for society?
To confront these questions, we need to look at the kinds of genetic conditions NIPT and PGD platforms pick up. Down syndrome (trisomy 21) understandably dominates discussions about prenatal screening, but it is the highly visible tip of a much larger, murkier iceberg. For every genetic variant that explains a well-characterized condition, there are many more whose implications are much harder to pin down. Some produce symptoms that are consistently severe, while others are variable or mild, but because of ascertainment bias we do not know their true range of health and developmental effects. Some are very rare, others are not; Precise estimates are notoriously elusive. Cumulatively, however, these disorders are quite common.
If NIPT and PGD become as widespread and comprehensive as experts anticipate, many thousands of expectant parents a year will learn that their fetus has a pathogenic variant. But we will not always be able to tell them what that means for their potential child’s future.
Companies often add genetic variants to their prenatal screens as soon as their technology can detect them, not because of careful assessments of severity or treatability. Very early on, NIPT expanded to include the 1 in 1,000 people with trisomy X (people with three X chromosomes) or XYY syndrome (an extra Y). Most people with trisomy X and XYY are so mildly affected they are never even referred for genetic testing. Whole extra chromosomes were just easy targets for a new screening technology.
Over the past few years NIPT has expanded to include a panoply of lesser-known and underdiagnosed disorders such as 22q11.2 deletion syndrome, 1p36 deletion syndrome and several others. PGD and invasive tests already include these and many more. With fierce competition and rapid innovation, it is clear where this is heading: mass prenatal genetic screening for an ever-growing list of genomic variants.
NIPT and PGD therefore raise ethical issues that do not fit neatly into futuristic discussions of “designer babies” or entrenched debates about abortion.
Identifying genomic variants in fetuses is getting easier and easier, but it will take years of investment to provide robust information, counseling and care for families confronting genetic diagnoses.
Many more parents will face wrenching dilemmas about selective abortion, the decision to terminate a pregnancy following a positive prenatal genetic test. Studies have shown that people often decide to terminate a pregnancy after finding even mild genetic conditions such as the trisomy X and XYY syndromes. After all, as disability advocates have long pointed out, including a condition on a prenatal genetic test that implies that it may be incompatible with a “life worth living”—especially in a society that places huge burdens on families raising a child who is disabled, ill or developmentally different.
NIPT and PGD may transform the landscape for genetic disorders and differences. Many more people will come into the world with a diagnosis. But the very demographics of these genetic conditions may change as a result of screening and selective abortion. They will probably become less common overall, but also skewed toward people who are more religious or less able to access genetic testing and abortion services—namely people who are socioeconomically disadvantaged or who live in solidly Republican states. Paradoxically, the patient advocacy groups dedicated to these conditions may end up with more members even as the populations they represent decline.
With so many genetic variants out there, NIPT and PGD have profound implications for the way we deal with disability and developmental difference as a society. It challenges us to consider a quickly emerging future where prenatal genetic screening has complex eugenic effects—not because of coercive, racist government programs that harken back to the early 20th century, but because thousands of legitimate, intensely personal decisions will transform the population-level distribution of some forms of disability and difference. That may be unsettling for those of us who ardently support women’s reproductive rights. interactive, non-invasive prenatal genetics is uncharted territory; we must grapple with the deep dilemmas it poses.