Ethics

A Newborn Challenge

Genomic sequencing at birth raises scientific, social, and ethical questions.

By Turna Ray
Illustration by Dan Matutina

A few days after Erica Chaplin gave birth to a healthy baby boy, Benjamin, she and her husband, Donald, were approached by a research assistant in the maternity ward of Brigham and Women’s Hospital in Boston and asked if they wanted to take part in a survey about genomic sequencing. Researchers were gauging new parents’ interest in a hypothetical option: If given the opportunity, would you have your newborn’s genome sequenced? Sequencing could reveal much more information about the child’s future health risks than the current, state-mandated blood screening test that at least 4 million newborns in the U.S. receive each year.

Given their backgrounds — Erica is a pharmacist and Donald previously worked at a genetic testing company — they were enthusiastic about the study. They read over information about genomics, discussed it, and responded, as did nearly 83 percent of the more than 500 parents surveyed at the hospital, that they would be interested in testing their newborn. The Chaplins understood that sequencing their son’s genes might reveal he had increased risks for serious diseases or that he had an inherited condition that might threaten his health.

“We were trying to think what would happen if the test came back and he had some kind of congenital heart condition or some devastating result,” Donald says. “For us there wasn’t any result that we could have had where we’d want to bury our head in the sand and not know about it.”

For us there wasn’t any result that we could have had where we’d want to bury our head in the sand and not know about it.

Not every parent was as excited about this hypothetical testing as the Chaplins were. Approximately 11 percent said they were “a little interested,” while 6 percent had no interest at all in having their baby tested. Nick Catella, an engineer who became the father of a healthy boy in 2013, was in the latter group of respondents. “I wasn’t really convinced of the upside of it,” Catella says. “For cases where you are able to determine your child is going to have some health issue, if there is nothing we can do … then I am not sure what the upside would be of screening.”

This hypothetical situation may not be so far from reality. While the current standard blood screening for newborns can identify certain disorders, genomic sequencing can reveal much more, such as the risk of future diseases, and that raises many questions. For example, if parents discover through sequencing that a child will develop cancer in the future, when should they tell the child? How would it change the care and surveillance the child receives? How would it affect the parents’ attitude towards the child and their willingness to exert discipline? How will the test results affect other family members? Who has a right to the information, and what if it was used against the child?

These are precisely the kinds of concerns that the National Institutes of Health (NIH) want researchers to explore before deploying this powerful technology in clinical practice. Although the survey showed the majority of parents are interested in genomic sequencing for their newborns, the technology as it stands today cannot replace the conventional biochemical testing performed on newborns, says Alan Beggs, who heads a center for rare disease research at Boston Children’s Hospital and is a co-leader of the BabySeq Project, a collaboration between Boston Children’s Hospital and the Brigham and Women’s Hospital.

In BabySeq, researchers are planning to sequence the exomes — some 20,000 genes that code for proteins — of healthy and neonatal intensive care unit babies, in addition to employing standard screening, and compare the results to those of babies who receive just the conventional screening. The NIH last year awarded $6 million over five years to BabySeq to investigate the scientific, social, and ethical questions surrounding sequencing newborns.

“There is this thought that this could be a new paradigm for the future, where every baby gets [sequenced] and that this may replace traditional newborn screening assays,” says Beggs. “I don’t see that that’s what we’re able to pilot now, nor do we want to pilot that now.” In the near term, if sequencing is implemented for newborns, he says, it will likely be used as a complement to traditional screening. Before that happens, he says, “the question is what additional things can we learn and are there any obvious risks or dangers that become apparent through doing this.”


Saving Babies

Newborn screening (NBS) started in the U.S. with the dogged efforts of microbiologist Robert Guthrie, who in the 1960s traveled from state to state convincing lab directors to implement his cheap and easy-to-use test for the birth defect phenylketonuria (PKU). This disorder, which affects one out of 10,000 to one out of 15,000 babies born in the U.S., is due to an inherited genetic mutation that causes the amino acid phenylalanine to build up in the body. If untreated, PKU can lead to severe intellectual disabilities. If identified early, it can be treated by a strict diet of foods containing low levels of phenylalanines.

Guthrie’s test involved pricking the heel of a newborn baby, collecting drops of blood on filter paper, and testing them in the lab to see if bacteria would grow, detecting the presence of phenylalanine. Today, all 50 states test for PKU, and the American College of Medical Genetics and Genomics (ACMG) recommends that state programs test for 29 other rare disorders. It is estimated that state NBS programs save or improve the lives of more than 12,000 babies born in the U.S. annually.

“Newborn screening is really based on that model, whereby catching all these conditions early, really within the first year of life, drastically improves a child’s health,” says Natasha Bonhomme, vice president of strategic development at Genetic Alliance, a nonprofit that provides educational resources to families living with genetic disorders.


Pros and Cons

The dropping cost and growing power of advanced sequencing technologies is challenging the principles on which NBS programs have operated for over 50 years. The roughly $100 million price tag of sequencing the first human genome 14 years ago has now dropped to less than $2,000, with researchers expecting to reach a goal of $1,000 soon. Using these tests, researchers are improving their ability to diagnose rare diseases, pinpoint genomic variations that increase patients’ chances of illness, and pick up a host of variants whose association with disease is uncertain.

Supporters of genomic sequencing say that providing such testing to newborns in a research setting would vastly improve the understanding of how genetic factors interact with the environment and influence health throughout our lives. It would also provide the greatest chance for preventing the ailments burdening society today. Others want to proceed with caution. They are particularly concerned about the impact that information about genetic risk might have on healthy babies.

“If you get a false positive, maybe you can make a decision that you might regret,” says Catella, who wasn’t interested in genomic testing his newborn in the survey. “You can do something that you don’t actually need, and it may end up hurting you or your child.”

Many, like the Chaplins, worry that such testing could reveal information with negative social implications for the child. Although the Genetic Information Non-Discrimination Act protects people against employers and health insurers who use test results against them, the law doesn’t cover life, disability, and long-term care insurance.

Then there are privacy concerns. Parents in Texas and Minnesota filed lawsuits in the last five years accusing the government of violating their rights by storing the results and blood spots from state-mandated NBS programs without appropriate consent. The lawsuits raised questions about whether parents in busy maternity wards were being educated or even informed about how their babies’ test results would be stored and used in research. Now, consider exome or whole-genome sequencing and the amount of data those yield and what might happen if these tests are offered as part of a state-run program.

Genetic Alliance’s Bonhomme points out that “you’re going to be elevating those privacy concerns quite a bit.” She adds that the prospect of such sequencing becoming part of a state-run NBS program is a long way in the future, however.


Ethical Questions

While considerations of what’s most beneficial to the baby are paramount in conventional screening programs, exome or genome sequencing can reveal information that affects extended family. Researchers working on newborn genomic testing projects are spending a lot of time with ethics committees figuring out what to report to families. In BabySeq, Beggs and his team are proposing to return only results that affect childhood onset conditions. But questions remain about what to do with genetic risk variants for adult onset conditions that might have health implications for the parents.

For example, a test could uncover that a newborn girl has a BRCA mutation that increases her risk for breast and ovarian cancer. Under the current study plan, Beggs’ team wouldn’t report that for the baby, since the mutation wouldn’t be a concern for her until she became an adult.

“We can, certainly for [the newborn’s] sake, wait to tell her until she’s old enough to decide for herself whether she wants this information,” Beggs says. But “if it’s inherited from the mom … you could potentially save [the mom’s] life by letting her know, and the same goes for any female relatives who carry it. Ethically there is an obligation to consider the health of these relatives, knowing what we know.” Relaying these actionable incidental findings to family members is also best for the baby, as Beggs sees it. “If you want to reduce it back to only the benefit for the infant, you could say if that infant’s mother dies while she is still a child, that would negatively impact her,” he says.

The ACMG caused a stir last year with its recommendation that for all patients who have had their exomes or genomes sequenced, doctors should return results on clinically actionable mutations in 56 disease-associated genes. After many in the medical community objected, arguing that patients should have the right to not know incidental findings, the group revised the guidelines to allow patients to opt out of having those genes analyzed.

Joe Vockley, chief operating officer and chief scientific officer of the Inova Translational Medicine Institute (ITMI), where researchers are whole-genome sequencing newborns, mothers, and fathers as part of a number of ongoing studies, says parents can survey a “laundry list” of options before deciding what they want to know. They can choose to get all or none of the results back, find out if they have mutations in the genes on ACMG’s list, or learn only about genes known to cause diseases.

“Most of them check the box that they want to know everything,” Vockley says. But researchers don’t report everything, he adds. A result showing a newborn has a mutation in the HTT gene responsible for Huntington disease, is one they wouldn’t report. “That’s a disease of late onset that has no therapy whatsoever,” Vockley says.

Moreover, the sequencing platforms need to be more accurate, the interpretive tools need further standardization, and the turnaround time needs to be quicker, researchers say. For whole-genome or exome sequencing to be informative for the baby during the critical early days, the results would have to be available around the same time as standard screening reports, which take about a week. Some labs take several months to return results from advanced sequencing tests.

According to Benjamin Solomon, chief of ITMI’s division of medical genomics, it’s possible to return results faster, but the problem, based on current technologies, is scale. “To do it across the country, it would break the bank,” he says.

The technology, the healthcare system, and society at large may not be ready for every newborn to have his or her genome or exome sequenced, but the studies at Inova and Boston Children’s and Brigham and Women’s hospitals are important first steps toward broader implementation. Beggs would want to live in a future where every baby is whole-genome sequenced at birth, but only if the benefits outweighed the risks, he says.

“Everything we do today is going to be superseded by newer, better, and more sensitive and specific methods,” he says. “But the promise is there, and today’s studies will help us make the most of that promise tomorrow.”