We probably saved their lives: DNA sequencing of newborns reveals high cancer risks for parents

Ten Years ago, doctors at a handful of hospitals across the United States began sequencing the genomes of apparently healthy babies, trying to figure out how the technology could reveal hidden genetic disorders that go undetected by routine newborn blood tests. New research from one such study suggests that the impact of having that kind of information extends far beyond the child whose DNA is being decoded.

In a study published Monday in the American Journal of Human Genetics, researchers at Mass General Brigham and Boston Childrens Hospital reported that of the first 159 children screened through genomic sequencing, 17 were found to have unexpected mutations in genes associated with the illness.

Over the next three to five years, in most of the 17 families of newborns, these findings prompted parents and other relatives to undergo further tests that led to the discovery of the cause of the diseases running through their family trees. In three cases, mothers who learned they carried a gene that dramatically increased their risks of certain cancers chose to have prophylactic surgeries to reduce those risks. for the newborn.

This is a real-world rebuttal to the prevailing idea that we shouldn’t share risk variants of adult-onset disease in children, said Robert Green, a medical geneticist at Harvard and Brigham and Womens Hospital who leads the BabySeq study. has produced the new research. There are ethicists who say that a child should not be used as a genetic canary in a coal mine and that a family member should not be used without their consent as an entry point for an entire family, but I would dispute that . Look at these mothers. We probably saved their lives. Are you really going to compare this to a theoretical loss of autonomy at some point in the child’s future?

As the cost of DNA sequencing plummets, the prospect of whole genome screening of millions of newborns has raised deep concerns about the usefulness of such information. Experts are divided on whether the benefits of catching disease early outweigh the costs and additional burdens on the health system, as well as the potential psychological impact on families of knowing they carry disease and child risk genes, make that decision for them before they are old enough to walk, talk, and give consent.

There are other ongoing clinical trials evaluating the health benefits, financial costs, and ethical implications of sequencing versus standard blood tests that all newborns can identify a limited number of hereditary conditions. They include a series of federally funded studies in the US and a pilot program in the UK that will sequence the genomes of 100,000 newborns over the next two years. Each of them returns different amounts of genetic information to families and their doctors. But only BabySeq provides a glimpse into what lurks in 78 genes associated with increased risk of diseases developing in adulthood.

BabySeq is a clinical trial involving several hundred families, some with sick children, some with healthy children; half of the babies received standard newborn screening and the other half received screening plus sequencing. When the trial was first launched in 2013, Green and his colleagues wondered how much genetic information to give back to parents about their new baby. Initially, they set out to reveal only the genetic variants implicated in a number of childhood-onset conditions. But two important things happened during that time that changed their minds.

The first was that the American College of Medical Genetics and Genomics came out with a new recommendation that the accidental discovery of any of 56 genes for highly actionable conditions means things you could diagnose and treat, or if not treat, at least monitor be carried back to all individuals undergoing clinical genomic sequencing, regardless of age. Three of these conditions only appeared in adulthood: cancers caused by variants in the BRCA genes and an aggressive form of colorectal cancer called Lynch syndrome.

The second is what happened with one of the first participants enrolled in the BabySeq sequencing arm. The baby was born with a serious heart problem and soon died. But lurking in her DNA data was the discovery of a BRCA variant associated with a 45 percent increased risk of breast cancer in women, as well as an elevated risk of other cancers in both sexes. The BabySeq team was able to deduce from saliva samples collected from the parents that the mutation came from the mother. But because of the study protocol, they weren’t allowed to tell the family what they found.

The uncomfortable situation led them to rethink their strategy and rework their protocol. Consequently, all subsequent families enrolled in BabySeq were given the opportunity to receive information on adult-onset disease risk genes. According to the latest data from the study, most of the families have joined. In 13 of the 17 children found to have disease-associated mutations, the information they received prompted additional screening for at-risk family members. The experience had a big impact on how the BabySeq project is now being scaled up.

Green and his collaborators recently began recruiting for a second phase of the trial, which aims to enroll more than 1,000 children and their families from racially, ethnically and socioeconomically diverse communities in Boston, New York and Birmingham, Ala. The first BabySeq study overwhelmingly featured wealthier, college-educated people with European ancestry, making the findings not very generalizable to the larger U.S. population. Other changes to this stage include the recruitment of slightly older infants up to 6 months of age.

Parents who enroll in this phase are notified that they will receive genetic information about their child related to adult-onset conditions, but there is no way to opt-out without refusing to participate altogether.

What this whole thing is helping us think about is the different ways we view benefits for families, Green said. I think it’s a good thing to find these variations in children for the benefit of the whole family.


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