DNA sequencing for metabolic disease in newborns may eventually replace traditional genetic screening methods, which check all newborns for a group of rare genetic disorders that can cause serious illness if not caught early. Nerve damage and death.
But now, research shows that these advanced genetic tests don’t work equally well for everyone: They are less accurate for non-white families, raising questions about how historical gaps in DNA research have contributed to health care inequities. worry.
A new study recently published by Stanford University School of Medicine details the problems with these genetic tests Medical Genetics. The authors describe how inequalities in the pool of collected information affect families and call for better scientific methods to fill knowledge gaps.
Traditional newborn screening, used since the late 1960s, measures biochemicals in a baby’s blood or urine, most commonly through a few drops of blood collected from a heel prick shortly after birth. It provides a clear diagnosis without relying on genetic knowledge and is not subject to the same biases as genetic testing.
Testing your blood for biochemicals is akin to tasting a baked cake, while testing your genes is more like reading a recipe to see if it works.
Testing your blood for biochemicals is akin to tasting a baked cake, while testing your genes is more like reading a recipe to see if it works.
This explains why advanced genetic testing has gained prominence in the past decade. Not only can they help families understand a diagnosis after the baby is born, they can also provide clues about the risk of the disease during pregnancy and help them understand the risk of having a child with the same disease in the future.
For now, researchers have concluded that when genetic and biochemical tests give conflicting answers, families and doctors should rely on biochemical results. At the same time, scientists must work to expand the knowledge base of genetic variants in minority groups so that when biochemical tests clearly indicate a significant risk to children, their results are not often declared “variants of uncertain significance.”
“This is what happens when the database is filled with white individuals, and this is a genetic variant in the Hispanic population,” said Christina Tise, assistant professor of pediatrics and senior author of the study. “It feels like Very unfair.”
When families are overwhelmed with a seriously ill newborn, receiving ambiguous genetic test results can be upsetting to them and can lead to confusion for health care providers, Thies said.
“The diseases we are screening for are very serious,” Thies said, adding that it is not uncommon for neonatal patients with metabolic diseases to fall into comas within days of birth. “If we can catch these patients before they develop symptoms, we can save lives and improve their outcomes.”
Although biochemical screening is the universal standard, genetic testing is increasingly offered before or after birth for a variety of reasons. Some groups are beginning to advocate for whole-genome sequencing of all newborns in neonatal intensive care units, but the findings cast doubt on whether such an approach would be equally helpful for all children and families because of historical gaps in DNA collection, Tice said. .
Her team decided to conduct the study to document the challenges they were seeing in different patient populations when using genetic testing.
Metabolism’s “Inborn Error”
Since California began screening infants for phenylketonuria in 1966, U.S. newborns have been increasingly screened early in life for genetic disorders that affect metabolic mechanisms. Most of these disorders are inherited in an autosomal recessive pattern, meaning that the baby inherits two non-functioning copies of the same gene, one from each (unaffected) parent.
Several metabolic diseases interfere with the body’s ability to process amino acids (the building blocks of food proteins). During pregnancy, when the fetus’ waste products enter the mother’s bloodstream, the mother’s body compensates for abnormal fetal metabolism. But soon after birth, because amino acids are not broken down, toxic molecules can accumulate in the newborn’s blood, which can lead to epilepsy, coma, or other serious neurological symptoms.
Newborn screening is designed to detect these diseases early: In the first days of life, a few drops of blood are collected from the baby’s heel onto a card, which is then analyzed for biochemicals that signal danger signs. Follow-up testing of biochemicals in the blood and urine can confirm whether the baby has a metabolic disease. Babies with this condition can be treated with medications, special diets and other measures to keep their brains safe.
Some medical organizations now recommend that parents be screened for disease-related genetics during pregnancy rather than waiting until the baby is born. In the best-case scenario, this “expanded carrier screening” could provide families with early warning that their child may be born with a metabolic disease so that it can be treated immediately at birth.
In the best-case scenario, this “expanded carrier screening” could provide families with early warning that their child may be born with a metabolic disease so that it can be treated immediately at birth.
Babies are also increasingly receiving genetic testing after birth. But it only works if the labs that perform the tests use genetic libraries that have previously linked specific genetic changes to a disease. Because of historical inequities in access to genetic testing and research, these tests are more likely to inform white families than other families, but few efforts have been made to measure that gap, and new research attempts to do just that.
Confusing test results
Among newborn patients with metabolic diseases at Lucile Packard Children’s Hospital at Stanford, Tice noticed that many Hispanic and Middle Eastern infants had equivocal genetic testing results, whether they were administered to their parents prenatally. The test is also a genetic test done on the newborn itself.
“Parents don’t get the same reminders during pregnancy that white families do, because the genetic variation in white families is so well understood,” Tice said.
After birth, the situation can be even more confusing: Parents may have a sick baby in the NICU whose biochemical tests clearly show a metabolic disease, but whose genetic testing results are inconclusive and confusing . This can lead to unnecessary debate about your child’s diagnosis.
In the most heartbreaking cases, some families have previously lost newborns born in places with fewer medical resources, and each newborn may have had the same genetic disease. If the genetic test is effective, it could give parents peace of mind or be able to screen for future pregnancies, Thies added.
It puts you in a different place emotionally when you have the consequences of this “uncertain meaning” lingering in your mind.
Christina Thies
“To say, ‘This genetic defect is the answer, not only to what happened to your newborn, but to why your other children died,’ is powerful.” It makes it possible for families to heal and process what happened,” she said. “But it puts you in a different place emotionally when you have this ‘uncertain meaning’ outcome lingering in your mind.”
Quantitative problem
To better understand the extent of the problem, Tise’s team compared the results of different types of newborn testing (biochemical and genetic) for all patients referred to the Metabolic Genetics Service over an 18-month period in 2020 and 2021. As a result of the first step of newborn biochemical screening (a test using a heel-spot blood sample), a total of 136 patients were referred with suspected metabolic disease. The test was designed to be overly sensitive, which meant that most patients who “screened positive” did not end up with metabolic disease.
A total of 19 of the original 136 infants were ultimately diagnosed with metabolic disease based on follow-up biochemical testing. Of those, 18 also underwent genetic testing. Of the 18 babies who underwent genetic testing, 10 had at least one “variant of uncertain significance,” although all of the patients actually had metabolic diseases, exactly the kind of confusing Tice had seen in the past Case. Of the 10 patients with confusing results, 9 were of non-white ancestry.
If the parents in the study were given expanded carrier screening (a genetic screen that looks for clues about a parent before or during pregnancy), 20 of the 36 parents (17 of whom were nonwhite) would have received inaccurate results. The results showed that their children were ultimately not at risk for metabolic disease.
What happens next?
In addition to drawing attention to the weaknesses of genetic testing and advocating for the continued use of biochemical tests even though they are less “advanced,” Thies is also considering better ways to systematically update genetic databases to reflect the causes of disease. Genetic variation in Caucasian populations. Currently, the process is cumbersome and essentially occurs one genetic variant at a time.
“This problem exists at every institution that has geneticists working on newborns, and working together we can make a big difference,” Thies said. But the time it takes to report these disease-causing genetic variants in scientific papers Usually outside the scope of work of geneticists. In the context of the vast human genome, with 3 billion sites at which genetic changes may occur, trying to increase awareness of one genetic change at a time may seem daunting.
Additionally, doctors need to overcome their reluctance to perform genetic screening on families from minority backgrounds, even though the results may be confusing, because their involvement could ultimately help other parents in the future.
The reality is that if you don’t test people of non-white ancestry, it’s a cycle of futility: the lab’s repository will never be diverse.
Christina Thies
“In the past, I’ve heard people say, ‘I don’t want to do genetic testing for this family because we’re going to get variants of uncertain significance, and it’s going to be confusing,'” Thies said. “But the reality is that if you don’t test people of non-white ancestry, it’s a cycle of futility: the lab databases will never be diverse.”
To illustrate her point, Thies describes an unexpected success. A few years ago, she reported on a genetic variant that causes an unusually severe rare disease called Zellweger spectrum disorder, moving the variant from “uncertain significance” to “pathogenic” in medical databases . Over the next 18 months, to her team’s surprise, several more families whose babies had the rare genetic variant were discovered at Packard Children’s Hospital in California and nearby hospitals.
“You never know when variants will emerge that are really important to people in the future,” Thies said. “We just won’t know how prevalent some of these variants are until the science is done.”
Image: Emily Moskal
More information about genetic testing
#Genetic #screening #inequities #DNA #tests #fail #nonwhite #families
Image Source : scopeblog.stanford.edu