There is mounting evidence that DNA sequencing can aid in the diagnosis of the youngest patients in the health care system: infants in their first year. Reading the genome is one challenge, but interpreting it is another, according to a new report on researchers’ efforts to transform long sequences of A’s, T’s, G’s, and C’s into information that physicians and patients can use.
Genomic Medicine in Ill Infants and Newborns, or GEMINI, is a prospective study in which the entire genomes of 400 hospitalized infants were sequenced and also tested with a targeted gene panel.
Although delayed, whole-genome sequencing outperformed the targeted test in identifying the cause of an infant’s symptoms, with a 49% diagnosis rate versus 27% for the narrower panel. For one-fifth of the participants, this resulted in treatment modifications, such as the use or avoidance of particular medications and surgical procedures.
Despite working with identical patient samples and medical records, the study revealed that laboratories frequently interpret genetic information differently. In 43% of instances, laboratories interpreted genetic variants differently, indicating the need for more standardized methods to determine which mutations could explain a patient’s symptoms.
The findings, which were published in the Journal of the American Medical Association on Tuesday, come as the price of genetic sequencing plummets.
Nevertheless, two decades after the initial completion of the Human Genome Project, the potential of DNA sequencing to revolutionize health care remains largely unrealized amidst unanswered questions regarding the total cost and utility of these tools.
The authors of the study say their findings contribute to the growing body of evidence that sequencing plays a role in diagnosing and treating infants with severe illnesses.
Jill Maron, a pediatrician at Women & Infants Hospital of Rhode Island and the study’s lead author stated, “This is yet another study demonstrating the efficacy of genomic sequencing when applied to the right population.” “Any test that can diagnose more than half of newborns is monumental.”
The GEMINI study, which operated from 2019 to 2021 and was led by Tufts Medical Center, united six hospitals from across the United States.
Babies with severe, otherwise unexplained symptoms, such as bleeding or seizures, who were suspected of having a disorder were included in the study. 58% of the neonates included in the study were male, 31% were Hispanic, 13% were Black, and 6% were Asian.
Less than a teaspoon of blood was collected from infants and sent to either Rady Children’s Hospital in San Diego, where infants’ whole genomes were sequenced, or Athena Diagnostics, a diagnostic testing company owned by Quest Diagnostics, where samples were tested on a panel of more than 1,700 genes.
While it typically took six days to yield whole-genome results compared to four days for the panel, the whole-genome method was more commonly used to diagnose infants. Scanning the billions of chemical letters in a person’s genome enabled researchers to analyze genes not included in the targeted panel and to examine larger-scale changes in which a segment of DNA is duplicated, reversed, or relocated.
“As a practicing clinician, I can tell you that it is counterproductive to perform panel after panel after panel after panel because insurers will pay for a panel,” Maron said. “You’ve actually wasted money if you’ve performed four panels when all you needed to do was a complete genome.”
In many instances, sequencing identified maladies that otherwise would not have been on a physician’s radar. Only one-third of geneticists’ pre-test reports included the disorder subsequently identified by testing as a potential cause.
Maron added that the benefits of sequencing extended beyond an initial diagnosis. In one instance, researchers diagnosed an infant with hemophilia, but an examination of the infant’s genome revealed that the infant was susceptible to a potentially fatal reaction to certain types of anesthesia.
Maron said this prompted a last-minute phone call as the infant was being wheeled into surgery to ensure distinct anesthetics were used. In other instances, sequencing neonates actually aided in the diagnosis of parents who had been afflicted with the same disorder for years, an unanticipated benefit identified by other studies as well.
These are impressive benefits, said Jason Vassy, a researcher at Harvard Medical School whose work resides at the intersection of primary care and genomics and who was not involved in this study. The main question: Whether sequencing would yield the same advantages in alternative health systems
These remain academic medical institutions. As a result, these clinicians are likely quite perceptive,” Vassy said. “In the hands of a real-world [neonatal intensive care unit], you might see a different kind of performance.”
In addition, researchers soon realized that generating this genetic information was only part of the difficulty. Both laboratories (Rady Children’s and Athena Diagnostics) detected the same variant but interpreted it differently in more than 80 instances.
This meant, for instance, that one lab reported a variant to be disease-causing while the other lab labeled it a variant of unknown significance, a catch-all term for genetic variations that researchers do not completely comprehend.
In the present investigation, researchers erred on the side of caution and chose the lab that expressed the most concern. However, the authors of the study assert that these disparities demonstrate the need for greater standardization in genome interpretation.
Scientists rely on algorithms that consider a patient’s symptoms, genetics, and the current understanding of gene function to generate ranked lists of variants suspected of causing disease. Then, geneticists manually review these inventories and compile a report using their own expertise.
“Sequencing is not what provides the answer. It’s all about interpretation,” said Maron. “You reason, ‘Well, if you sequence it, you must know.’ “This is not the case, and we must be mindful of this.”
The authors of the study are currently conducting a follow-up analysis to determine whether the advantages of whole-genome sequencing in GEMINI outweigh its costs.
Prior research in California determined that spending $2 million to sequence the DNA of critically ill infants resulted in savings of $2.5 million due to shorter hospital stays and other cost-saving measures.
Researchers also hope to diagnose the nearly 200 participants for whom the cause of their disease remains unclear. In some instances, the answer may not be genetic, but the authors are planning a future study to determine whether they overlooked any genetic disorders.
To accomplish this, they intend to use long-read sequencing, a technique that reads the genome in larger segments and can decipher more complex mutations, and artificial intelligence to more efficiently scan medical records for symptom information that can assist researchers in making sense of genetic variants.
The most recent study uncovered 134 genetic variants that have never been reported, information that will help future researchers better comprehend these variants. According to Maron, this is a clear indication that this discipline is still in its infancy, much like the tiny patients that doctors and scientists are attempting to aid.