Early detection and diagnosis of inherited conditions in newborns and infants can lead to more effective therapies and better health outcomes. A growing number of devastating childhood diseases now have targeted treatments, including gene and cell therapies, that can offer permanent prevention or cures. With these developments, the implementation of newborn DNA sequencing has taken on greater urgency.
A new national study from Tufts Medical Center in Boston has found whole genome sequencing to be nearly twice as effective as a targeted gene sequencing test at identifying abnormalities responsible for genetic disorders in newborns and infants.
The study was conducted at six US hospitals from June 2019 to November 2021 and enrolled 400 newborns and infants under the age of one year with a wide variety of suspected, undiagnosed genetic disorders. Each newborn or infant received both whole genome sequencing which can identify variants in all 20,000 genes in the human body, and NewbornDx. This targeted gene sequencing test can identify variants in 1,722 genes linked to genetic disorders in newborns and infants.
The researchers found that whole genome sequencing detected a genetic disorder in 49% of patients, while the targeted gene sequencing test identified a genetic disorder in 27% of study participants. The targeted panel also missed 40% of the diagnoses that WGS captured. In addition, the researchers also found 134 new genetic diagnoses that had never before been described. Overall, 51% of patients in the study were diagnosed with a genetic disorder with either test.
The results demonstrate that whole genome sequencing should remain the gold standard for accurate diagnosis of genetic disorders in newborns and infants. Another study by researchers from the Mass General Brigham and Boston Children’s Hospital also found that by screening apparently healthy newborns using whole genome sequencing, entire families were alerted for the first time that dangerous but treatable genetic variants were present.
However, there are presently several barriers and ethical concerns to rolling out whole genome sequencing on a broader population level. Whole genome sequencing is significantly more expensive than the targeted test, and healthcare payers may hesitate to absorb these costs creating equity issues. Yet the costs involved with a protracted diagnostic odyssey later in life for children with rare inherited conditions may prove even more expensive and distressing for families with worse health outcomes.
The targeted test also only screens for specific genetic disorders that only appear in newborns and infants. Whereas whole genome sequencing may unintentionally reveal potential health risks later in life, such as Alzheimer’s disease or cancer, that the child or their parents may not want to know. The knowledge that a child could be predisposed to an incurable disease could create lifelong anxiety and distress without any potential for intervention. There are also longstanding ethical questions about informed consent and data privacy for both the child and the parents.
The study also highlighted a lack of standardization in neonatal genetics interpretation. In 40% of cases, different laboratories disagreed on whether a mutually acknowledged gene abnormality was the cause of the suspected genetic disorder in the newborn or infant. This can lead to much uncertainty about the appropriate diagnosis, therapy, and follow-up.
We must continue exploring the potential, drawbacks, and ethical concerns of genome sequencing in newborns and infants for genetic disorders to ensure these vulnerable populations receive the best care possible.