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Targeted Genome Sequencing May Offer Clinical, Ethical Benefits in Diagnosing Genetic Disorders in Some Newborns, but More Research Needed

A national clinical trial led by Tufts Medical Center researchers has found that both targeted genome sequencing and whole genome sequencing may help diagnose genetic abnormalities in neonates and infants. However, the technology and interpretations of results continue to have significant limitations that require further research and understanding. The study, “Novel Variant Findings and the Challenges Associated with the Clinical Integration of Genomic Testing,” was first published online on the JAMA Pediatrics website on February 15, 2021. 

The research is supported by a five-year $8.3 million grant award from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The study is the first of its kind to compare targeted genomic sequencing, aimed at diagnosing genetic disorders that present in the newborn period and early infancy, with more comprehensive whole genome sequencing. The ongoing trial includes six study sites across the country with an anticipated enrollment of 400 newborns and infants with a wide variety of suspected genetic disorders that have not been diagnosed with standard testing. Each infant receives both whole genome sequencing and targeted genomic sequencing, which analyzes 1,722 genetic disorders known to affect newborns. The researchers then compared the benefits of the two approaches for identifying genetic abnormalities.

“To date, the study has shown that in about half the cases, the technologies quickly diagnose the infants’ genetic diseases,” said Jill Maron, MD, MPH Executive Director of the Mother Infant Research Institute at Tufts Medical Center, Vice Chair of Pediatric Research at Tufts Medical Center and Co-Principal Investigator of the study. “While a 50 percent diagnostic rate is encouraging, half of all enrolled subjects remain undiagnosed. We currently don’t understand whether these infants truly do not have a genetic disorder or if our limited understanding of the genome has failed to properly diagnose them.”

In an additional complexity found in the ongoing trial, the laboratories performing whole genome sequencing or the targeted analysis reported different interpretations of the role the detected genetic variants played in an infant’s disease about one-third of the time. 

Whole genome sequencing is more costly than targeted sequencing and comes with risks of unintentionally revealing potential issues that could affect the infant later in life. However, the targeted panel only screens for genetic disorders that appear in the newborn and can be addressed immediately. As a result, its use in place of the whole genome sequencing would minimize ethical dilemmas for physicians and avoid burdening families with information about diseases for which their infant might be at greater risk as an adult.

“It’s clear from this study that there is still much that needs to be learned about the best approach to integrate genetic testing into neonatal clinical care,” said Jonathan Davis, MD, Chief of Newborn Medicine at Tufts Medical Center and Co-Principal Investigator of the study. “While targeted genomic sequencing unquestionably offers great future potential, the technology is still in its infancy. More research needs to be done in this area to help us better understand and interpret the genetic variants that we are seeing and determine if they are causing the signs and symptoms in these infants.”

Additional study sites include Rady Children’s Hospital in San Diego, Mt. Sinai Hospital, University of North Carolina-Chapel Hill, Cincinnati Children’s Hospital and the University of Pittsburgh.

The study is supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number U01TR002271.


About Tufts Medical Center and Tufts Medical Center 

Tufts Medical Center is an exceptional, not-for-profit, 415-bed academic medical center that is home to both a full-service hospital for adults and Tufts Medical Center. Conveniently located in downtown Boston, the Medical Center is the principal teaching hospital for Tufts University School of Medicine. The Medical Center features a level one trauma center with rooftop helipad, the largest heart transplant center in New England and a renowned research program, ranking among the top 10 percent of independent hospitals to receive federal research funding. A physician network of 1,800 New England Quality Care Alliance doctors represents our strong commitment to health in the community. Tufts Medical Center is a founding member of Wellforce. For more information, visit