Targeted Genetic Testing of Newborns May be Missing Some Disorders, Leaving Infants Undiagnosed and Untreated

Diagnosing a genetic disorder in a newborn can give the healthcare team a chance to provide early treatment or intervention that could help prevent illness or disability—or even save a life. Genetic testing of newborns requires a simple blood test, but targeted testing commonly used at centers across the nation may be leaving some genetic disorders undetected, according to a recent study conducted in part at Cincinnati Children’s—confirming whole genome sequencing (WGS) as the gold standard for diagnosing genetic disorders in newborns.

The study published July 11, 2023, in the Journal of the American Medical Association (JAMA) reports that commonly used targeted genetic testing misses diagnoses more frequently than using broad testing of the whole genetic code from the beginning of the search for a diagnosis. Cincinnati Children’s provided the most participants for the study, which was led by researchers at Tufts and Brown universities. Jae Kim, MD, PhD, co-director of the Perinatal Institute and Division Director of Neonatology at Cincinnati Children’s, was a co-author.

“More than half of the babies in our study had a genetic disorder that would have remained undetected at most hospitals across the country if not for genome sequencing technologies,” says Jonathan Davis, MD, chief of Newborn Medicine at Tufts Medical Center and co-principal investigator of the study.

The study compared a rapid test that can detect variants in more than 1,700 genes associated with rare disorders to whole genome sequencing, which identifies variants in all 20,000 genes in the human body. The multicenter effort involved testing 400 newborns and infants with a wide variety of undiagnosed conditions. Using WGS, researchers found known genetic disorders in 49% of the patients, while the narrower test detected disorders in only 27% of the cases.

Additional team members involved in the research included Daniel Swarr, MD, Division of Neonatology; Loren Pena, MD, PhD, Division of Human Genetics; Nicole Weaver, MD, co-director, Cardiovascular Genetics Clinic; Farrah Jackson, MS, CCRP, Human Genetics research coordinator; and former neonatology faculty members Kristen Suhrie, MD, and Brenda Poindexter, MD, MS.

WGS Testing Detects Rare Disorders Early

Currently, pediatric specialists follow a wide range of practices when ordering tests to diagnose unusual, complex genetic conditions. While tests that target subsets of known genetic variants can be quicker and less costly to run, patients and families can be overwhelmed as specialists request one narrowly focused test after another—and some families may be falling through the cracks.

“The importance of this study was adding prospective data that evaluated the benefits of whole genome testing in neonates against traditional sequential testing,” Kim says. “Whole genome sequencing has rapidly emerged as the standard of care for newborn genetic testing, and this paper is helping to accelerate this change.”

In one case, a care team using WGS testing helped diagnose Kabuki syndrome within the first two weeks after the child was born, when the average time to an accurate diagnosis is about five years. In other cases, teams have made earlier diagnoses of factor XIII deficiency, retinoblastoma and malignant hyperthermia thanks to WGS testing, Kim says. Broader use of WGS in newborns could help more families benefit from early diagnosis of rare genetic disorders, so that treatment or management can begin and needed resources can be identified.

About the Study

The research was led by investigators at Tufts and Brown universities. Other participating centers included Rady Children’s Hospital in San Diego, Mt. Sinai Hospital, University of North Carolina-Chapel Hill and the University of Pittsburgh.

(Published February 2024)

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