A national study, led by researchers at Tufts Medical Center, has found whole genome sequencing (WGS) to be nearly twice as effective as a targeted gene sequencing test at identifying abnormalities responsible for genetic disorders in newborns and infants. The Genomic Medicine in Ill Infants and Newborns (GEMINI) study did, however, find that time to results was longer when carrying out WGS, when compared with a commercially available targeted neonatal gene-sequencing test.

“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,” said Jonathan Davis, MD, chief of newborn medicine at Tufts Medical Center and co-principal investigator of the study. “Successfully diagnosing an infant’s genetic disorder as early as possible helps ensure they receive the best medical care. This study shows that WGS, while still imperfect, remains the gold standard for accurate diagnosis of genetic disorders in newborns and infants.”

The study, “A Comparative Analysis of Rapid Whole Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants with a Suspected Genetic Disorder: The Genomic Medicine for Ill Neonates and Infants (GEMINI) Study,” is reported in The Journal of the American Medical Association (JAMA).

To improve the clinical diagnosis of acutely ill newborns and infants, genomic sequencing must be able to generate accurate molecular diagnoses quickly, and without “the ethical burden” of identifying unintended secondary findings, the authors noted. Commercially available targeted–sequencing tests can look at specific genes associated certain genetic disorders. Such gene panels are less costly than genomic sequencing, generate faster results, and rarely identify secondary findings, the team continued. However, they stated, “A comparative analysis between genomic sequencing and a targeted neonatal gene-sequencing test has not been previously performed.”

Funded by NIH, the first-of-its-kind GEMINI Study, carried out at six centers across the U.S., enrolled 400 newborns and infants under the age of one year, who had a wide variety of suspected undiagnosed genetic disorders. Each newborn/infant was tested using WGS, which can identify variants in all 20,000 genes in the human body, and NewbornDx, a targeted gene sequencing test that can identify variants in 1,722 genes known to be linked to genetic disorders in newborns/infants. “Primary end points included the molecular diagnostic yield of both tests, time to return of results (TTR), and clinical utility,” the investigators noted.

The researchers found that WGS detected a genetic disorder in 49% of patients, while the targeted gene sequencing test identified a genetic disorder in 27% of the study participants. The targeted panel missed 40% of diagnoses that were captured by WGS. Overall, 51% of patients in the study were diagnosed with a genetic disorder with either test. “Among 400 infants, 204 participants (51% [95% CI, 46%-56%]) had at least 1 genetic variant identified by either test that was deemed as causal (either pathogenic or likely pathogenic) or highly suspicious (VUS) [variant of unknown significance] of causing the presenting phenotype,” the scientists wrote in their paper.

The researchers also found 134 new genetic diagnoses that had never before been described. “GEMINI identified 134 novel variants in genes directly related to phenotype; 73 potentially causal variants were classified as a VUS per American College of Medical Genetics guidelines,” they reported.

WGS is not without its disadvantages, however, they noted. On average, it took nearly two full days longer to receive routine results from WGS (6.1 days) compared with the targeted gene sequencing test (4.2 days). The targeted test is also less expensive, and since it screens for specific genetic disorders that only appear in newborns and infants, its use eliminates the risk of unintentionally revealing potential health risks later in life, such as Alzheimer’s disease or cancer, that the child’s parents may not want to know.

The GEMINI 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/infant. The authors further noted, “Discordant variant identification and classification between laboratories occurred despite sharing identical DNA samples and clinical information.”

Most discrepancies were due to the inherent technical limitations of the targeted genomic sequencing test, they further pointed out. “However, more than 40% of incongruent variant reporting was due to algorithmic identification and human interpretation … Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.”

And while the team pointed out that “caution should be used by clinicians when interpreting molecular diagnostic results from any single genomic-sequencing platform,” they also noted that although direct clinical interventions were implemented for only 19% of infants, following genetic testing, “… most physicians viewed the testing as useful or very useful in their clinical decision-making, even when a nondiagnostic result was returned.”

Jill Maron, MD, MPH, chief of pediatrics at Women & Infants Hospital of Rhode Island and co-principal investigator of the study, commented, “Many neonatologists and geneticists use genome sequencing panels, but it’s clear there are a variety of different approaches and a lack of consensus among geneticists on the causes of a specific patient’s medical disorder. Genome sequencing can be costly, but in this targeted, at-risk population, it proves to be highly informative. We are supportive of ongoing efforts to see these tests covered by insurance.”

Stephen F. Kingsmore, MD, DSc, president and CEO of Rady Children’s Institute for Genomic Medicine and a co-investigator and second author of the study, added, “This study provides further evidence that genetic disorders are common among newborns and infants. The findings strengthen support for early diagnosis by rapid genomic sequencing, allowing for the use of precision medicine to better care for this vulnerable patient population.”

Noting limitations of their study, the authors concluded, “GEMINI confirms the need to have such testing widely available and covered by Medicaid and commercial insurance. Additionally, earlier diagnoses may lead to new therapeutics. These technologies hold great promise for improving access to pharmacologic, biologic, and gene therapies in high-risk populations.”

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