Genome Sequencing Shows Strong Efficacy in Diagnosing Infant Genetic Disorders


In a clinical study diagnosing genetic disorders, genomic sequencing did not report 19 variants found by a targeted neonatal gene-sequencing test and the targeted panel did not report 164 variants recognized by genomic sequencing.

 Jonathan Davis, MD, chief of newborn medicine at Tufts Medical Center

Jonathan Davis, MD

Recently published in JAMA, results from the Genomic Medicine for Ill Neonates and Infants study (GEMINI; NCT03890679) showed that whole genome sequencing (WGS) had a higher diagnostic yield for genetic disorders in newborns and infants than targeted gene sequencing test despite slower result turnout.1 These findings suggest that WGS can guide medical decisions and can improve health outcomes among infants.

Among 400 newborns and infants, findings showed 49% of patients had a genetic disorder detected with WGS (95% CI, 44%-54%) in comparison with 27% (95% CI, 23%-32%) of those through targeted gene sequencing test (95% CI, 23%-32%). Most discrepancies were because of the inherent technical limitations of the targeted genomic-sequencing test; however, more than 40% of incongruent variant reporting was because of algorithmic identification and human interpretation. Of the cohort, more than half (51%; 95% CI, 46%-56%) had at least 1 genetic variant identified by either test that was deemed as causal or highly suspicious of causing the presenting phenotype.

“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,” coprincipal investigator Jonathan Davis, MD, chief of newborn medicine at Tufts Medical Center, said in a statement.2 “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.”

GEMINI, a prospective, comparative, multicenter study, enrolled newborns and infants under the age of 1 year with several different suspected, undiagnosed genetic disorders between June 2019 and November 2021 from 6 centers across the United States. The participants had testing with genomic sequencing and a targeted neonatal gene-sequencing test, called NewbornDx. In each lab, researchers conducted an independent interpretation of the variants, which were guided by the phenotype in the patient, then had the results returned to the clinical care team.

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Based on the findings from either platform, families were given genetic information such as change in clinical management, therapies offered, and redirection of care. The primary end points in the analysis included molecular diagnostic yield of participants with at least 1 pathogenic variant or variant of unknown significance, the time of return with the results, and the changes in care for the patient.

“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,” coprincipal investigator Jill Maron, MD, MPH, chief of pediatrics at Women & Infants Hospital of Rhode Island, said in a statement.2 “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.”

The unidentified variants by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar OR, 8.6;95% CI, 5.4-14.7). Interpretation of the variants in the labs differed by 43%. Notably, the changes in care impacted 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in decision-making, regardless of the diagnosis.

In light of limitations, using WGS for genetic diagnosis took an average of nearly 2 days longer to for routine results compared with the targeted gene sequencing test (6.1 days vs. 4.2 days). For urgent cases (n = 107) the time for return on the results was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Also, the targeted test was less costly, and screens for specific genetic disorders only in newborns and infants, eliminating the risk of revealing potential health risks later in life unintentionally. Another concern was the lack of standardization in neonatal genetics interpretation since in 40% of cases labs contradicted whether a gene abnormality, mutually acknowledged, was the cause of the suspected genetic disorder in the patient.

"This study provides further evidence that genetic disorders are common among newborns and infants," coinvestigator Stephen F. Kingsmore, MD, DSc, president and CEO of Rady Children's Institute for Genomic Medicine, said in a statement.2 "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."

1. Maron JL, Kingsmore S, Gelb BD, et al. Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder. JAMA. 2023;330(2):161-169. doi:10.1001/jama.2023.9350
2. Genome sequencing nearly twice as effective as a targeted gene-sequencing test at diagnosing genetic disorders in newborns and infants. News Release. Tufts University. Published July 11, 2023. Accessed August 21, 2023.
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