Identifying Genetic Disorders in Infants with Whole Versus Targeted Genome Sequencing: Insights from The GEMINI Study
October 11, 2023
The Genomic Medicine for Ill Neonates and Infants (GEMINI) study, funded by the National Institutes of Health (NCT03890679), investigated the effectiveness and cost of two genetic testing methods on babies and infants suspected to have genetic disorders.
The multicenter trial was conducted at six U.S. hospitals, including locations in Boston, Cincinnati, New York, Chapel Hill, San Diego, and UPMC Children’s Hospital of Pittsburgh. Enrolling 400 participants in the study between June 2019 and November 2021, the GEMINI research team compared rapid whole genomic sequencing (rWGS) and a targeted genomic sequencing panel, NewbornDx, in diagnosing high-risk infants.
The study also examined the cost-effectiveness of these tests against standard care and aimed to use the data to evaluate the lifetime cost-effectiveness of these genetic testing strategies. A web-based resource was also developed to provide medical providers and parents with relevant information and support for various conditions identified through testing.
Findings from the study were first published in July 2023 in the Journal of the American Medical Association (JAMA) and offer important insights into neonatal care and genetic disorder diagnosis.
Leading the study at UPMC Children’s was Jerry Vockley, MD, PhD, FACMG, director of the Division of Genetic and Genomic Medicine and the Center for Rare Disease Therapy.
Central Questions of the Study
The primary issue for the study is how rWGS compares to a targeted neonatal gene-sequencing test in diagnostic yields and result delivery times. Given that genetic testing can inform medical decisions and improve health outcomes for infants in the NICU displaying symptoms of unknown or confounding etiology for which a potential genetic basis can provide clinical clarity, it is clinically necessary to understand the comparative benefits/drawbacks of the sequencing options available.
Key Findings
A significant finding was that rWGS had a molecular diagnostic yield of 49% (with a 95% CI of 44%-54%), which is higher than the 27% (95% CI of 23%-32%) yield from the targeted neonatal gene-sequencing test. However, the targeted test provided results more quickly, with a median time of 4.2 days compared to 6.1 days for rWGS. For urgent cases, whole genome sequencing delivered results in a median time of 3.3 days, compared to 4.0 days for the targeted test.
Despite its diagnostic yield, rWGS did not report 19 variants detected by the targeted test. Conversely, the targeted test did not report 164 variants identified by genomic sequencing. A 43% variance in variant interpretation by laboratories indicates that interlaboratory differences can significantly impact the diagnostic yield of testing and, consequently, the downstream clinical management of individual patients.
Implications of the Study
With the identification of at least one genetic variant in 51% of participants and clinical interventions impacting 19% of participants, the GEMINI study highlights the influential role of rWGS in neonatal care. Without sequencing, a significant number of diagnoses would likely have been missed, considering that a molecular diagnostic variant was identified in 51% of participants and genomic sequencing had a 49% molecular diagnostic yield. Essentially, not using sequencing could drastically reduce the ability to identify pathogenic variants or variants of unknown significance, which are critical for guiding clinical interventions.
Around half of the cases with a genetic disorder might not have been identified or could have been misdiagnosed if evaluations were based solely on visible symptoms. Moreover, without sequencing, insights into new variants and their effects on the disorder and its management would be lost, potentially limiting treatment to managing symptoms instead of addressing the underlying genetic cause.
Looking Ahead with Genomic Data
Although the GEMINI study supports using rWGS by displaying higher diagnostic yields, it also highlights considerations regarding time efficiency and the need for consistent variant interpretation between laboratories. While rWGS and targeted gene panels are powerful tools for understanding genetic issues in critically ill infants, optimizing their use requires balancing the diagnostic ability against time constraints and consistent variant interpretations.
Reference
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.
