Jill Maron, MD, MPH Chief of Pediatrics Executive Director, Mother Infant Research Institute Vice Chair, Pediatric Research, Tufts Medical Center Women & Infants Hospital of Rhode Island

TUFTS GEMINI Study Finds Whole Genomic Sequencing Identifies More Pathogenic Genes than Targeted Panels

MedicalResearch.com Interview with:

Professor, Jonathan Davis, MD,Chief of Newborn Medicine Tufts Medical Center and

Dr. Davis

Prof. Jonathan Davis, MD,
Chief of Newborn Medicine
Tufts Medical Center and

Jill Maron, MD, MPHChief of Pediatrics Executive Director, Mother Infant Research Institute Vice Chair, Pediatric Research, Tufts Medical Center Women & Infants Hospital of Rhode Island

Dr. Maron


Jill Maron, MD, MPH
Chief of Pediatrics
Women & Infants Hospital of Rhode Island


MedicalResearch.com: What is the background for this study?

Response: The Genomic Medicine for Ill Neonates and Infants (GEMINI) trial was designed to be the first comparative study to explore the diagnostic yield, clinical utility and time to diagnosis between whole genomic sequencing (WGS) and a targeted genomic sequencing panel specifically designed to detect gene disorders that present in early life. GEMINI was a US based study that enrolled 400 hospitalized infants, along with their available parents, suspected of having an undiagnosed genetic diagnosis. Every participant underwent testing on each platform simultaneously, allowing us to better understand the limitations and advantages of each approach.

MedicalResearch.com: What are the main findings?

Response:  GEMINI found that genomic sequencing technologies [e.g., WGS at Rady Genomics Institute or a targeted neonatal genomic sequencing test – NewbornDxä [Athena Diagnostics] were able to identify at least one pathogenic, likely pathogenic, or highly suspicious VUS in 51% of enrolled patients < 1 year of life. These diagnostic yields are comparable to other recently reported studies (range 25-50%).

However, while the targeted test returned results sooner than whole genomic sequencing (6 days vs. 3 days), WGS had nearly double the diagnostic yield (49% v 27%). Thus, in these high-risk infants suspected of having a genetic disorder, WGS was >10 times more likely to make a diagnosis compared to the targeted test. This disparity is partly due to the large number of infants who were found to have structural variants not detected by the targeted test and/or gene variants not currently included on the targeted test. 

MedicalResearch.com: What should readers take away from your report?

Response: There were many aspects to the GEMINI study that made it unique. Not only was it the first study to perform a comparative analysis of the diagnostic yield, clinical utility, and time to diagnosis between WGS and a targeted neonatal genomic sequencing test, but it also included detection of a suspicious VUS in calculating diagnostic yield. A suspicious VUS was defined as a variant found in a gene suspected of causing the presenting phenotype and was reported to the clinical care team to inform medical management. In a number of these cases, care was modified based on this reporting. Most importantly, when both tests detected the same genetic variant, their interpretation on the importance of the findings were different 40% of the time.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: The broad Inclusion criteria in GEMINI reinforced our lack of understanding of early life presentation of many genetic diseases. GEMINI identified 134 novel variants among infants < 1 year of age and the ultimate diagnosis was only suspected by consulting geneticists 33% of the time. Many variants detected by WGS were not identified by the targeted test and would not have been detected even if whole exome sequencing had been performed. The overall result of these data suggest that WGS has a higher diagnostic yield in these high risk populations. It should also be noted that surveyed clinicians highly valued access to these genetic platforms, even if a diagnosis was not made. GEMINI did highlight differences in variant classification that can occur between laboratories despite having access to the same clinical and phenotypical data for interpretation. Clinicians need to be cognizant that it is the interpretation of the genome that drives diagnostic rates, not simply the sequencing. Thus, a negative report by one laboratory may not be recapitulated by another. GEMINI serves as a reminder that while our technology has streamlined the pipeline from sequencing to variant call, much work remains on how to best standardize the interpretation of the genome to better inform clinical care.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: This study strongly supports the position that Medicaid and Commercial Insurance carriers should cover WGS (whose costs are decreasing as the technology improves). The early diagnosis should also open tremendous opportunities for industry to develop many other novel genomic approaches to successfully treat many genetic disorders, many of which are currently fatal.

All disclosures are listed in the JAMA article.



Maron JLKingsmore SGelb 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

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Last Updated on July 18, 2023 by Marie Benz MD FAAD