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Original Investigation
February 15, 2021

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study

Author Affiliations
  • 1Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts
  • 2Rady Children’s Institute for Genomic Medicine, San Diego, California
  • 3Department of Pediatrics, University of California, San Diego, San Diego
  • 4Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia
  • 5Perinatal Institute, Cincinnati Children’s Hospital, Cincinnati, Ohio
  • 6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 7UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 8Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
  • 9Department of Pediatrics, Cohen Children’s Medical Center, New Hyde Park, New York, New York
  • 10University of North Carolina Children’s Research Institute, University of North Carolina Health Children’s Hospital, Chapel Hill
  • 11Athena Diagnostics/Quest Diagnostics, Marlborough, Massachusetts
  • 12Department of Obstetrics and Gynecology, Tufts Medical Center Boston, Boston, Massachusetts
  • 13Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts
  • 14The Tufts Clinical and Translation Science Institute, Tufts University School of Medicine, Boston, Massachusetts
JAMA Pediatr. Published online February 15, 2021. doi:10.1001/jamapediatrics.2020.5906
Key Points

Question  Can a targeted genomic sequencing platform diagnose neonates and infants suspected of having a genetic disorder as accurately as rapid whole-genomic sequencing?

Findings  In this comparative effectiveness study of 113 infants, diagnostic and/or phenotypically related variants of unknown significance were returned for 51 patients (45%), while 62 (55%) had negative results; results were concordant between platforms in 73% of patients. Of 51 positive cases, 67% differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, and/or filtering discrepancies.

Meaning  The diagnostic capabilities of genomic sequencing technologies have the ability to affect clinical care but have significant limitations that must be better understood.


Importance  A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing.

Objective  To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy.

Design, Setting, and Participants  The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020.

Interventions  Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results.

Main Outcomes and Measures  Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing.

Results  Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes.

Conclusions and Relevance  As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.

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