The Genomic Medicine for Ill Neonates and Infants (The GEMINI Study) is a research study aimed at comparing the clinical and economic utility of performing rapid whole genomic sequencing versus a targeted genomic sequencing panel on neonates and infants suspected of having a genetic disorder. This study is funded by the National Institutes of Health.

This multicenter, prospective clinical trial will enroll 400 subjects at the Floating Hospital for Children at Tufts Medical Center (Boston, MA), Cincinnati Children's Hospital Medical Center (Cincinnati, OH), Mount Sinai Kravis Children's Hospital (New York, NY), North Carolina Children's Hospital (Chapel Hill, NC), Children's Hospital of Pittsburgh (Pittsburgh, PA), and Rady Children's Hospital (San Diego, CA).

This multicenter, prospective clinical trial will examine the diagnostic yield and clinical utility of NewbornDx, a targeted genomic sequencing panel for use in the neonate, and rapid whole genomic sequencing (rWGS) testing in high-risk infants with signs/symptoms consistent with a possible genetic disorder. Infants will undergo NewbornDx and rWGS (proband) testing. The biological parent(s), when available, will undergo NewbornDx testing at the same time as the infant. For rWGS,the infant will undergo testing first. If a specific diagnosis that is consistent with the phenotype is not made with rWGS proband analysis alone, the parent(s) will undergo rWGS. The study will also evaluate the cost effectiveness of each test as well as standard of care (SOC) testing. A retrospective chart review of infants with suspected genetic disorders will be done to understand 1-year cost and health outcomes that would have been incurred in the absence of the advanced testing. The resulting data from the trial will be used in the economic evaluation comparing NewbornDx, rWGS, and SOC over a 1-year period and used as basis to simulate the lifetime cost-effectiveness of these testing strategies. A web-based clinical reference database to provide references, clinical management guidelines, opportunities for clinical trial participation, and support groups for each condition will be developed with separate interfaces for the parent/guardian(s) and medical provider. The clinical reference database will be qualitatively assessed by a survey of medical providers.

Inclusion Criteria:

• Documented informed consent from the parent/guardian
• Signs/symptoms consistent with a possible genetic disorder
• Admitted to a hospital participating in this study at the time of enrollment
• Less than one year corrected gestational age

Exclusion Criteria:

• A known genetic diagnosis (e.g. prenatal testing)
• Major congenital anomaly associated with a chromosomal anomaly detected on prenatal testing
• Presence of documented congenital infection
• Infants considered non-viable due to prematurity (< 23 0/7 weeks GA)

Sequencing data that relates genomic data to phenotype or other biological states will be generated and released in accordance to the NIH GDS Policy. Data, including genome sequences (fastq files), variants (vcf files), and associated HIPAA compliant clinical metadata will be deposited in the Longitudinal Pediatric Data Resource (LPDR; https://www.nbstrn.org/research-tools/longitudinal-pediatric-data-resource). The LPDR, in turn, will deposit data in the NCBI dbGAP. Variants with ACMG recommended pathogenicity assessments will be deposited in ClinVar. Novel disorder gene assertions will be deposited in ClinGen (https://clinicalgenome.org/).

Annual data submissions supplemented by specific dataset deposits as manuscripts arising from this work are submitted for publication.

Individual level data will be made available through controlled access. Genomic Summary Results will be made available through unrestricted access.

1 year