Prospective, multi-site, study to evaluate the clinical utility of cWGS in a proband. One group will receive cWGS and a clinical report approximately 15 days after blood samples are received, while the other group will continue to receive standard of care until Day 60. The standard of care group will receive cWGS and a clinical report at Day 60 as part of secondary and tertiary analyses. Both groups will be followed for a total of 90 days.

This is a prospective, multi-site, randomized study to evaluate the clinical utility of cWGS in each proband. Throughout this study, each proband will receive SOC testing as determined by the site clinical team. Upon enrollment in the study, each proband will be randomly assigned to the 15 day cWGS group or the SOC group. SOC is defined as the management of the proband's care under the same or similar conditions as if the proband was not enrolled in this study. A blood sample from each enrolled proband will be collected and shipped to the Illumina Clinical Services Laboratory ("ICSL"), which is Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited. ICSL will conduct cWGS testing with the TruGenome Undiagnosed Disease Test ("TruGenome Test"). The TruGenome Test cWGS results will be provided to the Principal Investigator (PI) or designee who will evaluate each proband test outcome based on the aggregate medical information, informed by the cWGS or SOC results.

Proband Inclusion Criteria

1. Current admission in a Neonatal Intensive Care Unit/Intensive Care Unit at a participating clinical site at the time of enrollment from day of life 0 to 120 days
2. A suspected genetic etiology of disease, based on objective clinical findings or other phenotypic defects for which a genetic test would be considered
3. Must be able to have 1 - 1.25 ml tube of whole blood drawn for testing
4. One parent of the proband must be able to provide written informed consent
5. At least one biological parent must agree to participate and provide at least 4 ml of whole blood for testing

Exclusion Criteria:

Proband Exclusion Criteria

1. Known non-genetic cause(s) of disease, disorder, or phenotypic defect
2. The phenotype is fully explained by complications of prematurity
3. Trisomy 13, 18 or 21 or Turner Syndrome is the likely diagnosis; such a proband will be eligible if a diagnostic karyotype is normal
4. Blood transfusion within 48 hours (each proband will be re-eligible 48 hours after the most recent transfusion)
5. The PI decides that the study is not in the best interest of the proband (for example, the neonate or infant is at a high risk of severe morbidity or mortality within the next 7 days and these risks could be mitigated by alternative testing). Subsequent eligibility for enrollment of each proband is at the discretion of the site PI.

Deidentified and curated variant and limited phenotype information will be submitted to ClinVar. ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes hosted by the National Center for Biotechnology Information (NCBI) and funded by Intramural National Institutes of Health (NIH) funding. No personal health information (PHI) or information identifying the participant or family will be submitted.

All investigators are masked to the study arm until Day 15 to ensure SOC throughout first 15 days on study.