Acutely ill infant inpatients who have an undiagnosed illness, and their families, will be eligible to participate in the study. The investigators will enroll up to 1,000 infants. Locally, the study population will be recruited from Rady Children's Hospital (RCH) inpatient population, primarily the neonatal intensive care unit (NICU), pediatric intensive care unit (PICU), and cardiovascular intensive care unit (CVICU), with a smaller population presenting to other hospital in-patient services. Recruitment will be targeted at the RCH main campus, but it may include referrals from satellite locations in the RCH network (particularly the RCH NICU network throughout San Diego County). All patients will continue to receive routine care as clinically indicated, including the state newborn screen and other genetic testing as determined by their treating providers. Half of the affected study participants will be randomized to receive rapid whole genome sequencing (WGS) and the other half will receive rapid whole exome sequencing (WES). Each arm will initially be analyzed using the patient's (proband's) sample only. If a proband-only analysis fails to yield a diagnosis, genomic data from the biological family members (typically parents), when available, will be used to supplement analysis (trio analysis). Occasionally, a second affected sibling may be available for family analysis. Not infrequently, the father is not available for study. Similarly, the investigators anticipate the need for targeted genetic analysis of biological parents, and possibly other family members, to confirm diagnostic results and/or provide additional information regarding inheritance.

The investigators anticipate that in rare cases a newborn may be so ill that the team lacks equipoise that the child can wait for the estimated ten day turnaround time of our send-out exome testing. In these rare cases, the PI, or his delegate, will decide if the child is not eligible for randomization. These children will remain in the research study throughout the entirety of the study, but will receive in-house ultra-rapid whole genome sequencing by the Rady Children's Institute for Genomic Medicine (RCIGM, also called RadyPGSMI) laboratory in lieu of either a rapid genome or rapid exome (both anticipated to be 10 day turn-arounds).

Enrollment will be sought within the first 96 hours following admission to RCH or an RCH network ICU or within 96 hours of meeting criteria for the study if the infant was not previously eligible. Patients and their family members who consent to participate will have their blood drawn and will be randomized to receive either rapid WGS or rapid WES. The initial symptom-driven analysis will be conducted on the patient's sample only (singleton analysis). If a diagnosis is not found promptly (within 24 hours) via a singleton analysis, the family (or any combination of parents and/or other family members) will be analyzed using the same technology that the patient was randomized to receive. Pathogenic and likely pathogenic variants (as determined by American College of Medical Genetics (ACMG) guidelines) that relate in part or in whole to the patient's current phenotype will be clinically confirmed and reported into the patients' medical record. Although the intention of the study is to return symptom-driven results to the medical record, the clinical report for confirmation of symptom-driven findings may include negative findings of testing. In the event that our analysis incidentally finds a pathogenic variant for which a treatment or intervention exists to improve morbidity and/or mortality, families may choose not to receive this additional information.