Perinatal Precision Medicine

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
RCIGM 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 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.

Inclusion Criteria:

Individual in whom one of the following criteria is met:

1. Acutely ill inpatient of less than 4 months of age and within 96 hours of admission.

2. Acutely ill inpatient of less than 4 months of age and within 96 hours of development
of an abnormal response to standard therapy for an underlying condition.

3. Acutely ill inpatient of less than 4 months of age and within 96 hours of development
of clinical feature or laboratory test value suggestive of a genetic condition.

4. Biological relative of an infant enrolled in this study.

Exclusion Criteria:

Inpatients of greater than 4 months of age, or who do not meet any of the inclusion
criteria, or with:

1. Neonatal infection or sepsis with normal response to therapy

2. Isolated prematurity

3. Isolated unconjugated hyperbilirubinemia

4. Hypoxic Ischemic Encephalopathy with clear precipitating event

5. Previously confirmed genetic diagnosis that explains their clinical condition (i.e.
have a positive genetic test)

6. Isolated Transient Neonatal Tachypnea

7. Permission is unable to be obtained by a legal guardian or court-appointed
representative within 96 hours of becoming eligible for enrollment.

8. Non-viable neonates - newborns less than 28 days of life with a modified code status
(only full code patients may be enrolled).