Whole Genome Sequencing in the Neonatal Intensive Care Unit

1.0 Objectives

1.1 Study Objectives The goal of this research project is to assess the potential for
applying whole genome sequencing (WGS) as a diagnostic tool in the neonatal intensive care
unit. Newborn children who require treatment in the neonatal intensive care unit (NICU) often
suffer from genetic defects, the nature of which is difficult to diagnose. The investigators
currently know of more than 5000 genes in which mutations may cause diseases that can affect
newborn children, so determining which one is responsible for a new neonatal patient's
disease is daunting. However, many of these diseases can be effectively treated if they are
diagnosed in a timely fashion. The investigators propose to use new sequencing
instrumentation coupled with rapid analytical tools to sequence NICU patients along with both
parents to identify whether a patient carries a de novo mutation or compound heterozygous
variants in one of the known disease genes. If so, the mutation will be confirmed in an
in-house CLIA laboratory and the results provided within 72 hours to attending neonatologists
to inform treatment decisions.

1.2 Primary Study Endpoints

The primary goal of this protocol will be an assessment of the degree to which WGS improves
diagnosis of patients admitted to the NICU. The investigators propose to perform sequencing
on approximately 50 patients over the course of this project. The investigators will evaluate
on an ongoing basis the success rate for identifying clinically actionable genetic defects in
the selected patients, particularly as that would inform the initial selection criteria used
to enroll the patient. This information will be useful to determine whether such sequencing
efforts can improve the outcome of NICU patients and which class of patients are most likely
to benefit from the procedure.

1.3 Secondary Study Endpoints

A second goal will be an assessment of the effectiveness of targeted sequencing of the whole
exome or a panel of 5000 genes in identifying the genetic defects revealed by whole genome
sequencing and the relative cost in money and time of the various approaches. This could
yield a significantly more efficient and cost effect method over that currently described
elsewhere.

Finally, the investigators propose to use the data to begin to develop a cost-benefit
analysis of WGS in the NICU. The investigators will assess the extent to which WGS provided a
diagnosis distinct from that initially proposed by the neonatologists and the extent to which
that change in diagnosis altered the treatment regimen. If the novel diagnosis did, in fact,
alter treatment, The investigators would use historical data to assess the degree to which
that altered treatment affected the number of days the patient remained in the NICU. The
investigators can then estimate the cost savings/loss as the number of NICU days saved times
the cost per day of NICU residence versus the cost of performing the sequencing over the
entire cohort of sequenced patients. While this is not as rigorous as a randomized clinical
trial, it would point to whether this is a methodology worth exploring in more depth.

Child:Inclusion Criteria:

1. Age: ≤ 180 days

2. Sex: male or female

3. Admitted to the Hershey Medical Center NICU with a clinical presentation consistent
with a genetic disease, e.g. congenital malformations, metabolic disorder,
uncontrolled seizures or unexplained abnormal neurological findings.

4. Both Biological Parents are involved in the study

Child:Exclusion Criteria:

1. Age: > 180 days

2. Known genetic mutation.

Biological Parents : Inclusion Criteria

1. Age: ≥18 years

2. Both biological parents must be willing to participate in the research.

3. Fluent in written and spoken English.

Biological Parents: Exclusion Criteria

1. Age: <18 years

2. Prisoner

3. Cognitive impairment