Whole Genome Uncertainty: Palliative Care's role in Navigating Genetic Results (SA306A).

1. Recognize the uncertainty inherent across the spectrum of whole genome sequencing result types. 2. Consider the challenges for pediatric palliative care teams in navigating uncertain genetic test results to inform goals of care and medical decision making. Genetic disease, including chromosomal and single gene disorders, account for substantial infant morbidity and mortality. Rapid whole genome sequencing (rWGS) combines and expands upon conventional stepwise genetic diagnostics into one rapid test, streamlining clinical diagnosis of genetic conditions. rWGS aims to inform medical decision making early in the course of care, though often yields uncertain results that confound prognostic uncertainty. Interpretation of genome results is complex, with clear pathogenic variants identified only in a minority of cases. Genome results are categorized on a spectrum from benign to pathogenic, with variant of uncertain significance (VUS) representing a grey zone. Even for pathogenic variants, there can be uncertainty regarding how they manifest in phenotypes due to factors such as penetrance and expressivity. Such uncertainty leads to significant challenges in understanding how to proceed with both nondiagnostic and diagnostic results alike. Pediatric palliative care intensively supports family-centered goals of care for neonates with potentially life-limiting genetic diseases. This case series will explore the impact of neonatal genome results on pediatric palliative care consultation: Case 1: A neonate with respiratory failure on ECMO was found to have a pathogenic variant in the FOXF1 gene consistent with the life-limiting disease alveolar capillary dysplasia with misalignment of the pulmonary veins, prompting transition to comfort measures. Case 2: A neonate with intractable epilepsy and structural brain abnormality was found to have a likely pathogenic variant in the NPRL3 gene. Genome results impacted medical decision making, including trial of a new medication and limitation of surgical interventions with discharge home on hospice. Case 3: An infant with congenital hypotonia and episodic metabolic crises and clinical decompensation was diagnosed with a VUS in the AIFM1 gene revealing a potential relevant mitochondrial disease. Given the infant's ongoing clinical decompensation, the genetic results informed shared decisions to limit interventions including intubation and resuscitation. [ABSTRACT FROM AUTHOR]