(692) Genetic findings among neonates with perinatal hypoxic-ischemic encephalopathy

Objective: Neonatal encephalopathy (NE) occurs in 3 out of 1000 births, causing substantial morbidity and neurodevelopmental sequelae. Although more than 50% of NE cases are attributed to hypoxic-ischemic encephalopathy (HIE), most newborns with HIE have limited evidence of perinatal hypoxia. We hypothesized that some infants diagnosed with HIE have an identifiable genetic disorder with phenotypic features that resemble encephalopathy.


Study Design: We reviewed HIE cases referred for genetic analysis in a clinical diagnostic laboratory between October 2014 - September 2022. Cases were included if they were given a diagnosis of HIE by the referring physician, were ≥35 wks at birth and < 1 yo at the time of genetic analysis, and if they underwent exome sequencing. Cases were excluded if there was significant cardiopulmonary pathology resulting in hypoxia or if clinical features or neuroimaging suggested a postnatal cause for hypoxic ischemic injury. This research was IRB approved (H-18414).

Results: Twenty-three cases met inclusion criteria. A total of four (17.4%) had pathogenic or likely pathogenic variants linked to adverse neurologic outcomes with phenotypic features resembling encephalopathy (Table 1). Two additional neonates had pathogenic or likely pathogenic variants in genes associated with unrelated phenotypes, including congenital hypothyroidism and Noonan syndrome (Table 1). Two neonates had isolated HIE without significant comorbidities to suggest an underlying genetic disorder. There was no correlation between cord gas or Apgar values and genetic findings.

Conclusion: In this cohort, 17.4% of perinatal HIE cases had a genetic syndrome with a known neuromuscular or neurodevelopmental phenotype that overlaps with HIE. Notably, a subset of these neonates had isolated HIE without other clinical features to suggest that there may be an underlying genetic disorder. The variants identified in non-encephalopathy genes may be incidental or may represent a phenotypic expansion for these genes. These results, while limited by biases inherent in retrospective studies, call for prospective investigation.