Genetic and epigenetic contributors and mimickers of phenotypic hypoxic-ischemic encephalopathy (HIE)

Hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of neonatal morbidity and mortality despite advancement in care. Over 60 % of infants presenting with phenotypic HIE lack a clear identifiable acute sentinel event. Clinical genetic testing in neonates with suspected HIE has uncovered an increasing number of genetic conditions and epigenetic modifications that impair their ability to tolerate the stress of labor and delivery or exacerbate the severity of clinical symptoms following a hypoxic-ischemic insult. While most of those conditions are rare, many of the identified alterations involve common biological pathways and organ systems - particularly those affecting energy metabolism or the function of cells and organs of high energy demand such as brain, heart, and skeletal muscle - as well as genetic epilepsies. Here we provide an overview of the genetic makeup and epigenetic signatures associated with HIE and the insights they have provided into distinguishing genetic etiologies from true HIE. By outlining modern genetic testing modalities and their clinical applications, we provide a structured diagnostic approach for clinicians evaluating neonates with phenotypic HIE and highlight the clinical and therapeutic implications of early genetic diagnosis. This review underscores the critical importance of recognizing that HIE may not always represent a purely hypoxic-ischemic etiology, but rather a final common pathway influenced by underlying genetic predisposition and environmental factors that highlight the potential for precision medicine approaches to improve outcomes in this vulnerable population.