(24) Genetic Diagnoses and Outcomes Among Infants with Neonatal Encephalopathy

Background: Neonatal encephalopathy secondary to hypoxia-ischemia (HIE) often cannot be distinguished from genetic disorders presenting in the perinatal period. Both genetic disorders and HIE are major causes of neonatal morbidity and mortality, and often have overlapping clinical presentation, particularly in the absence of perinatal events. Genetic disorders are often identified later in an infant’s clinical course after therapeutic hypothermia (TH). Earlier identification of infants with genetic disorders may help target treatment and avoid potentially harmful complications of TH.

Objectives: To determine if infants presenting with encephalopathy and treated with TH who subsequently are diagnosed with an underlying genetic disorder can be distinguished a priori before treatment with TH.

Design/Methods: We performed a retrospective review of all infants who underwent TH for suspected HIE admitted to the St. Louis Children’s Hospital NICU between 2018-2023. Clinical characteristics, genetic testing results, and outcomes were extracted from the medical records.

Results: Of the 319 infants identified, 62 (19%) underwent genetic testing. Of these 9/62 (15%) had pathogenic variants identified, 22/62 (35%) had one or more variants of uncertain significance identified, 3/62 (5%) had benign variants identified, and 31/62 (50%) had non-diagnostic results. Pathogenic variants identified included 1q21.1 microduplication, tetrasomy 18p, trisomy 21, 16p11.2 duplication, 3q29 deletion and 15q11.2 duplication, 15q16.1 deletion, and pathogenic variants in SCN1A and MT- RNR1. Clinical characteristics of infants based on genetic testing status are presented in Table 1. Infants who underwent genetic testing had higher mortality, increased length of stay, and increased need for feeding support at discharge compared to those who did not receive genetic testing (Table 1). There were no cases of perinatal placental abruption, uterine rupture, shoulder dystocia, or cord prolapse among the infants who underwent TH and received a genetic diagnosis.

Conclusion: In our cohort who underwent TH for suspected HIE, 19% received genetic testing and 15% of these infants were identified to have a pathogenic single nucleotide or copy number variant. As infants with HIE are at increased risk for adverse neurodevelopment, the identification of a genetic diagnosis may further impact prognosis, neurodevelopment, and recurrence risk. Indications for genetic testing in this population need to be further defined to guide clinicians in optimizing the management neonatal encephalopathy.