Previously Undiagnosed Clinically Significant Neurogenetic Disorders in Neonates Treated for Presumed Hypoxic–Ischemic Encephalopathy: A Real-World Cohort Study

Background/Objectives: To evaluate the diagnostic yield of stepwise genetic testing and characterize previously undiagnosed clinically significant neurogenetic disorders in term neonates treated with therapeutic hypothermia for presumed hypoxic–ischemic encephalopathy (HIE) who met objective criteria for perinatal asphyxia. Methods: This retrospective study included 57 term neonates treated with therapeutic hypothermia for presumed HIE who completed stepwise genetic evaluation and had at least 12 months of neurological follow-up. All patients underwent conventional karyotyping and chromosomal microarray analysis; patients without a diagnostic finding on first-tier testing subsequently underwent clinical exome sequencing, whole-exome sequencing, or targeted familial variant analysis when applicable. We performed exploratory comparisons of clinical, perinatal, neuroimaging, and neurodevelopmental characteristics between patients with and without pathogenic or likely pathogenic neurogenetic findings. Results: Pathogenic or likely pathogenic (P/LP) neurogenetic findings were identified in 12 of 57 patients, corresponding to a diagnostic yield of 21.1%. Four patients harbored pathogenic copy-number variants involving 7p21.1, 15q11.2–q13.1, Xq27.2–q28, or 16p11.2. P/LP sequence variants in OCLN, SCN8A, FGFR3, FAR1, PURA, KCNQ2, CYB5R3, and PAK3 were identified in eight patients. In exploratory analyses, P/LP-positive patients had lower 10 min Apgar scores (median, 5 vs. 7; p = 0.029), more frequent HIE-consistent MRI patterns (83.3% vs. 48.9%; p = 0.049), and more frequent severe motor impairment (GMFCS levels IV–V: 75.0% vs. 20.0%; p < 0.001). No other demographic, perinatal, or clinical variables differed significantly between the groups. Conclusions: Objective criteria for perinatal asphyxia, clinical features of neonatal encephalopathy, and HIE-consistent neuroimaging findings do not exclude an underlying neurogenetic disorder. Stepwise genetic evaluation may provide additional diagnostic information and support prognostic assessment, genetic counseling, and individualized follow-up in selected neonates treated for presumed HIE.