Genetic spectrum of unexplained neonatal seizures: a single-center study

Up to 40% of neonatal seizures remain unexplained after standard evaluation, creating a diagnostic imperative. Distinguishing genetic etiologies is critical, as it enables the identification of treatable conditions and informs prognosis and family counseling. In this study, we aimed to define the genetic spectrum of unexplained neonatal seizures in a Chinese cohort.

In this single-center retrospective case series, we enrolled 40 neonates [2016-2024] admitted to the neonatal intensive care unit with video electroencephalography (vEEG)-confirmed seizures that were "unexplained" after a comprehensive evaluation including neuroimaging and metabolic screening. Exclusion criteria included identified causes such as hypoxic-ischemic encephalopathy or confirmed metabolic disorders. Genetic analysis involved whole-exome sequencing (WES), clinical exome sequencing (CES), WES of patient and parents (trio) (trio-WES), and mitochondrial DNA analysis.

The cohort included 29 male and 11 female neonates, with a median seizure onset at 1.5 days of life. Pathogenic or likely pathogenic variants were detected in 67.5% (27/40) of cases, including, but not limited to, variants in KCNQ2, ALDH7A1, and SUOX. A dual diagnosis was identified in one individual with compound heterozygous SUOX mutations and a de novo TUBG1 deletion. Additionally, nine of the 28 identified variants were novel. Although diagnostic yields varied among methodologies, the differences were not significant. Three patients with ALDH7A1 mutations achieved seizure freedom with vitamin B6 alone. All patients with SUOX nonsense/frameshift mutations had severe phenotypes and poor outcomes.

Our findings demonstrate a high diagnostic yield of next-generation sequencing (NGS) in unexplained neonatal seizures and underscore its clinical utility in pinpointing treatable conditions and prognosticating severe disorders.