Pediatr Res. 2025 Aug 15. doi: 10.1038/s41390-025-04335-z. Online ahead of print.
ABSTRACT
BACKGROUND: NHS gene encodes a protein with four conserved nuclear localization signals that regulates actin assembly and cell spreading. NHS variants are associated with cataract-related disorders with/without seizures. However, the NHS-epilepsy association remains unclear.
METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy of unknown cause. Previously reported variants were reviewed to analyze the mechanisms underlying phenotypical variations.
RESULTS: Seven NHS variants were identified in one female and six male patients. All the variants were not present in the controls and were predicted to be damaging by in silico tools. The female patient with a de novo heterozygous missense variant presented with mild epilepsy with a favorable outcome. One patient with a variant within the functional WHD domain displayed refractory epilepsy, whereas patients with variants within the c-terminal showed mild epilepsy. Among the two patients with adjacent variants, the patient with a variant of mild hydrophobicity change had mild epilepsy, whereas the one with a significant hydrophobicity change showed refractory epilepsy and intellectual disability. Further analysis showed that the proportion of epilepsy with/without cataract in patients with missense variants was significantly higher than in patients with null variants, suggesting a potential genotype-phenotype correlation.
CONCLUSION: NHS is potentially a novel causative gene of epilepsy.
IMPACT: The NHS gene is a potential causative gene of epilepsy, expanding the phenotypic spectrum. While most of the patients with missense variants within the C-terminal region were associated with mild epilepsy, the only patient with a missense variant located at the functional WHD domain displayed refractory epilepsy, suggesting a sub-molecular effect. Genotype-phenotype correlation is shown by the fact that the proportion of epilepsy with/without cataract in patients with missense variants was significantly higher than in patients with null variants, helping to understand the mechanism underlying phenotype variation.
PMID:40817290 | DOI:10.1038/s41390-025-04335-z
