NEXMIF Gene Variants and Epilepsy: A Mini Review of Genotype–Phenotype Correlations and Clinical Practice Implications

Abstract

Abstract NEXMIF gene variants are increasingly recognized as a significant cause of X-linked developmental and epileptic encephalopathies, presenting unique sex-related patterns that challenge traditional inheritance expectations. This article systematically analyzes genotype–phenotype correlations in NEXMIF-related epilepsy and provides evidence-based clinical management recommendations. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, searching PubMed, Scopus, Google Scholar, Web of Science, and Embase (January 2010–December 2024) using terms “NEXMIF” and “KIAA2022” combined with “epilepsy,” “seizures,” and “encephalopathy.” Studies were included if they reported patients with confirmed pathogenic NEXMIF variants and detailed epileptic phenotype data. Fourteen studies (218 patients) were included. Epilepsy occurred in 185/218 patients (85%, 95% confidence interval [CI]: 79.3–89.4%). Null variants caused significantly more severe phenotypes than missense variants: earlier seizure onset (median 14 vs. 126 months; mean difference 112 months, 95% CI: 98–126; p < 0.001), higher developmental epileptic encephalopathy rates (85% vs. 7%; odds ratio [OR] 94.4, 95% CI: 32.1–277.8; p < 0.001), and increased pharmacoresistance (75% vs. 24%; OR 9.6, 95% CI: 4.1–22.4; p < 0.001). Females experienced higher seizure occurrence than males (99% vs. 62%; OR 42.5, 95% CI: 13.7–131.9; p < 0.001), though pharmacoresistance rates were comparable (70% vs. 60%; p = 0.21). NEXMIF variant type strongly predicts epileptic severity, enabling precision medicine approaches. These findings should be interpreted cautiously given the retrospective nature and methodological heterogeneity of included studies.