| Summary: | (1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood. <i>KDM6B</i> variants were reported to cause neurodevelopmental diseases; however, the association between <i>KDM6B</i> and CFD is unknown; (2) Methods: Exome sequencing (ES) was performed on 48 isolated CFD cases. The effect of <i>KDM6B</i> variants on KDM6B protein expression, Histone H3 lysine 27 epigenetic modification and FOLR1 expression were examined in vitro. For each patient, serum FOLR1 autoantibodies were measured; (3) Results: Six <i>KDM6B</i> variants were identified in five CFD patients, which accounts for 10% of our CFD cohort cases. Functional experiments indicated that these <i>KDM6B</i> variants decreased the amount of KDM6B protein, which resulted in elevated H3K27me2, lower H3K27Ac and decreased FOLR1 protein concentrations. In addition, FOLR1 autoantibodies have been identified in serum; (4) Conclusion: Our study raises the possibility that <i>KDM6B</i> may be a novel CFD candidate gene in humans. Variants in <i>KDM6B</i> could downregulate FOLR1 gene expression, and might also predispose carriers to the development of FOLR1 autoantibodies.
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