Molecular mechanism study of novel compound heterozygous EOGT mutations leading to Adams-Oliver syndrome type 4.

Abstract

Adams-Oliver Syndrome Type 4 (AOS4) is a rare autosomal recessive disorder primarily characterized by aplasia cutis congenita and cranial defects. Pathogenic variants in several genes, including DOCK6, ARHGAP31, EOGT, RBPJ, DLL4, and NOTCH1, have been implicated in the etiology of AOS. In this study, we identified two novel compound heterozygous mutations in the EOGT gene (c.961 C>T, p.R321C and c.1115 G>A, p.R372Q) in a patient with AOS4. Both variants were predicted to be deleterious through structural and computational analyses, and these mutations are likely to impair enzymatic function without affecting subcellular localization. Given the established role of EOGT in O-GlcNAcylation and its regulatory relationship with Notch signaling, we further proposed that these mutations may disrupt Notch pathway activity through aberrant modification of Notch receptors, thereby contributing to the defective skin development observed in AOS4. These findings highlight a potential pathogenic mechanism for AOS4 and underscore the critical role of EOGT-mediated glycosylation in human development.