️ 18: Bi-allelic UGGT1 Variants Define a Distinct Congenital Disorder of Glycosylation

️ Episode 18: Bi-allelic UGGT1 Variants Define a Distinct Congenital Disorder of Glycosylation In this episode of PaperCast Base by Base, we explore the identification of bi-allelic variants in the UGGT1 gene as the cause of a novel congenital disorder of glycosylation characterized by neurodevelopmental impairment, seizures, dysmorphic features, and multiorgan involvement within the broader landscape of gene–disease associations and variant interpretation. Study Highlights:Genomic and exome sequencing of 15 affected individuals from 10 unrelated families revealed nine distinct UGGT1 variants including missense, nonsense, and indel alleles that co-segregate with disease. Detailed clinical phenotyping uncovered a spectrum of severity ranging from infantile lethality with multiorgan pathology to complex syndromic neurodevelopmental disorders in survivors. Functional assays in cellular models demonstrated that pathogenic UGGT1 variants impair enzyme-mediated reglucosylation, disrupt mRNA splicing, or alter subcellular localization, thereby compromising N-linked glycoprotein quality control. Genotype–phenotype correlations showed that loss-of-function alleles associate with more severe clinical presentations. Conclusion:These findings expand the spectrum of N-linked glycosylation disorders and provide new insights into the essential role of UGGT1 in human glycoprotein quality control and disease pathogenesis. Reference:Dardas Z, Harrold L, Calame DG, Salter CG, Kikuma T, Guay KP, Ng BG, Sano K, Saad AK, Du H, Sangermano R, Patankar SG, Jhangiani SN, Gürsoy S, Abdel-Hamid MS, Ahmed MKH, Maroofian R, Kaiyrzhanov R, Salayev K, Jones WD, Pérez Caballero A, McGavin L, Spiller M, Durkie M, Neumeyer AM, Begtrup A, Abdel-Ghafar SF, Zaki MS, Van Esch H, Posey JE, Wenger OK, Scott EM, Bujakowska KM, Gibbs RA, Pehlivan D, Marafi D, Leslie JS, Ubeyratna N, Day J, Owens M, Settle J, Balkhy S, Tamim A, Alabdi L, Alkuraya FS, Takeda Y, Freeze HH, Hebert DN, Lupski JR, Crosby AH, Baple EL. Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation. American Journal of Human Genetics. 2025 May 1;112(2):1139–1157. https://doi.org/10.1016/j.ajhg.2025.03.018 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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