Susceptibility of human glycogenes to functional variations

Taha Mohseni Ahooyi (1) Benjamin Stear (1) Deanne Taylor (1,2) (1) Department of Biomedical and Health Informatics (DBHi), The Children's Hospital of Philadelphia, Philadelphia, PA (2) Perelman School of Medicine, University of Pennsylvania

Glycosylation of proteins and lipids and its regulatory enzymes (glycoenzymes) have myriad of implications in the cellular homeostasis and human health and disease. A wealth of research has noted how dysregulation of glycosylation contribute to a wide range of diseases with different onsets ranging from developmental disorders -commonly referred to as congenital disorders of glycosylation (CDG)- to late onset complications as in Alzheimer's disease. In many cases, irregularities in glycosylation can arise from mutations in the protein-coding regions of the genes encoding glycosylated proteins1. Numerous accounts of single nucleotide variants affecting codons corresponding to glycosylation sites have been reported. Moreover, structural variations in glycoenzymes (e.g. glycosyltransferases) have also been linked to downstream effects on cellular glycosylation. Our project introduces a systematic framework to prioritize glycogenes in terms of their intolerance to mutations using other published variant intolerance score systems such as pLI and CADD and amino acid variation intolerance score MTR. The main aim in this project is to improve sensitivity and specificity for predicting variant pathogenicity due to likely changes in glycosylation activity, in both changes to specific predicted glycosylation sites, and in impacts to the functions of glycosylation enzymes. Of particular interest is to assess downstream impacts of glycoslylation-related variants on various biological pathways and to assign these variants a susceptibility score based on the findings of this analysis. References 1. Vogt, G., Vogt, B., Chuzhanova, N., Julenius, K., Cooper, D. N., & Casanova, J. L. (2007). Gain-of-glycosylation mutations. Current opinion in genetics & development, 17(3), 245-251.