Application of pathogenicity scores as diagnostic and prognostic markers for MPS disorders: In-silico analysis in MPS I

Abstract Mucopolysaccharidoses (MPSs) is a major group of the Lysosomal storage disorders (LSDs) with defective degradation of glycosaminoglycans (GAGs) due to deficiency of certain lysosomal enzymes. Enzyme replacement therapy (ERT) or bone marrow transplantation are the key therapeutic options available for MPS disorders. Early diagnosis and appropriate intervention improve the therapeutic efficacy. To establish a genotype-phenotype correlation of MPS disorders, a combination of bioinformatic tools including FATHMM, I-Mutant, PolyPhen-2, PATHER, PHD-SNP, SNP&GO, SIFT, PROVEAN, CUPSAT, SNAP2 are utilized. These in silico tools and urinary GAG levels helped in monitoring the response to enzyme replacement therapy (ERT). Enzyme activity was inversely associated with SNAP2 (r= -0.36, p = 0.04), Polyphen-2 (r = − 0.44, p = 0.009) and Evolutionary preservation time (r= -0.396, p = 0.02). This suggests that subjects having mutations with higher SNAP2 and Polyphen-2 score tend to have lower enzyme activity. ERT lead to 7–31% decrease in urinary GAG levels in seven MPS I patients. The determined pathogenicity scores using the bioinformatic tools are serving as prognostic markers indicating a response to therapy. Urinary GAG excretion is the primary end point to monitor the therapeutic efficacy.