Cross-Omics: Integrating Genomics with Metabolomics in Clinical Diagnostics
Marten H. P. M. Kerkhofs, Hanneke A. Haijes, A.M. Willemsen, Koen L.I. van Gassen, Maria van der Ham, Johan Gerrits, Monique G.M. de Sain–van der Velden, Hubertus C.M.T. Prinsen, Hanneke W. M. van Deutekom, Peter M. van Hasselt, Nanda M. Verhoeven‐Duif, Judith Jans
Abstract
Next-generation sequencing and next-generation metabolic screening are, independently, increasingly applied in clinical diagnostics of inborn errors of metabolism (IEM). Integrated into a single bioinformatic method, these two -omics technologies can potentially further improve the diagnostic yield for IEM. Here, we present cross-omics: a method that uses untargeted metabolomics results of patient's dried blood spots (DBSs), indicated by Z-scores and mapped onto human metabolic pathways, to prioritize potentially affected genes. We demonstrate the optimization of three parameters: (1) maximum distance to the primary reaction of the affected protein, (2) an extension stringency threshold reflecting in how many reactions a metabolite can participate, to be able to extend the metabolite set associated with a certain gene, and (3) a biochemical stringency threshold reflecting paired Z-score thresholds for untargeted metabolomics results. Patients with known IEMs were included. We performed untargeted metabolomics on 168 DBSs of 97 patients with 46 different disease-causing genes, and we simulated their whole-exome sequencing results in silico. We showed that for accurate prioritization of disease-causing genes in IEM, it is essential to take into account not only the primary reaction of the affected protein but a larger network of potentially affected metabolites, multiple steps away from the primary reaction.