Cross-Omics: Integrating Genomics with Metabolomics in Clinical Diagnostics

• Main Authors: Marten H. P. M. Kerkhofs, Hanneke A. Haijes, A. Marcel 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 J. M. Jans
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Metabolites
• Subjects: cross-omics; untargeted metabolomics; genomics; diagnostics; data integration; next-generation sequencing
• Online Access: https://www.mdpi.com/2218-1989/10/5/206

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.