Inborn Errors of Metabolism and Other Mendelian Disorders
We are interested in a large category of Mendelian diseases called inborn errors of metabolism (IEMs). These diseases are caused by pathogenic genomic variants (i.e. mutations) in genes encoding metabolic enzymes, nutrient transporters, and other components of the metabolic network. We are developing approaches to make it easier to recognize these disorders in patients by combining an unbiased analysis of the metabolome with genome/exome sequencing. Integrating metabolomics data with gene sequencing makes it possible to infer the impact of genomic variants of uncertain significance (see figure, DeBerardinis and Keshari, Cell 2022). Variants suspected of causing disease can then be subjected to functional analyses in cells or mice to understand how specific metabolic anomalies cause tissue dysfunction. We have used this approach to characterize rare Mendelian disorders and discover entirely new ones(Ni et al, Cell Reports 2019, Ni et al, Genetics in Medicine 2021) , with the long-term goal of developing better diagnostic techniques and treatments. Our clinical cohort of over 1,000 individuals provides a powerful resource to classify and explore metabolic variation in humans.