The diagnosis of inborn errors of metabolism by an integrative “multi‐omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics

Abstract

Given the rapidly decreasing cost and increasing speed and accessibility of massively parallel technologies, the integration of comprehensive genomic, transcriptomic, and proteomic data into a “multi‐omics” diagnostic pipeline is within reach. Even though genomic analysis has the capability to reveal all possible perturbations in our genetic code, analysis typically reaches a diagnosis in just 35% of cases, with a diagnostic gap arising due to limitations in prioritization and interpretation of detected variants. Here we review the utility of complementing genetic data with transcriptomic data and give a perspective for the introduction of proteomics into the diagnostic pipeline. Together these methodologies enable comprehensive capture of the functional consequence of variants, unobtainable by the analysis of each methodology in isolation. This facilitates functional annotation and reprioritization of candidate genes and variants—a promising approach to shed light on the underlying molecular cause of a patient's disease, increasing diagnostic rate, and allowing actionability in clinical practice.

Detection of urinary metabolites of metabolic pathway disorders by using VTGE and LC-HRMS techniques

“…Organic aciduria can be found in both children and adults that shows various symptoms as tremors, sleepiness, headaches, feeling tired, and seizures (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). In line with existing evidence on the potential use of 2-hydroxyglutaric acid, 2-methylglutaric acid, the authors report on a novel methods and processes to detect these urine metabolites as a source of biomarkers for metabolic disorders.…”

“…In human metabolome database, 2-methylglutaric acid is known as a derivative of leucine metabolite (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). It is suggested that secretion of methylglutaric acid can be found in the urine of patients showing lack of 3-methylglutaconyl coenzyme A hydratase and 3-hydroxy-3methylglutaryl-CoA lyase deficiency during a type of inborn error of metabolisms.…”

“…It is suggested that secretion of methylglutaric acid can be found in the urine of patients showing lack of 3-methylglutaconyl coenzyme A hydratase and 3-hydroxy-3methylglutaryl-CoA lyase deficiency during a type of inborn error of metabolisms. Another example of metabolite as 2-Hydroxyglutaric acid is known to be accumulated in an organic aciduria condition (1)(2)(3)(4)(5). There is an indication that 2-hydroxyglutaric acid can be generated due to the enzymatic action of hydroxyacid-oxoacid transhydrogenase and further 2-Hydroxyglutaric acid is shown to be converted into alpha-ketoglutaric acid by 2-hydroxyglutarate dehydrogenase.…”

“…It is interesting to note that 2-hydroxyglutaric acid may inhibit a range of enzymes such as histone lysine demethylases (KDMs) and members of the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases (1)(2)(3)(4)(5). In summary, the uses of 2-hydroxyglutaric acid as metabolite biomarkers is having relevance in metabolic disorders and also as a key oncometabolites.…”

“…Among various classes of metabolic disorders, organic acidurias a type of inherited metabolic disorders is known to surface as intermediate steps in a metabolic pathways of anabolism and catabolism of lipid, carbohydrate, nucleic acids and amino acids (1)(2)(3)(4)(5). In essence, these metabolic disorders are indicated to lead to abundance of organic acids including 2methyluridine, 2-Methylglutaric acid, 2-Methyl citric acid, 2-Hydroxyglutaric acid in a relevant tissues and these metabolites are potentially excreted in urine (5)(6)(7)(8)(9)(10)(11)(12)(13).…”