Urinary metabolomic profiling in 22q11.2 deletion syndrome reveals microbial and mitochondrial signatures related to autism and psychosis risk

Aim 22q11.2 deletion syndrome (22qDS) is the most common copy‐number‐variation disorder, associated with multi‐organ anomalies and elevated risk for schizophrenia and other neuropsychiatric conditions. Previous metabolomic studies have used blood samples, implicating mitochondrial dysfunction and amino acid imbalance, but no urinary metabolomic analysis has been reported. We aimed to characterize the urinary metabolomic profile of 22qDS. Methods We conducted an exploratory study comparing urine from 10 individuals with 22qDS and 10 age‐ and sex‐matched healthy controls. Metabolites were quantified using capillary electrophoresis time‐of‐flight mass spectrometry and liquid chromatography time‐of‐flight mass spectrometry. Data were analyzed using principal component analysis and Wilcoxon rank‐sum tests with false‐discovery‐rate adjustment. Results Principal component analysis indicated separation between groups. Several metabolites differed significantly, defined by a false discovery rate q < 0.20 and fold change > 1.5 or <0.67. Elevated metabolites in 22qDS included 2‐hydroxyglutaric acid, p ‐cresol sulfate, p ‐cresol glucuronide, trimethylamine‐ N ‐oxide, and 3‐indoxylsulfuric acid, whereas citrulline and lysine were reduced. These metabolites are implicated in mitochondrial dysfunction, amino acid imbalance, and gut microbial dysbiosis. A substantial proportion of altered metabolites corresponded to those previously reported in autism spectrum disorder (ASD), predominantly microbiota‐related. Conclusion This first urinary metabolomic study of 22qDS demonstrates systemic metabolic alterations, including mitochondrial and microbiota‐associated changes. The overlap with ASD is suggestive of a possible shared metabolic signature. Our findings provide initial insights into systemic and microbial contributions to neuropsychiatric vulnerability in this genetically defined high‐risk population.