Metabolic perturbations associated with ADAT3 variant–related intellectual disability revealed by untargeted metabolomics

Untargeted metabolomics is a powerful analytical approach for characterizing global metabolic alterations associated with physiological and pathological states. This approach is particularly valuable for rare genetic disorders, where metabolic consequences are poorly understood and diagnostic biomarkers are lacking. Adenosine deaminase tRNA-specific 3 ( ADAT3 )-related intellectual disability (ID) is a rare autosomal recessive neurodevelopmental disorder caused by bi-allelic ADAT3 , most frequently the founder variant p. Val128Met, yet its metabolic consequences remain largely unknown. To investigate the metabolic signatures associated with this condition, we performed untargeted metabolomics on plasma samples from affected patients ( n = 10), carrier parents ( n = 14), and healthy controls ( n = 56) using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). A total of 1,909 ion features were significantly altered. Out of 100 endogenous metabolites, thirty-nine metabolites were genotype-associated (26 decreased, 13 increased), four metabolites were phenotype- associated, and three metabolites were altered by both genotype and phenotype. Pathway analysis revealed major metabolic disruptions in various pathways, including purine metabolism and vitamin B6. Receiver operating characteristic (ROC) analysis identified 1-methylhistamine (AUC = 0.984; IUPAC: 2-(1-methyl-1 H-imidazol-4-yl)ethan-1-amine) and 4-phenyl-2-butenal (AUC = 1.00; IUPAC: (2E)-4-phenylbut-2-enal) as preliminary discriminative features within this discovery cohort. Notably, the putative increase in 1-methylhistamine suggests a possible alteration in histamine-related metabolism; however, histamine concentrations and histamine N-methyltransferase (HNMT) activity were not directly assessed. Together, these results provide the first metabolomic characterization of ADAT3- related ID and highlight preliminary discriminative metabolites and perturbed metabolic pathways that warrant targeted confirmation and validation in larger, independent cohorts.