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. Department of Biochemistry and Molecular Medicine, College of Medicine, Al Faisal University, Riyadh, 11533, Saudi Arabia Department of Translational Genomics, Genomic Medicine Center of Excellence (GMCoE), King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh, 11211, Saudi Arabia Amal Jaafar, Omar Abuyousef, Fowzan S.

Abdel Rahman Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, 11961, Saudi Arabia Metabolomics Section, Precision Medicine Laboratory Department (PMLD), Genomic Medicine Center of Excellence (GMCoE), King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Saudi Arabia Reem AlMalki, Maha Al Mogren, Ahmad Alfares & Anas M. Abdel Rahman College of Medicine, Alfaisal University, Riyadh, 11533, Saudi Arabia Lifera Omics, Riyadh, 13519, Saudi Arabia Precision Medicine Laboratory Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Saudi Arabia The authors declare no competing interests. The study protocol was reviewed and approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia (IRB No. 2080 006).

Written informed consent was obtained from all participants and/or their legal guardians. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.