Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation.

Autor: Courraud J; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.; Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, Leof. Vasilissis Sofias 80, Athens, 11528, Greece., Russo F; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark., Themudo GE; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Institute of Biological Psychiatry, Copenhagen University Hospital, Copenhagen Mental Health Services, Kristineberg 3, DK-2100, Copenhagen Ø, Denmark.; CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal.; Centre for Ecology, Evolution and Environmental Changes (CE3C), Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal., Laursen SS; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark., Ingason A; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Institute of Biological Psychiatry, Mental Health Center Sankt Hans, DK-4000, Roskilde, Denmark., Hougaard DM; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark., Cohen AS; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark., Werge T; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. thomas.werge@regionh.dk.; Institute of Biological Psychiatry, Copenhagen University Hospital, Copenhagen Mental Health Services, Kristineberg 3, DK-2100, Copenhagen Ø, Denmark. thomas.werge@regionh.dk.; Department of Clinical Sciences, Faculty of Health, University of Copenhagen, Blegdamsvej 3, DK-2200, København N, Denmark. thomas.werge@regionh.dk.; GLOBE Institute, LF Center for GeoGenetics, Faculty of Health, University of Copenhagen, Oester Voldgade 5-7, 1350, Copenhagen K, Denmark. thomas.werge@regionh.dk., Ernst M; Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark. maet@ssi.dk.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. maet@ssi.dk.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2023 Dec 14; Vol. 13 (1), pp. 391. Date of Electronic Publication: 2023 Dec 14.
DOI: 10.1038/s41398-023-02697-8
Abstrakt: Large deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes. Here, we used targeted metabolomics to compare neonatal dried blood spot samples from 203 individuals clinically identified as carriers of a deletion at chromosome 22q11.2 with 203 unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers. We found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%), and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength. Targeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis.
(© 2023. The Author(s).)
Databáze: MEDLINE
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