Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation
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Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation. / Courraud, Julie; Russo, Francesco; Themudo, Gonçalo Espregueira; Laursen, Susan Svane; Ingason, Andrés; Hougaard, David M.; Cohen, Arieh S.; Werge, Thomas; Ernst, Madeleine.
I: Translational Psychiatry, Bind 13, 391, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation
AU - Courraud, Julie
AU - Russo, Francesco
AU - Themudo, Gonçalo Espregueira
AU - Laursen, Susan Svane
AU - Ingason, Andrés
AU - Hougaard, David M.
AU - Cohen, Arieh S.
AU - Werge, Thomas
AU - Ernst, Madeleine
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41398-023-02697-8
DO - 10.1038/s41398-023-02697-8
M3 - Journal article
C2 - 38097559
AN - SCOPUS:85179664335
VL - 13
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
M1 - 391
ER -
ID: 378374372