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Künzel, R.* ; Faust, H.* ; Bundalian, L.* ; Blüher, M. ; Jasaszwili, M.* ; Kirstein, A.S.* ; Kobelt, A.* ; Körner, A. ; Popp, D.* ; Wenzel, E. ; Jamra, R.A.* ; Lemke, J.R.* ; Schöneberg, T.* ; Stein, R. ; Garten, A.* ; Le Duc, D.*

Detecting monogenic obesity: A systematic exome-wide workup of over 500 individuals.

Int. J. Obes., DOI: 10.1038/s41366-025-01819-0 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND/OBJECTIVES: Obesity poses a major public health concern. Although BMI heritability is estimated at 40-80%, genetic diagnostics remain challenging. This study aims to (i) assess the diagnostic yield of monogenic obesity in a large patient sample using exome-wide data, (ii) identify predictors to improve genetic testing criteria, and (iii) evaluate whether the identified genes are included in public obesity gene panels. SUBJECTS/METHODS: We reviewed the genetic test results of 521 patients with obesity. 84.7% underwent whole-exome analysis, 15.3% were analyzed using a multi-thousand-gene panel. RESULTS: Monogenic obesity was diagnosed in 5.8% of patients, while 7.1% carried a potentially obesogenic variant. Diagnostic yield was higher in children (6.3%) and patients with syndromic obesity (7.0%). Surprisingly, diagnostic yield was lower in severe obesity cases. 40% of patients with monogenic obesity carried variants in genes not included in current obesity panels. CONCLUSION: Overall, 12.9% of patients had monogenic obesity or a potentially obesogenic variant. These findings suggest that genetic testing should not be limited to patients with extreme obesity. Current obesity panels miss crucial syndromic genes, demonstrating a need for more comprehensive panels and the superiority of whole-exome sequencing in obesity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Variants; Association; Overweight; Genetics; Children; 16p11.2; Weight; Energy; Sh2b1; Mc4r
ISSN (print) / ISBN 0307-0565
e-ISSN 1476-5497
Journal International Journal of Obesity
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants Projekt DEAL
German Research Foundation (DFG)