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.

M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Novartis, Novo Nordisk, Pfizer and Sanofi. The other authors declare no competing financial interests.

This project was funded by the German Research Foundation (DFG) through the CRC 1052, Obesity Mechanisms, B10 (project number 209933838) and project number 493646873 - MD-LEICS.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved and monitored by the Ethics Committee of the University of Leipzig, Germany (224/16-ek and 402/16-ek) and was conducted in concordance to the declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.