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Background/objectives <p>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.</p> Subjects/methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月16日

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  • Robert Künzel,
  • Helene Faust,
  • Linnaeus Bundalian,
  • Matthias Blüher,
  • Mariami Jasaszwili,
  • Anna Kirstein,
  • Albrecht Kobelt,
  • Antje Körner,
  • Denny Popp,
  • Eric Wenzel,
  • Rami Abou Jamra,
  • Johannes R. Lemke,
  • Torsten Schöneberg,
  • Robert Stein,
  • Antje Garten,
  • Diana Le Duc

摘要

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.