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Genetic obesity: next-generation sequencing results of 1230 patients with obesity
  1. Lotte Kleinendorst1,
  2. Maarten P G Massink2,
  3. Mellody I Cooiman3,
  4. Mesut Savas4,
  5. Olga H van der Baan-Slootweg5,
  6. Roosje J Roelants6,
  7. Ignace C M Janssen3,
  8. Hanne J Meijers-Heijboer1,7,
  9. Nine V A M Knoers2,
  10. Hans Kristian Ploos van Amstel2,
  11. Elisabeth F C van Rossum4,
  12. Erica L T van den Akker8,
  13. Gijs van Haaften2,
  14. Bert van der Zwaag2,
  15. Mieke M van Haelst1,7
    1. 1 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
    2. 2 Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
    3. 3 Departmentof Bariatric Surgery, Rijnstate Hospital, Arnhem, The Netherlands
    4. 4 Department of Internal Medicine, division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
    5. 5 Childhood Obesity Center Heideheuvel, Merem, Hilversum, The Netherlands
    6. 6 Child Obesity Expert Centre Amsterdam, Women and Child Clinic, VU Medical Center (previously Deptartment of Pediatrics Slotervaartziekenhuis), Amsterdam, The Netherlands
    7. 7 Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands
    8. 8 Department of Pediatric Endocrinology, Sophia kinderziekenhuis Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
    1. Correspondence to Dr Mieke M van Haelst, Department of Clinical Genetics VU Medical Center Amsterdam The Netherlands; m.vanhaelst{at}


    Background Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity.

    Methods DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes.

    Results In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance.

    Conclusions NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

    • genetic obesity
    • endocrinology
    • leptin-melanocortin pathway
    • diagnostics tests
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    • Contributors LK, MM, GvH, BvdZ and MMvH contributed to the study design and acquisition and/or analysis of the data. All authors contributed to the data interpretation, provided critical revisions of the manuscript and approved the final version.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Disclaimer All authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. We attest that we have obtained appropriate permissions. Required fees for use of copyright-protected materials: not applicable.

    • Competing interests None declared.

    • Patient consent Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Extra clinical information might be available for some patients. Data that underlie the results reported in this article (after deidentification) can be requested if relevant. Proposals should be directed to

    • Collaborators Genetic Obesity Consortium: FJ Berends; EO Aarts; S Bouma-de Jongh; I von Rosenstiel; EGAH van Mil; CJ De Groot; HE Veenstra-Knol; JBGM Verheij; KE Stuurman; VL Wester; YMC Hendriks; M Bakker.

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