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J Med Genet. 2018 Sep;55(9):578-586. doi: 10.1136/jmedgenet-2018-105315. Epub 2018 Jul 3.

Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

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Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
Departmentof Bariatric Surgery, Rijnstate Hospital, Arnhem, The Netherlands.
Department of Internal Medicine, division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Childhood Obesity Center Heideheuvel, Merem, Hilversum, The Netherlands.
Child Obesity Expert Centre Amsterdam, Women and Child Clinic, VU Medical Center (previously Deptartment of Pediatrics Slotervaartziekenhuis), Amsterdam, The Netherlands.
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
Department of Pediatric Endocrinology, Sophia kinderziekenhuis Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.



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.


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.


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.


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.


diagnostics tests; endocrinology; genetic obesity; leptin-melanocortin pathway

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