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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.

Author information

1
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
2
Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
3
Departmentof Bariatric Surgery, Rijnstate Hospital, Arnhem, The Netherlands.
4
Department of Internal Medicine, division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
5
Childhood Obesity Center Heideheuvel, Merem, Hilversum, The Netherlands.
6
Child Obesity Expert Centre Amsterdam, Women and Child Clinic, VU Medical Center (previously Deptartment of Pediatrics Slotervaartziekenhuis), Amsterdam, The Netherlands.
7
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
8
Department of Pediatric Endocrinology, Sophia kinderziekenhuis Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Abstract

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.

KEYWORDS:

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

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