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

Lotte Kleinendorst, Maarten P G Massink, Mellody I Cooiman, Mesut Savas, Olga H van der Baan-Slootweg, Roosje J Roelants, Ignace C M Janssen, Hanne J Meijers-Heijboer, Nine V A M Knoers, Hans Kristian Ploos van Amstel, Elisabeth F C van Rossum, Erica L T van den Akker, Gijs van Haaften, Bert van der Zwaag, Mieke M van Haelst

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)578-586
Number of pages9
JournalJournal of Medical Genetics
Volume55
Issue number9
DOIs
Publication statusPublished - Sep 2018

Cite this

Kleinendorst, L., Massink, M. P. G., Cooiman, M. I., Savas, M., van der Baan-Slootweg, O. H., Roelants, R. J., ... van Haelst, M. M. (2018). Genetic obesity: next-generation sequencing results of 1230 patients with obesity. Journal of Medical Genetics, 55(9), 578-586. https://doi.org/10.1136/jmedgenet-2018-105315
Kleinendorst, Lotte ; Massink, Maarten P G ; Cooiman, Mellody I ; Savas, Mesut ; van der Baan-Slootweg, Olga H ; Roelants, Roosje J ; Janssen, Ignace C M ; Meijers-Heijboer, Hanne J ; Knoers, Nine V A M ; Ploos van Amstel, Hans Kristian ; van Rossum, Elisabeth F C ; van den Akker, Erica L T ; van Haaften, Gijs ; van der Zwaag, Bert ; van Haelst, Mieke M. / Genetic obesity : next-generation sequencing results of 1230 patients with obesity. In: Journal of Medical Genetics. 2018 ; Vol. 55, No. 9. pp. 578-586.
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title = "Genetic obesity: next-generation sequencing results of 1230 patients with obesity",
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.",
author = "Lotte Kleinendorst and Massink, {Maarten P G} and Cooiman, {Mellody I} and Mesut Savas and {van der Baan-Slootweg}, {Olga H} and Roelants, {Roosje J} and Janssen, {Ignace C M} and Meijers-Heijboer, {Hanne J} and Knoers, {Nine V A M} and {Ploos van Amstel}, {Hans Kristian} and {van Rossum}, {Elisabeth F C} and {van den Akker}, {Erica L T} and {van Haaften}, Gijs and {van der Zwaag}, Bert and {van Haelst}, {Mieke M}",
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Kleinendorst, L, Massink, MPG, Cooiman, MI, Savas, M, van der Baan-Slootweg, OH, Roelants, RJ, Janssen, ICM, Meijers-Heijboer, HJ, Knoers, NVAM, Ploos van Amstel, HK, van Rossum, EFC, van den Akker, ELT, van Haaften, G, van der Zwaag, B & van Haelst, MM 2018, 'Genetic obesity: next-generation sequencing results of 1230 patients with obesity' Journal of Medical Genetics, vol. 55, no. 9, pp. 578-586. https://doi.org/10.1136/jmedgenet-2018-105315

Genetic obesity : next-generation sequencing results of 1230 patients with obesity. / Kleinendorst, Lotte; Massink, Maarten P G; Cooiman, Mellody I; Savas, Mesut; van der Baan-Slootweg, Olga H; Roelants, Roosje J; Janssen, Ignace C M; Meijers-Heijboer, Hanne J; Knoers, Nine V A M; Ploos van Amstel, Hans Kristian; van Rossum, Elisabeth F C; van den Akker, Erica L T; van Haaften, Gijs; van der Zwaag, Bert; van Haelst, Mieke M.

In: Journal of Medical Genetics, Vol. 55, No. 9, 09.2018, p. 578-586.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genetic obesity

T2 - next-generation sequencing results of 1230 patients with obesity

AU - Kleinendorst, Lotte

AU - Massink, Maarten P G

AU - Cooiman, Mellody I

AU - Savas, Mesut

AU - van der Baan-Slootweg, Olga H

AU - Roelants, Roosje J

AU - Janssen, Ignace C M

AU - Meijers-Heijboer, Hanne J

AU - Knoers, Nine V A M

AU - Ploos van Amstel, Hans Kristian

AU - van Rossum, Elisabeth F C

AU - van den Akker, Erica L T

AU - van Haaften, Gijs

AU - van der Zwaag, Bert

AU - van Haelst, Mieke M

N1 - © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2018/9

Y1 - 2018/9

N2 - 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.

AB - 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.

U2 - 10.1136/jmedgenet-2018-105315

DO - 10.1136/jmedgenet-2018-105315

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VL - 55

SP - 578

EP - 586

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

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ER -

Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. Journal of Medical Genetics. 2018 Sep;55(9):578-586. https://doi.org/10.1136/jmedgenet-2018-105315