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• Reply to "Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586."
  Lotte Kleinendorst, Bert van der Zwaag and Mieke M. van Haelst
  Published on: 11 December 2018
• Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586.
  Jean-Claude Chèvre, Darlène Antoine, Vivian Tam, Laurent Brunaud, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant and David Meyre
  Published on: 27 November 2018

• Published on: 11 December 2018

  Reply to "Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586."

  • Lotte Kleinendorst, MD, PhD student Clinical Genetics Amsterdam University Medical Centers
  • Other Contributors:
    • Bert van der Zwaag, Clinical laboratory geneticist
    • Mieke M. van Haelst, Clinical geneticist

  In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.

  The authors question the validity of how we determine the pathogenicity of identifi...

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  In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.

  The authors question the validity of how we determine the pathogenicity of identified variants. Our diagnostics lab is ISO15189 accredited and, as a member of the Dutch Society of Clinical Genetic Laboratory Diagnostics, adheres to the ACMG guidelines for the interpretation of sequence variants [2]. As such, our variant interpretation is in line with the guideline.

  Thirdly the authors suggest to use ‘severe/morbid early-onset obesity’ rather than ‘obesity’ to describe our cohort. We deliberately used the term ‘obesity’, since pathogenic mutations were also identified in patients who did not have severe obesity or only became obese in adulthood.

  References
  1. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, Janssen ICM, Meijers-Heijboer HJ, Knoers N, Ploos van Amstel HK, van Rossum EFC, van den Akker ELT, van Haaften G, van der Zwaag B, van Haelst MM. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018;55:578-86.
  2. Richards S , Aziz N , Bale S , Bick D , Das S , Gastier-Foster J , Grody WW , Hegde M , Lyon E , Spector E , Voelkerding K , Rehm HL , ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–23.doi:10.1038/gim.2015.30

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  Conflict of Interest:
  None declared.

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• Published on: 27 November 2018

  Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586.

  • Jean-Claude Chèvre, Postdoctoral fellow Inserm UMRS 954 N-GERE (Nutrition-Genetics-Environmental Risks), University de Lorraine, Faculty of Medicine, Nancy, France
  • Other Contributors:
    • Darlène Antoine, Doctoral student
    • Vivian Tam, Research assistant
    • Laurent Brunaud, Professor
    • Rosa-Maria Guéant-Rodriguez, Professor
    • Jean-Louis Guéant, Professor
    • David Meyre, Associate Professor

  To the Editor:
  We read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
  First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
  Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
  Third, the authors should have...

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  To the Editor:
  We read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
  First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
  Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
  Third, the authors should have used the term ‘severe/morbid early-onset obesity’ rather than ‘obesity’ to describe the study participants, given their extreme anthropometric characteristics (age of obesity onset <5 years, median adult body mass index (BMI) 43.6 kg/m2, median child BMI-standard deviation score (SDS) +3.4). Patients with early-onset/extreme forms of obesity are likely to be enriched for monogenic mutations, which may lead to biased prevalence estimates of monogenic mutations that are not transferable to common obesity (BMI ≥30 kg/m2, BMI-SDS ≥2).

  References
  1. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, Janssen ICM, Meijers-Heijboer HJ, Knoers N, Ploos van Amstel HK, van Rossum EFC, van den Akker ELT, van Haaften G, van der Zwaag B, van Haelst MM. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018;55:578-86.
  2. Philippe J, Stijnen P, Meyre D, De Graeve F, Thuillier D, Delplanque J, Gyapay G, Sand O, Creemers JW, Froguel P, Bonnefond A. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int J Obes (Lond) 2015;39:295-302.
  3. Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond) 2016;130:943-86.
  4. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev 2017;18:603-34.
  5. Pigeyre M, Meyre D. Monogenic obesity. In: Freemark MS, eds. Pediatric Obesity: Etiology, Pathogenesis and Treatment. Cham: Springer International Publishing AG 2018:135-52

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  Conflict of Interest:
  None declared.

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