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Genetic obesity: next-generation sequencing results of 1230 patients with obesity
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  • Published on:
    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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    Conflict of Interest:
    None declared.
  • Published on:
    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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    Conflict of Interest:
    None declared.