Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.Reportar como inadecuado




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* Corresponding author 1 Service de génétique médicale 2 Centre de génomique intégrative 3 Department of Genomics of Common Disease 4 Department of Medical Genetics 5 SIB - Swiss Institute of Bioinformatics 6 Laboratory Medicine 7 Center for Human Genetic Research 8 Ludwig Institute for Cancer Research 9 deCODE Genetics 10 Laboratoire de Génétique Médicale 11 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques 12 Estonian Genome and Medicine 13 Department of human genetics 14 Institute of Molecular and Cell Biology 15 Disciplines of Genetics and Medicine 16 IDIBELL - Department of Psychiatry 17 Section of Diabetes, Endocrinology and Nutrition 18 CRG-UPF - Center for Genomic Regulation 19 Institute of Human Genetics 20 Department of child and adolescent health 21 Department of Medical Genetics 22 Service d-ORL et de Chirurgie Cervicofaciale 23 Service de cytogénétique constitutionnelle 24 Department of Medical Genetics 25 Institutes of Biomedical Science 26 Shanghai Children-s Medical Center 27 Département de génétique 28 Service de cytogénétique 29 Génétique médicale 30 MRGM - Maladies Rares - Génétique et Métabolisme 31 Service de génétique médicale 32 Service de génétique Angers 33 URCA - Université de Reims Champagne-Ardenne 34 Department of Molecular Genetics 35 Laboratoire de Génétique 36 Mendel Laboratory 37 Service de Génétique clinique 38 Laboratoire de cytogénétique CHU de Dijon 39 Laboratoire de Cytogénétique 40 Département de génétique et procréation 41 AGIM - AGeing and IMagery 42 Laboratoire de biochimie et génétique moléculaire 43 Service de Neuropédiatrie 44 Service de génétique 45 Centre de Génétique Chromosomique 46 Service de génétique médicale 47 Centre hospitalier de Béthune 48 Service de Génétique Clinique 49 Department of Biotechnology 50 Service de Génétique 51 IGDR - Institut de Génétique et Développement de Rennes 52 Department of Epidemiology and Public Health 53 Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen 54 Department of Experimental Cardiology 55 Service de Génétique Cytogénétique et Embryologie CHU Pitié-Salpêtrière 56 Institute of human genetics 57 Division of genetic epidemiology 58 Institute of Experimental Medicine 59 Department of Obstetrics and Gynecology 60 Laboratorio di citogenetica 61 Department of Psychiatry and Psychotherapy 62 Interfaculty Institute for Genetics and Functional Genomics 63 Abteilung für Kinder und Jugendheilkunde 64 Service de Génétique 65 The Habilitation Unit of Folkhalsan 66 Institute of human genetics 67 Medical Genetics Unit 68 Unité de Cytogénétique et Génétique Médicale 69 Service de médecine infantile III et génétique clinique 70 Institute of Human Genetics and Anthropology 71 Department of Medical Genetics 72 North West Thames Regional Genetics Service 73 Child and Adolescent Psychiatry 74 Program in Genetics and Genomic Biology 75 OCDEM - Oxford Centre for Diabetes, Endocrinology and Metabolism 76 Wellcome Trust Centre for Human Genetics 77 Institute of Human Genetics 78 Medical Genetics Unit 79 Genetics, GlaxoSmithKline R&D 80 Institute of Clinical Chemistry and Laboratory Medicine 81 GC - Génétique cardiovasculaire 82 Molecular Medicine and Surgery department 83 Service de génétique 84 Department of Pathology 85 Division of pediatrics 86 Institute of Medical Genetics 87 Department of pediatrics and CEBR 88 Department of Internal Medicine 89 Division of Human Genetics 90 Autism Research Unit 91 State Diagnostic 92 University of Iceland Reykjavik 93 Department of Pediatric Laboratory Medicine 94 Genetic Services 95 Department of Endocrinology and Nutrition 96 Centre de Maladies Rares 97 Department of Internal Medicine 98 Institute for Community Medicine 99 Department of Medical Genetics 100 The Centre for Applied Genomics, Toronto 101 IBLI - Institut de biologie de Lille - IBL

Abstract : Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index BMI ≤ 18.5 kg per m2 in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and-or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase kb region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers including 132 novel cases and 108 unrelated carriers from individuals clinically referred for developmental or intellectual disabilities DD-ID or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.





Autor: Sébastien Jacquemont - Alexandre Reymond - Flore Zufferey - Louise Harewood - Robin Walters - Zoltán Kutalik - Danielle Martine

Fuente: https://hal.archives-ouvertes.fr/



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