title: Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population.
abstract: Single gene mutations leading to severe obesity have so far been identified in 3-5% cases in European populations. However, prevalence of these pathogenic mutations has not systematically been examined in specific consanguineous populations. Here we describe the incidence of obesity-associated mutations through a step-wise sequence analysis, in a cohort of 73 Pakistani children with severe obesity from consanguineous families.
  
  
  
  Initially, all subjects were screened for mutations in coding regions of leptin (LEP) and melanocortin 4 receptor (MC4R) genes by direct sequencing. Subjects negative for mutation in these genes were screened using microdroplet PCR enrichment and NGS. Genomic structural variation was assessed by genotyping. Serum leptin, insulin, and cortisol were determined by ELISA.
  
  
  
  Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants. Hypercortisolemia was significantly emphasized in LEP mutation carriers.
  
  
  
  The prevalence of pathogenic mutations in genes known to directly influence leptin-melanocortin signaling is 30% in our cohort. The results of this study emphasize the desirability of undertaking systematic and in-depth genetic analysis of cases with severe obesity in specific consanguineous populations.
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.affiliation: European Genomic Institute for Diabetes (EGID), Lille, France.|CNRS-Umr8199, Lille Pasteur Institute, Lille, France.|Lille University, Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: Department of Paediatric Endocrinology, Children's Hospital, Lahore, Pakistan.
authors.forename: Jaida
authors.initials: J
authors.lastname: Manzoor
authors.affiliation: Department of Biological Sciences, Forman Christian College, Lahore, Pakistan.
authors.forename: Faiza
authors.initials: F
authors.lastname: Shabbir
authors.affiliation: Department of Paediatrics, Punjab Medical College, Faisalabad, Pakistan.
authors.forename: Hina
authors.initials: H
authors.lastname: Ayesha
authors.affiliation: European Genomic Institute for Diabetes (EGID), Lille, France.|CNRS-Umr8199, Lille Pasteur Institute, Lille, France.|Lille University, Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Philippe
authors.affiliation: European Genomic Institute for Diabetes (EGID), Lille, France.|CNRS-Umr8199, Lille Pasteur Institute, Lille, France.|Lille University, Lille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Durand
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: Hutokshi
authors.initials: H
authors.lastname: Crouch
authors.affiliation: European Genomic Institute for Diabetes (EGID), Lille, France.|CNRS-Umr8199, Lille Pasteur Institute, Lille, France.|Lille University, Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sand
authors.affiliation: Department of Paediatrics, Mayo Hospital, King Edward Medical University, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Paediatrics, Fatima Memorial Hospital, Lahore, Pakistan.
authors.forename: Taeed
authors.initials: T
authors.lastname: Butt
authors.affiliation: Department of Paediatric Endocrinology, Children's Hospital, Lahore, Pakistan.
authors.forename: Ahsan W
authors.initials: AW
authors.lastname: Rathore
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Department of Biological Sciences, Forman Christian College, Lahore, Pakistan.|Centre for Research in Molecular Medicine, the University of Lahore, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arslan
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.|European Genomic Institute for Diabetes (EGID), Lille, France.|CNRS-Umr8199, Lille Pasteur Institute, Lille, France.|Lille University, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020738:Leptin / Q000235:genetics*; D008297:Male; D009154:Mutation; D009765:Obesity / Q000453:epidemiology; D009767:Obesity, Morbid / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D054411:Receptors, Leptin / Q000235:genetics*
chemical_list: D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin