title: Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls.
abstract: Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls.
  
  
  
  Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway.
  
  
  
  In total 151 variants were detected. Twenty-eight (18.5%) of these were rare, coding or splice variants and five (3.3%) were novel. All individuals, except one control, were heterozygous for the 28 variants, and the distribution of the rare variants showed a significantly higher carrier frequency among cases than controls (9.9% vs. 4.9%, p=0.011). Four variants in MC4R were classified as pathogenic or likely pathogenic.
  
  
  
  Four cases (0.8%) of monogenic obesity were detected, all due to MC4R variants previously linked to monogenic obesity. Significant differences in carrier frequencies among patients with morbid obesity and normal weight controls suggest an association between heterozygous rare coding variants in these five genes and morbid obesity. However, additional studies in larger cohorts and functional testing of the novel variants identified are required to confirm the findings.
authors.affiliation: Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway; Department of Occupational and Environmental Medicine, Telemark Hospital, Skien, Norway; Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway. Electronic address: grynor@sthf.no.
authors.forename: Gry B N
authors.initials: GBN
authors.lastname: Nordang
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Øyvind L
authors.initials: ØL
authors.lastname: Busk
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Tveten
authors.affiliation: Fertilitetsavdelingen Sør, Telemark Hospital, Porsgrunn, Norway.
authors.forename: Hans Ivar
authors.initials: HI
authors.lastname: Hanevik
authors.affiliation: Department of Occupational and Environmental Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Anne Kristin M
authors.initials: AKM
authors.lastname: Fell
authors.affiliation: Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Jøran
authors.initials: J
authors.lastname: Hjelmesæth
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Øystein L
authors.initials: ØL
authors.lastname: Holla
authors.affiliation: Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway.
authors.forename: Jens K
authors.initials: JK
authors.lastname: Hertel
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D020738:Leptin / Q000235:genetics; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D009664:Norway; D009767:Obesity, Morbid / Q000235:genetics*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D045664:Proprotein Convertase 1 / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
chemical_list: C515448:LEPR protein, human; D020738:Leptin; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; D011333:Pro-Opiomelanocortin; C587576:PCSK1 protein, human; D045664:Proprotein Convertase 1
keywords: BMI; Morbid obesity; Mutation; Next-generation sequencing; Rare sequence variant