title: Whole-exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity.
abstract: OBJECTIVE
  Obesity is a major public health problem that increases the risk for a broad spectrum of co-morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance.
  
  
  METHODS
  Deploying a strategy combining analysis of exome sequencing data in extremely obese members of four consanguineous families with segregation analysis, we screened for causal genetic variants. Filter-based analysis and homozygosity mapping were used to identify and prioritize putative functional variants.
  
  
  RESULTS
  Two novel frameshift mutations in the leptin receptor in two of the families were identified.
  
  
  CONCLUSIONS
  These results provide proof-of-principle that whole-exome sequencing of families segregating for extreme obesity can identify causal pathogenic mutations. The methods described here can be extended to additional families segregating for extreme obesity and should enable the identification of mutations in novel genes that predispose to obesity.
authors.affiliation: Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gill
authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Patricia
authors.initials: P
authors.lastname: Lanzano
authors.forename: Nazrat M
authors.initials: NM
authors.lastname: Mirza
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ten
authors.forename: Noel K
authors.initials: NK
authors.lastname: Maclaren
authors.forename: Roja
authors.initials: R
authors.lastname: Motaghedi
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D000052:Acanthosis Nigricans / Q000209:etiology; D000293:Adolescent; D015992:Body Mass Index; D002648:Child; D003241:Consanguinity; D059472:Exome; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D006720:Homozygote; D006801:Humans; D007223:Infant; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D063766:Pediatric Obesity / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010375:Pedigree; D054411:Receptors, Leptin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D007328:Insulin; C515448:LEPR protein, human; D020738:Leptin; D054411:Receptors, Leptin