title: A novel LIPE nonsense mutation found using exome sequencing in siblings with late-onset familial partial lipodystrophy.
abstract: BACKGROUND
  Familial lipodystrophies are rare inherited disorders associated with redistribution of body fat and development of dyslipidemia, insulin resistance, and diabetes. We previously reported 2 siblings with unusual late-onset familial partial lipodystrophy in whom heretofore known causative genes had been excluded. We hypothesized they had a mutation in a novel lipodystrophy gene.
  
  
  METHODS
  Our approach centred on whole exome sequencing of the patients' DNA, together with genetic linkage analysis and a bioinformatic prioritization analysis. All candidate variants were assessed in silico and available family members were genotyped to assess segregation of mutations.
  
  
  RESULTS
  Our prioritization algorithm led us to a novel homozygous nonsense variant, namely p.Ala507fsTer563 in the hormone sensitive lipase gene encoding, an enzyme that is differentially expressed in adipocytes and steroidogenic tissues. Pathogenicity of the mutation was supported in bioinformatic analyses and variant cosegregation within the family.
  
  
  CONCLUSIONS
  We have identified a novel nonsense mutation in hormone sensitive lipase gene, which likely explains the lipodystrophy phenotype observed in these patients.
authors.affiliation: Departments of Medicine and Biochemistry, Western University, London, Ontario, Canada; Robarts Research, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Sali M K
authors.initials: SM
authors.lastname: Farhan
authors.affiliation: Robarts Research, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Robinson
authors.affiliation: Robarts Research, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Adam D
authors.initials: AD
authors.lastname: McIntyre
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Marrosu
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Ticca
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Istituto Mendel, San Giovanni Rotondo, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Loddo
authors.affiliation: Division of Neurology, Hospital San Francesco of Nuoro, Nuoro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Carboni
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio University of Chieti-Pescara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Departments of Medicine and Biochemistry, Western University, London, Ontario, Canada; Robarts Research, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000328:Adult; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D008040:Genetic Linkage; D005838:Genotype; D006720:Homozygote; D006801:Humans; D052496:Lipodystrophy, Familial Partial / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies; D035781:Siblings; D002787:Sterol Esterase / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D002787:Sterol Esterase