A Novel LIPE Nonsense Mutation Found Using Exome Sequencing in Siblings With Late-Onset Familial PartialLipodystrophy

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.