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

Sali M K Farhan, John F. Robinson, Adam D. McIntyre, Maria G. Marrosu, Anna F. Ticca, Sara Loddo, Nicola Carboni, Francesco Brancati, Robert A. Hegele

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1649-1654
Number of pages6
JournalCanadian Journal of Cardiology
Volume30
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

Fingerprint

Exome
Nonsense Codon
Lipodystrophy
Siblings
Sterol Esterase
Computational Biology
Mutation
Genes
Familial Partial Lipodystrophy
Genetic Linkage
Dyslipidemias
DNA Sequence Analysis
Adipocytes
Computer Simulation
Virulence
Insulin Resistance
Adipose Tissue
Phenotype
Enzymes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Farhan, S. M. K., Robinson, J. F., McIntyre, A. D., Marrosu, M. G., Ticca, A. F., Loddo, S., ... Hegele, R. A. (2014). A Novel LIPE Nonsense Mutation Found Using Exome Sequencing in Siblings With Late-Onset Familial PartialLipodystrophy. Canadian Journal of Cardiology, 30(12), 1649-1654. https://doi.org/10.1016/j.cjca.2014.09.007

A Novel LIPE Nonsense Mutation Found Using Exome Sequencing in Siblings With Late-Onset Familial PartialLipodystrophy. / Farhan, Sali M K; Robinson, John F.; McIntyre, Adam D.; Marrosu, Maria G.; Ticca, Anna F.; Loddo, Sara; Carboni, Nicola; Brancati, Francesco; Hegele, Robert A.

In: Canadian Journal of Cardiology, Vol. 30, No. 12, 01.12.2014, p. 1649-1654.

Research output: Contribution to journalArticle

Farhan, SMK, Robinson, JF, McIntyre, AD, Marrosu, MG, Ticca, AF, Loddo, S, Carboni, N, Brancati, F & Hegele, RA 2014, 'A Novel LIPE Nonsense Mutation Found Using Exome Sequencing in Siblings With Late-Onset Familial PartialLipodystrophy', Canadian Journal of Cardiology, vol. 30, no. 12, pp. 1649-1654. https://doi.org/10.1016/j.cjca.2014.09.007
Farhan, Sali M K ; Robinson, John F. ; McIntyre, Adam D. ; Marrosu, Maria G. ; Ticca, Anna F. ; Loddo, Sara ; Carboni, Nicola ; Brancati, Francesco ; Hegele, Robert A. / A Novel LIPE Nonsense Mutation Found Using Exome Sequencing in Siblings With Late-Onset Familial PartialLipodystrophy. In: Canadian Journal of Cardiology. 2014 ; Vol. 30, No. 12. pp. 1649-1654.
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AB - 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.

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