title: APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.
abstract: BACKGROUND
  Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.
  
  
  METHODS
  We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.
  
  
  RESULTS
  A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.
  
  
  CONCLUSIONS
  The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.
authors.affiliation: Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Alameda, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Dussaillant
authors.forename: Valentina
authors.initials: V
authors.lastname: Serrano
authors.forename: Alberto
authors.initials: A
authors.lastname: Maiz
authors.forename: Susana
authors.initials: S
authors.lastname: Eyheramendy
authors.forename: Luis Rodrigo
authors.initials: LR
authors.lastname: Cataldo
authors.forename: Matías
authors.initials: M
authors.lastname: Chavez
authors.forename: Susan V
authors.initials: SV
authors.lastname: Smalley
authors.forename: Marcela
authors.initials: M
authors.lastname: Fuentes
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
authors.forename: Lorena
authors.initials: L
authors.lastname: Rubio
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.forename: José Alfredo
authors.initials: JA
authors.lastname: Martinez
authors.forename: José Luis
authors.initials: JL
authors.lastname: Santos
mesh_terms: D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics*; D002677:Chile; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A