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APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

Catalina Dussaillant1, Valentina Serrano1, Alberto Maiz1, Susana Eyheramendy2, Luis Rodrigo Cataldo1, Matías Chavez2, Susan V Smalley1, Marcela Fuentes1, Attilio Rigotti1, Lorena Rubio1, Carlos F Lagos3, José Alfredo Martinez4 and José Luis Santos1*

Author affiliations

1 Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile

2 Department of Statistics, School of Mathematics, Pontificia Universidad Católica de Chile, Santiago, Chile

3 Department of Pharmacy, School of Chemistry, Pontifica Universidad Católica de Chile, Santiago, Chile

4 Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain

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Citation and License

BMC Medical Genetics 2012, 13:106  doi:10.1186/1471-2350-13-106

Published: 15 November 2012



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.


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.


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.


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.

Hypertriglyceridemia; Genetic; Chylomicronemia; Mutation; Homozygosity mapping; APOA5