Martin-Campos_2014_Clin.Chim.Acta_429_61

BACKGROUND: Familial chylomicronemia (type I hyperlipidemia) is a rare autosomal recessive disease due mainly to rare variants in the lipoprotein lipase (LPL) gene sequence. Molecular diagnosis of LPL deficiency is now a requirement for the first gene therapy treatment approved in the European Union. Altered coding sequence variants in APOC2, APOA5 or GPIHBP-1 can also cause familial chylomicronemia. Herein, we report the results of our molecular diagnostic activity in this topic, carried out in the setting of a Spanish clinical practice hospital laboratory, which was also extended to some patients who were more likely to have type V hyperlipidemia. METHODS: Samples from twenty-nine unrelated probands with severe hypertriglyceridemia were referred for molecular diagnosis. Samples were first screened for LPL sequence variants by DNA sequencing and, in the absence of alterations, subsequent analysis of APOC2, APOA5, and GPIHBP1 genes was undertaken. Analysis of LPL function in vitro was further studied in two previously uncharacterized LPL sequence variants. RESULTS: Fourteen different, loss-of-function variants were found in the LPL gene: 4 were novel or uncharacterized allelic variants, and of these, 2 were directly shown to affect function. Twenty of 29 probands presented at least one LPL gene allele variant: 8 were homozygous, 9 compound heterozygous and 3 heterozygous. In 13 probands, the finding of two loss-of-function variants supported the diagnosis of LPL deficiency. None of the probands presented sequence variants in the APOC2 gene, whereas 3 presented rare variants within the APOA5 gene. Four of the five patients heterozygous for a common variant in the GPIHBP-1 gene also carried APOA5 sequence variants. CONCLUSIONS: Loss-of-function LPL variants leading to familial chylomicronemia were found in 13 patients, accounting for a significant proportion of the LPL-deficient patients predicted to live in Spain.