223, P223

The use of design programs from Sequenom when diagnosing familial hypercholesterolemia

Peter Benedek1,*, Juha Kere2, Kristina Duvefelt3, Malin Linde3, Mats Eriksson1, Bo Angelin1

1Dep.of Endocrinology, MK-division 1, Huddinge, Karolinska University hospital, 2Institution of bioscience, 3Mutation Analysis Facility, MAF, STOCKHOLM, Sweden

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disease causing high levels of LDL cholesterol and high risk of premature cardiovascular events and death. The incidence of FH is approximately 1/400 making it a rather common disease. Early detection and treatment are essential. Unfortunately the diagnosis is often missed and most cases are discovered after the first cardiovascular event.

Lower costs for gene sequencing has made it an useful tool in gene diagnostics. However, in common diseases such as FH, that can be caused by several different mutations, in more than one gene, the cost becomes substantial.  More than 1800 different mutations in the LDLr-gene alone has been described and several different mutations in the APO-B and PCSK-9 gene as well. When considering the incidence of FH, the cost of using gene sequencing would be enormous.

Often a smaller number of mutations are responsible for the vast majority of FH-cases in a certain population. This fact could allow us to consider other methods than sequencing of genes to diagnose FH.

Objectives: To evaluate whether a different method, other than sequencing could be used to identify most of the mutations, in three different genes, known to cause FH. 

Methods: A total number of 118 known mutations were selected on the hypothesis that they would be likely to be found in the Swedish FH-population.In collaboration with MAF (Mutation Analysis Facility), Huddinge, assays were designed using the platform from Sequenom based on Massarray technique.The DNA of 37 unrelated individuals with probable FH based on the Dutch lipid clinic network diagnostic criteria, were selected.

Results:  In 22 out of the 37 individuals with probable FH a mutation was detected.This represents a detection rate of about 59 %.

Conclusion: The result may indicate that this diagnostic method could be of value when investigating patients of Swedish origin with probable FH. However a much larger number of individuals needs to be evaluated before any certain conclusions can be made.

Keywords: Cardiovascular, DNA, Genomics