The molecular basis of familial hypercholesterolemia in The Netherlands.

Mutations in the low-density lipoprotein (LDL) receptor gene are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations in this gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL-receptor gene mutations in a population is a prerequisite for the implementation of nation-wide genetic testing for FH. In the Netherlands, mutation analysis by denaturing gradient gel electrophoresis and sequencing in 1641 clinically diagnosed FH patients resulted in the characterization of 159 different LDL-receptor gene defects. The nine most common mutations were responsible for 66.5% of our FH index cases. Of these, four mutations occurred with relatively high frequencies in specific parts of the Netherlands. The remaining mutations were only encountered in single FH patients, comprising 22.2% of the patient cohort analyzed. Subsequent genetic testing of relatives of the index cases within the national FH screening program resulted in the identification of 5,531 FH patients in total. The analysis for LDL-receptor mutations is a continuing effort to update the LDL-receptor mutation catalogue. Subsequently, with the newly generated index cases, the screening program can be extended and continued to identify and treat FH patients as early as possible and reduce cardiovascular morbidity and mortality in these patients at high risk.