Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non-LDLR/non-APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening.