Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia

Abstract

The lipid disorder familial hypercholesterolemia (FH) predisposes to cardiovascular disease. With a prevalence of approximately one in 500 in the general Caucasian population, FH is one of the most frequent single-gene disorders. As the mutational spectra vary between populations, it is crucial to identify the mutations in a given population in order to implement a molecular genetic screening strategy. A total of 1053 referred individuals with clinical signs of FH were investigated, and mutations were identified in 425 individuals. Fifty-four different mutations were identified, of which 13 are novel. The five most frequent mutations accounted for 56.3% of all disease-causing mutations. The majority of the remaining mutations were of a private nature only encountered in single families. In this study, a reliable molecular genetic screening protocol was established, and the relevance of performing presymptomatic genetic analysis as part of a preventive strategy was documented. We have acquired knowledge of the mutational spectra in the Danish population and thus will be able to trace mutations in their relatives through our index cases.

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

“…In two members of one family this was found on same allele as p.Y375SfsX6, and as a compound heterozygote with p.A50S & p.T761M (Brusgaard et al 2006). Non-conservative Found with p.C696W (predicted to be pathogenic) in this report (Salazar et al 2002).…”

No certain predictors for mutation status in a Danish cohort with familial hypercholesterolemia: A descriptive study

“…Mutation-positive probands were significantly younger than probands without a mutation ( Table 1). As earlier reported, 54 different mutations were found, of which 13 were previously un-described [17]. In probands, 84% of all mutations were in the LDLR gene, while the remaining 16% were in the APOB gene.…”

“…Samples without mutations or polymorphisms were analyzed for major rearrangements by Long-PCR, covering major rearrangements previously observed in the Danish population. The criteria for a pathogenic mutation have previously been described [17].…”

“…Genomic DNA from peripheral leukocytes was extracted by a modified salt precipitation procedure and mutation analyses were carried out as previously described [17]. Briefly, samples were tested for deletions, insertions or point mutations in all 18 exons, the promotor and the flanking introns of the LDLR gene using DHPLC (Wave 3500; Transgenomic, Elancourt, France).…”

Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia

“…This excess relies upon the high frequency of the c.1048C>T, p.Arg350X mutation, formerly called FH-Fossum. Indeed, this mutation is reported in 9 apparently unrelated patients from different geographic origins: Norway (Solberg et al 1994), the Netherlands (Lombardi et al 1995), the U.K. (Day et al 1997), Poland (Gorski et al 1998, Germany , Canada (Gaudet et al 1999), Japan (Yu et al 2002), Denmark (Damgaard et al 2005) and Spain (Brusgaard et al 2006). In the absence of haplotypes demonstrating a common ancestor, these mutational events are supposed to be recurrent and to correspond to a mutational hot-spot in the LDLR gene.…”