Abstract

In the majority of patients, familial hypercholesterolaemia (FH) is caused by different mutations affecting the well defined low density lipoprotein receptor (LDLR) gene. However, 3% of patients in Munich with a clinical diagnosis of FH have a particular mutation in the apolipoprotein B gene causing familial defective apolipoprotein B-100 (FDB). To date none of the LDLR mutations causing FH in German patients has been identified and it is therefore not yet possible to use DNA technology for direct diagnosis. However, indirect molecular diagnosis based on genetic linkage of common restriction fragment length polymorphisms (RFLPs) of the LDLR gene can be used for diagnosis in family studies. Patients with FDB were excluded from this study. Genotypes and haplotypes of four RFLPs (StuI, ApalI 5', PvuII, and NcoI) were determined in a total of 164 independent alleles from 31 pedigrees that included 222 subjects. Allele frequencies and four RFLP haplotype distribution did not differ significantly from those reported in other populations. The applicability of DNA diagnosis in our lipid clinic is comparable with the estimation from calculations on frequencies and heterozygosities of RFLPs, as predicted using these four RFLPs before. On the basis of cosegregation of haplotypes and normo- or hypercholesterolaemia in one or more sibs or offspring, defective and normal LDLR gene alleles could be distinguished in 42 of 58 heterozygous FH patients who were heterozygous for at least one RFLP. In 97 of 134 (72%) children of these 42 subjects, diagnosis of FH could be carried out unambiguously.(ABSTRACT TRUNCATED AT 250 WORDS)