Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrentLDLR mutations

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B-100 ( APOB ), or proprotein convertase subtilisin/kexin type 9 ( PCSK9 ). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR , and a fragment of exon 26 of APOB . Additionally, the MLPA technique was applied to detect rearrangements within LDLR . In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR , 40 novel and 59 previously described sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4–8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB . Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB ) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the studied group confirms the requirement for complex molecular studies of Polish ADH patients.