Familial hypercholesterolemia (FH) is commonly caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes. The study aim was to investigate patients with FH in Taiwan, using molecular diagnostic methods, and compare the abnormalities in the small mutation and large DNA rearrangement subgroups. In total, 102 unrelated probands with FH were tested for mutations by exon-by-exon sequence analysis (EBESA) and multiple ligation-dependent probe amplification (MLPA). EBESA identified gene apolipoprotein B R3500W in 8 probands and 25 mis-sense, 5 nonsense, and 6 frameshift LDLR mutations in 52 probands; 11 were novel mutations. Of the 42 probands with mutations undetected by EBESA, 8 had abnormal MLPA patterns, including 2 with exon 6 to 18 deletions, 2 with exon 9 deletion, 1 with exon 6 to 8 deletions, 1 with exon 11 deletion, 1 with exon 3 to 5 duplications, and 1 with exon 7 to 12 duplications. Pedigree analysis showed mutation cosegregation with hypercholesterolemia in affected family members. Mean lipid profiles and rate of failure to lower LDL cholesterol <100 mg/dl in response to rosuvastatin/ezetimibe treatment were similar in groups with abnormal MLPA patterns and groups carrying nonsense or frameshift mutations. In conclusion, frequency of large LDLR rearrangement was approximately 8% in Taiwanese patients with FH. The response to statin drugs differed between probands with abnormal MLPA patterns and probands carrying mis-sense or undetected mutations.
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