Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.

Familial hypercholesterolaemia (FH) results from defective catabolism of low density lipoproteins (LDL), leading to premature atherosclerosis and early coronary heart disease. It is commonly caused by mutations in LDLR, encoding the LDL receptor that mediates hepatic uptake of LDL, or in APOB, encoding its major ligand. More rarely, dominant mutations in PCSK9 or recessive mutations in LDLRAP1 (ARH) cause FH, gene defects that also affect the LDL-receptor pathway. We have used multiplex ligation-dependent probe amplification (MLPA) to identify deletions and rearrangements in LDLR, some not detectable by Southern blotting, thus completing our screening for mutations causing FH in a group of FH patients referred to a Lipid Clinic in London. To summarise, mutations in LDLR were found in 153 unrelated heterozygous FH patients and 24 homozygotes/compound heterozygotes, and in over 200 relatives of 80 index patients. LDLR mutations included 85 different point mutations (7 not previously described) and 13 different large rearrangements. The APOB R3500Q mutation was present in 14 heterozygous patients and a mutation in PCSK9 in another 4; LDLRAP1 mutations were found in 4 "homozygous" FH patients. Our data confirm that DNA-based diagnosis provides information that is important for management of FH in a considerable number of families.