Patients homozygous or compound heterozygous for LDLR mutations or double heterozygous for LDLR and
apo B R3500Q mutation have higher
LDL-C levels, more extensive
xanthomatosis and more severe premature
coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced
Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (
LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (
LDL-C 8.07 mmol/L) and a PCSK9 mutation (p.R496W) from her mother (
LDL-C 5.58 mmol/L). Proband L.R. and her sister (
LDL-C 11.51 and 10.47 mmol/L,
xanthomatosis and
carotid atherosclerosis) were heterozygous for an LDLR mutation (p.Y419X) inherited from their mother (
LDL-C 6.54 mmol/L) and a PCSK9 mutation (p.N425S) probably from their deceased father. The
LDL-C levels in double heterozygotes of these two families were 56 and 44% higher than those found in simple heterozygotes for the two LDLR mutations, respectively. The two PCSK9 mutations are novel and were not found in 110 controls and 80 patients with co-dominant
hypercholesterolemia. These observations indicate that rare missense mutations of PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.