Objective:
Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (
LDLR
) mutations account for >90% of cases, apolipoprotein B (
APOB
) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (
PCSK9
) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel
PCSK9
variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays.
Approach and Results:
Patients with clinically diagnosed FH underwent genetic analysis of
LDLR
, and if negative, sequential testing of
APOB
and
PCSK9
. We analyzed cosegregation of hypercholesterolemia with novel
PCSK9
variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous
PCSK9
variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel
PCSK9
variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL;
P<
0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
Conclusions:
In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in
PCSK9
. Pathogenicity is established beyond doubt for the G516V variant.
12-Week Effectiveness and Safety of Low-Density Lipoprotein Cholesterol-Lowering Therapy by Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition in Patients With Familial Hypercholesterolemia and Hypercholesterolemia ― Data From a Real-World Observational Study of Evolocumab in Japan ―