Characterization of the first PCSK9 gain of function homozygote

Abstract

Gain of function (GOF) mutations in proprotein convertase subtilisin kexin type 9 (PCSK9) are a rare cause of familial hypercholesterolemia (FH). We identified a child with a clinical diagnosis of FH with 2 novel putative PCSK9 GOF missense variants (p.[(Ala62Asp)]; [(Pro467Ala)]), and no mutation in the low-density lipoprotein (LDL) receptor (LDLR) or in apolipoprotein B100 (APOB) genes. We fully characterize here the first compound heterozygote FH patient with 2 PCSK9 GOF variants. The experiments conducted on the proband’s lymphocytes clearly suggest that this patient should respond particularly well to a treatment combining a statin and a PCSK9 inhibitor.