Characterization of the Effects of Familial Hypercholesterolemia Mutations in LDLR on PCSK9 Binding

Familial Hypercholesterolemia (FH) is an autosomal dominant condition characterised by substantially increased plasma LDL-C concentrations from birth, leading to premature atherosclerosis. FH is one of the most common inherited disorders associated with premature CHD, with a heterozygous frequency of 1/250-1/500 worldwide. Loss-of-function mutations in the LDLR account for more than 90% of the cases. Mutations in APOB or gain-of-function mutations in PCSK9 are also associated with FH, but are found less frequently in FH patients (APOB 5-10%, PCSK9 <3%). There are >3000 unique variants identified in LDLR, APOB and PCSK9 in ClinVar, but about 50% are variants of unknown significance and most of these variants have not been classified following ACMG classification. This chapter aims to help readers to understand the most important information to perform variant classification and interpretation in FH.