A gain-of-function (GOF) mutation in the PCSK9 gene (p.(Ser127Arg)) was identified in two large French families with multiple consanguineous hypercholesterolemia/hyper LDL-C, tendinous xanthomas, acute myocardial infarction (MI), and stroke, which most likely had a common ancestor. Here, PCSK9 is linked to familial hypercholesterolemia.