FH4=STAP1. Another Gene for Familial Hypercholesterolemia?
Relevance to Cascade Testing and Drug Development?
The average rate of discovery of new genes causing familial hypercholesterolemia (FH) has been ≈1 per decade since the 1970s, a meagre diversity compared with the complexity more recently discovered in familial cardiomyopathies1 and conduction disorders.2 In contrast to studies in monogenic FH, genome-wide association studies have unearthed far more than 100 genomic regions, many of unknown functionality, making small contributions to polygenic lipid traits in the general population, with many of these loci influencing low-density lipoprotein (LDL) cholesterol.3 Nonetheless, the several genes implicated in monogenic pure hypercholesterolemia (Table) have given powerful insight into the role of LDL cholesterol in cardiovascular risk and have opened new avenues in pharmaceutical development. They have also enabled a molecular classification of cardiovascular risk, enabling focused diagnostics in conjunction with cascade testing in mutation-positive families. The apparent identification of a further FH gene (dubbed FH4 by Fouchier et al4) should, therefore, be of significant interest to geneticists, lipid clinics, general doctors, and cardiologists with an interest in tracing or treating familial hypercholesterolemics. It may also be of interest to pharmaceutical companies engaged with the development of new approaches to treating hypercholesterolemia.
Article, see p 552
Monogenic hypercholesterolemia has a long history. Familial occurrence of tendon xanthomata was documented by Fagge5 in 1873. Subsequent observations led to the recognition of arterial deposits and the contribution of these atheromatous deposits to early coronary artery disease and coronary events. It was soon recognized that the familial pattern was autosomal codominant, passing from an affected parent to half of their children. In rare instances where both parents are affected, 1 in 4 of their offspring will inherit 2 defective copies, leading to an extreme hypercholesterolemia with overt vascular disease developing even during childhood years. The incidence of …