Genetic screening to improve the diagnosis of familial hypercholesterolemia

Abstract

Abstract Familial hypercholesterolemia (FH) is a common inherited disorder that causes premature atherosclerosis due to defective clearance of LDL. With current mutation screening strategies, the success rate of finding a causative LDLR or other mutation in a clinically diagnosed FH patient is approximately 70–80%. High-throughput next-generation sequencing approaches are now being introduced to not only identify mutations in genes not previously suspected to be important to FH, but also to screen the currently known gene variants more comprehensively with greater success. Where conventional methods have failed to disclose a causative mutation in one of the known genes, a polygenic mode of inheritance has been proposed to account for FH in these ‘mutation-negative’ patients. Identifying the precise molecular basis of the disorder is important for family cascade screening as well as to optimize treatment and clinical management, thereby preventing the otherwise fatal consequences of undiagnosed and untreated FH.