Gene

Intensive care medicine

Biology

Cholesterol

Familial hypercholesterolemia

Clinical phenotype

Environmental health

Genetics

Genetic testing

Bioinformatics

Population

Internal medicine

Family history

Medicine

Genetic counseling

Disease

Phenotype

Nature Reviews Cardiology

Familial hypercholesterolaemia is the most commonly encountered genetic condition that predisposes individuals to premature cardiovascular disease. Nevertheless, most patients are undiagnosed, and treatment is often suboptimal even when the diagnosis seems certain. Advances in molecular technologies are reshaping our understanding of this condition, including revision upwards of the population prevalence. Furthermore, the underlying pathophysiological complexity has been exposed by the range of causative genetic loci, breadth of types and classes of rare disease-causing variants, and polygenic basis of the phenotype in many patients. Genetic testing is not always helpful or definitive. Familial hypercholesterolaemia can be envisioned as a group of related disorders, of which the classic ‘textbook’ phenotype is a subset. Features such as clinical stigmata, family history of dyslipidaemia or cardiovascular disease, and presence of a rare pathogenic variant all increase diagnostic certainty. However, even in the absence of these elements, the essential feature remains an elevated level of plasma LDL cholesterol, which alone should prompt a dialogue between the care provider and the patient on lifestyle modification and lipid-lowering therapy as the foundation of a long-term strategy to prevent or delay the onset of cardiovascular disease. Familial hypercholesterolaemia (FH) is the most commonly encountered genetic condition that predisposes to premature cardiovascular disease. In this Review, Berberich and Hegele revisit the genetic complexity of FH and discuss our revised understanding of the mechanisms of FH and the implications for screening, diagnosis, and patient management.

The complex molecular genetics of familial hypercholesterolaemia