A study recently published in Science systematically maps the functional impact of nearly all approximately 17,000 possible missense variants in the LDLR gene. The comprehensive functional data generated by an international team of researchers will facilitate the precise classification of previously unclear LDLR variants, improve risk prediction for familial hypercholesterinemia and support early intervention strategies.

LDLR encodes the low density lipoprotein receptor, primarily expressed on liver cells, which mediates the uptake of LDL from the bloodstream. Pathogenic LDLR variants are the main genetic cause of familial hypercholesterinemia. This condition is characterized by markedly elevated circulating LDL cholesterol from childhood and adolescence, leading, if untreated, to premature atherosclerosis and an increased risk of myocardial infarction and stroke at an early age. Heterozygous familial hypercholesterinemia is one of the most common genetic disorders, yet it is frequently only diagnosed after a myocardial infarction occurs in a young patient or if there is a family clustering of cardiovascular events. This is also due to the fact that most identified missense variants in LDLR lack definitive classification regarding their pathogenicity.

The authors of the current study used a multiplexed in vitro assay to measure the impact of nearly all possible LDRL protein missense variants on LDL uptake and cell-surface abundance of LDL receptors. For over 7,000 of these LDLR missense variants, they generated and validated specific functional scores, which may now be used for the interpretation of previously ambiguous variants, helping to improve risk prediction and therapeutic intervention in patients and their families.