Key result
Functional testing of ~17,000 LDLR variants correlates with hyperlipidemia and improves polygenic risk scores.
Why the study?
Definitive classifications are lacking for nearly half of clinically encountered LDLR missense variants, limiting interventions that reduce the burden of premature atherosclerosis.
A comprehensive functional map of nearly all possible LDLR coding variants improves the interpretation of clinical variants and risk inference for familial hypercholesterolemia.
May aid LDLR variant classification in FH; leaves open integration into polygenic risk models pending prospective validation.
Variants in the familial hypercholesterolemia gene LDLR-the most important genetic driver of cardiovascular disease-can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis. Definitive classifications are lacking for nearly half of clinically encountered LDLR missense variants, limiting interventions that reduce disease burden. We tested the impact of ~17,000 (nearly all possible) LDLR coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence-function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants. Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.
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Tabet et al. (2025) studied Familial hypercholesterolemia. LDLR coding variants was evaluated on LDLR cell-surface abundance and LDL uptake. Functional testing of ~17,000 LDLR coding variants yielded sequence-function maps that correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic risk scores.
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