1,CONCATENATE(R[0]C[-32],” (“,R[0]C[-30],”) “,R[0]C[-31],”. “,R[0]C[-29],”, “,R[0]C[-28],”, “,R[0]C[-27],”. doi: “,R[0]C[-26], “, BioISI Groups involved: “,R[0]C[-10]))”>Graça R, Alves AC, Zimon M, Pepperkok R, Bourbon M.

Background

Familial Hypercholesterolemia (FH) is a semidominant disorder of the lipid metabolism associated with premature atherosclerosis and coronary heart disease. So far, about 3,000 unique LDLR variants have been described, most of which lack functional evidence proving their effect on LDLR function, despite the important role that functional studies play in variant classification.

Objective

In this work, we aimed to functionally characterize 13 rare missense variants, identified worldwide and in Portugal, in clinical FH patients.

Methods

LDLR-deficient CHO-ldlA7 cells were transfected with plasmids carrying different LDLR variants generated by site-directed mutagenesis. LDLR activity and expression were assessed by FACS.

Results

11/13 variants affect LDLR function (p.Cys109Phe; p.Cys143Arg; p.Glu267Lys; p.Cys352Ser; p.Ile451Thr; p.His485Gln; p.Asp492Asn; p.Val500Ala; p.Gly529Arg; p.Phe614Ile; p.Glu626Lys) and 2/13 are inconclusive (p.Arg81Cys; p.Gly98Arg;).

Conclusion

Of the 13 variants studied, 8 were classified as VUS by ACMG criteria, but for 7 of these 8, our functional studies were able to reassign them as Likely pathogenic or Pathogenic. For an accurate diagnosis, an effort must be made to improve functional characterization of putative disease-causing variants.

Doi: 10.1016/j.jacl.2022.04.005

Graça R, Alves AC, Zimon M, Pepperkok R, Bourbon M (2022) Functional profiling of LDLR variants: Important evidence for variant classification: Functional profiling of LDLR variants. Journal of Clinical Lipidology, 16(4), 516-524. doi: 10.1016/j.jacl.2022.04.005