Novel start codon variant in the 5’UTR of LDLR associated with familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH.