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

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• Familial hypercholesterolaemia (FH) is a genetic disorder linked to LDLR, APOB, and PCSK9 gene variants.
• It significantly increases the risk of premature coronary heart disease due to elevated LDL-C.
• Current genetic screening primarily focuses on coding regions.

Purpose of the Study:

• To identify novel genetic variants causing FH.
• To investigate the functional impact of a newly identified variant in the LDLR 5 UTRs.
• To assess the role of 5 UTRs in FH pathogenesis.

Main Methods:

• Whole genome sequencing data from 536 FH patients were analyzed using VEP plugin UTRannotator.
• Reporter assays (promoter and epitope) were employed to study variant function.
• Functional characterization of a novel c.-35C>G variant and a previously reported c.-22del variant in the LDLR 5 UTR.

Main Results:

• A novel variant, c.-35C>G, was identified in the LDLR 5 UTR of FH patients.
• This variant introduces an upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence.
• Reporter assays confirmed that the c.-35C>G variant leads to preferential use of the upstream AUG codon, resulting in premature translation initiation and protein truncation, similar to the c.-22del variant.

Conclusions:

• A novel class of FH-causing LDLR variants located in the 5 UTR has been identified.
• These variants lead to premature translation initiation and protein truncation.
• Expanded genetic screening beyond coding regions is crucial for comprehensive FH diagnosis.