Systematic evaluation of mobile element insertions in autosomal dominant hypercholesterolemia genes using short-read...

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• Autosomal dominant hypercholesterolemia (ADH) significantly increases cardiovascular risk.
• Short-read next-generation sequencing (NGS) often misses mobile element insertions (MEIs), a known cause of LDLR-related ADH.
• The prevalence and diagnostic utility of MEIs in ADH remain underexplored.

Purpose of the Study:

• To systematically evaluate the contribution of MEIs to ADH in a large patient cohort.
• To assess the frequency and functional impact of MEIs in the LDLR gene.
• To determine the role of MEIs in patients with suspected ADH who are negative for other genetic variants.

Main Methods:

• Retrospective screening of NGS data from 2393 unrelated probands using MELT software for MEIs.
• Orthogonal sequencing for validation of candidate MEI variants.
• Luciferase assays to assess functional consequences of MEIs on LDLR promoter activity.

Main Results:

• An adjusted prevalence of 0.04% (1/2393) for LDLR MEIs in ADH patients was determined.
• One confirmed MEI (AluYb8b1 insertion) was identified, but functional assays classified it as a variant of uncertain significance.
• One false-positive tandem duplication was detected, emphasizing the need for careful validation.

Conclusions:

• LDLR MEIs are extremely rare but can occur in ADH.
• MEIs may provide diagnostic information for ADH patients negative after standard genetic testing.
• Optimized MEI detection pipelines could improve molecular diagnosis of ADH.