Analysis of variants at splicing sites in patients with Familial Hypercholesterolemia

Abstract

Currently, only the clinical evaluation of patients with high levels of serum cholesterol has been shown to be insufficient for the correct identification of FH cases. Thus, to increase the diagnostic accuracy of this condition, molecular diagnostic tools have proved to be adequate and important strategies. This pathology is characterized by genetic variants found in four main genes, LDLR, APOB, PCSK9, and LDLRAP1. However, most patients who meet the clinical criteria for the diagnosis of FH do not have variants in these genes that could explain the phenotype of the disease. This impasse has led research in this area to hypothesize possible explanations for these findings. Among these possibilities, we can mention variants involved in the splicing mechanism occurring in exons and introns and consequently affecting their normal functioning. The presence of variants at splicing sites can lead to dysfunctional or alternative splicing of pre-mRNA mediating the possible translation of altered and generally non-functional proteins. Furthermore, most of these transcripts generated with errors in the splicing mechanism enter the mRNA decay pathway, resulting in transcript degradation and leading to functional consequences for this pathology. For the analysis of these variants, not only the four main genes of the molecular diagnosis of FH will be used, but the entire exonic panel of 84 genes involved in cholesterol metabolism and biosynthesis, in addition to genes involved in the pharmacogenomics of statins. With this approach, it is expected to be able to clarify the molecular diagnosis of more patients clinically diagnosed with FH in the present study.(AU)