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Novel genetic strategies for the characterization of Familial Hypercholesterolemia phenotype
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Familial Hypercholesterolemia (FH) is the most common genetic lipid disorder with increased risk of atherosclerotic cardiovascular disease due to lifelong elevated low density lipoprotein cholesterol (LDL-C). FH is known to be caused by pathogenic/likely pathogenic (P/LP) variants in LDLR, APOB, PCSK9 genes, but remains underdiagnosed worldwide due to lack of clinical identification. In 40-70% of the clinical FH cases, depending on clinical criteria applied, no P/LP variants are found in FH genes.
An extended next generation sequencing (NGS) panel was developed and divided in three genetic strategies to characterize the FH phenotype in individuals of the Portuguese FH cohort. In a first approach, a virtual FH panel was analysed, covering 8 genes and a polygenic risk score (PRS). FH was genetically confirmed in 42% of the cohort. In the FH-negative individuals, other causes were identified, as hyper-lipoprotein(a) (30%), high PRS (16%), other monogenic lipid metabolism disorders (1%) and heterozygous pathogenic variants in FH-phenocopy genes (2%).
In a second approach, SNPs within 3’-UTR sequence of FH genes (LDLR and PCSK9) were analysed in FH-negative individuals. These SNPs were predicted to disturb miRNA:mRNA interactions, potentially affecting the post-transcriptional regulatory effect of miRNAs, and possibly contributing to hypercholesterolemia in 6,4% of FH-negative individuals. These individuals had a higher frequency of SNPs within miRNA-binding sites in PCSK9 3’-UTR (4.2%), which can lead to an increase in PCSK9 expression.
In a third approach, a virtual NGS panel covering 27 candidate lipid genes associated to hyperlipidemia was explored. An accumulation of rare variants was identified in 51% of the FH-negative individuals, suggesting top 5 relevant genes that could potentially disrupt lipoprotein metabolism.
This work unravels other genetic causes of the FH phenotype. Understanding the genetic background of FH-negative cases is crucial for an accurate disease diagnosis and to tailor the treatment for the specific affected pathway.
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Familial Hypercholesterolemia (FH) FH-phenocopy genes polygenic hypercholesterolemia 3’-UTR variants candidate lipid genes Hipercolesterolemia Familiar genes fenocópias de FH hipercolesterolemia poligénica variantes 3’-UTR genes candidatos