Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

Abstract

Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.

Genetic testing for familial hypercholesterolemia

“…FH was traditionally considered an autosomal dominant inherited disorder most frequently associated with variants in three genes: the LDL receptor ( LDLR ) gene, apolipoprotein B ( APOB ) gene, and proprotein convertase subtilisin/kexin 9 ( PCSK9 ) gene [3,9 ▪ ]. Variants in the LDLR gene lead to a decrease in LDLR activity and consequently impaired clearance of LDL-C by the receptors (Fig.…”

“…Variants in the LDLR gene lead to a decrease in LDLR activity and consequently impaired clearance of LDL-C by the receptors (Fig. 1) [3,9 ▪ ]. FH-causative variants in the APOB gene are mostly in regions encoding for the LDLR binding domains and can cause impaired binding of LDL-C to LDLR [3,9 ▪ ].…”

“…FH-causative variants in the APOB gene are mostly in regions encoding for the LDLR binding domains and can cause impaired binding of LDL-C to LDLR [3,9 ▪ ]. Gain-of-function variants in the PCSK9 gene increase the ability of the PCSK9 protein to promote degradation of LDLRs, leading to decreased LDLR availability for LDL-C uptake [3,9 ▪ ]. Variants in LDLR account for > 90% of genetically confirmed FH cases, while APOB variants account for 5–10% and PCSK9 variants <1% [3,10].…”

Regulation of cholesterol metabolism: New players for an old physiological process

“…Passive processes include simple diffusion through the aqueous phase and facilitated diffusion mediated by SR‐B1. Active pathways are mediated by ABC family proteins, 20 in particular ABC‐A1, ABC‐G1, ABC‐G5, and ABC‐G8 21 …”

“…Active pathways are mediated by ABC family proteins, 20 in particular ABC-A1, ABC-G1, ABC-G5, and ABC-G8. 21…”