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. 2024 Feb;65(2):100490.
doi: 10.1016/j.jlr.2023.100490. Epub 2023 Dec 18.

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Ana Margarida Medeiros  1 , Ana Catarina Alves  1 , Beatriz Miranda  1 , Joana Rita Chora  1 , Mafalda Bourbon  2 ; investigators of the Portuguese FH Study
Collaborators, Affiliations

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Ana Margarida Medeiros et al. J Lipid Res. 2024 Feb.

Abstract

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.

Keywords: FH-phenocopy genes; familial hypercholesterolemia; hyper-Lp(a); polygenic hypercholesterolemia.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Fig. 1
Fig. 1
Diagram of molecular study in the FH cohort. About 1,005 individuals with clinical diagnosis of FH were selected for molecular study: 417 have FH confirmed genetically, 73 carry VUS in FH primary genes, and 7 have other monogenic causes. In the group of FH-negative individuals: 226 were analyzed for 5 FH-phenocopy genes, 425 for LDL-C PRS, and 131 for LPA genetic score.
Fig. 2
Fig. 2
A: Genetic background of individuals with clinical FH phenotype from the Portuguese cohort. B: Genetic background of FH-negative individuals. Comp Htz, compound heterozygous; Hmz, homozygous; Htz, heterozygous.
Supplemental Figure S1
Supplemental Figure S1
See this image and copyright information in PMC

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