Genetic background of individuals with clinical diagnosis of FH from the Portuguese FH Study cohort

Medeiros, Ana Margarida; Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz Raposo; Bourbon, Mafalda

http://hdl.handle.net/10400.18/9005

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Authors

Medeiros, Ana Margarida

Alves, Ana Catarina

Chora, Joana Rita

Miranda, Beatriz Raposo

Bourbon, Mafalda

Abstract(s)

Aim: Familial Hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism associated to increased CAD risk. Three genes are associated with FH (LDLR, APOB, PCSK9). Variants in FH phenocopies genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8), LDL-C polygenic risk score (PRS) and hyper-Lp(a) can mimic the FH phenotype. In the present work we intend to unravel the genetic background in individuals with clinical diagnosis of FH. Methods: A biochemical and genetic study was performed to 1005 patients with clinical diagnosis of FH referred to the Portuguese FH Study until December 2021. Since 2017, genetic diagnosis is performed by an NGS panel with 8 genes and 6-SNPs to determine PRS. Results: FH was genetically confirmed in 41% of the cases. In the FH-negative cohort (N=590), 30% (N=177) present Lp(a)>50mg/dl, 16% (N=95) have high PRS, 1% (N=7) have other monogenic cause and 1% (N=7) have one pathogenic variant in ABCG5/ABCG8. Additionally, 11% (N=61) carry heterozygous VUS in either LDLR, APOB or PCSK9 and 5% (N=29) carry heterozygous variants of unknown significance (VUS) in FH phenocopies genes. No identifiable cause of dyslipidemia was found in the remaining 36% patients. Conclusions: Overall, FH was confirmed genetically in 41% of the cohort. In 50% of the FH negatives the FH phenotype can be caused by Hyper-Lp(a) or high PRS. A small part of patients has pathogenic variants in ABCG5/8 in heterozygosity and this can be the cause of hypercholesterolemia and should be further investigated. This extended NGS panel is important to identify FH/FH-phenocopies and therefore personalize each patient’s treatment