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Clinical and genetic characteristics of patients with a clinical diagnosis of Familial Hypercholesterolemia in Portugal
Session:
Comunicações Orais - Sessão 25 - Prevenção Cardiovascular e Reabilitação
Speaker:
Ana Margarida Medeiros
Congress:
CPC 2023
Topic:
J. Preventive Cardiology
Theme:
29. Rehabilitation and Sports Cardiology
Subtheme:
29.2 Cardiovascular Rehabilitation
Session Type:
Comunicações Orais
FP Number:
---
Authors:
Ana Margarida Medeiros; Ana Catarina Alves; Joana Rita Chora; Beatriz Raposo Miranda; Mafalda Bourbon
Abstract
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Aim: Familial Hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism with an increased risk of coronary artery disease (CAD) due to lifelong exposure of elevated LDL-C levels. FH is caused by pathogenic/likely pathogenic (P/LP) variants in <em>LDLR</em>, <em>APOB,</em> <em>PCSK9.</em> Variants in FH phenocopies genes (<em>LDLRAP1</em>, <em>APOE</em>, <em>LIPA</em>, <em>ABCG5</em>, <em>ABCG8</em>), LDL-C polygenic risk score (PRS) and hyper-Lp(a) can mimic the FH phenotype. In this work we present the clinic and genetic results of the Portuguese FH Study cohort.</span></span></p> <p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Methods: A biochemical and genetic study was performed to 1005 index-cases (IC) 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.</span></span></p> <p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Results: A total of 106 IC (18%) with clinical diagnosis of FH had suffered a premature CV event with a mean age of 43.9±9.2 years. Mean LDL-C values for adults was 232.4±86.8 mg/dL and for children 191.3±57.4 mg/dL.</span></span></p> <p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">FH was genetically confirmed in 418 IC (406 heterozygous (HtFH), 4 true-homozygous, 7 compound-heterozygous, 1 double-heterozygous), all carrying P/LP variants in the 3 genes causing FH<em>.</em> Cascade screening identified 581 HtFH, one compound-heterozygous and one <em>LDLR</em>-<em>APOB</em> double-heterozygous.</span></span></p> <p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">In the FH-negative cohort (N=590), 33% have hyper-Lp(a), 17% have high PRS, 1% have other monogenic cause and 1% have one pathogenic variant in <em>ABCG5</em>/<em>ABCG8</em>. Also, 5% carry variants of unknown significance (VUS) in FH genes<em> </em>and<em> </em>5% carry VUS (in heterozygosity) in FH phenocopies genes<em>.</em> In the remaining 38% FH-negative IC the cause of dyslipidemia was not identified.</span></span></p> <p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">In the group of adults IC FH-positive CAD and premature CAD (pCAD) were statistically significant higher in the group with hyper-Lp(a) when compared with IC with normal Lp(a) levels (CAD: 31.5% vs 13.6%, p=0.005; pCAD: 27% vs 9%, p=0.002). The same results were obtained for the FH-negative cohort (CAD: 27% vs 16.7%, p=0.038; pCAD: 24.5% vs 14%, p=0.029).</span></span></p> <p><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">Conclusions: FH was confirmed genetically in 41% of the cohort. In 50% of the negative ICs the FH phenotype can be caused by hyper-Lp(a) or high PRS. A small part of these has </span></span><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">heterozygous </span></span><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">pathogenic variants in <em>ABCG5/8</em> that should be further investigated since it could be the cause of hypercholesterolemia. The use of the described NGS FH diagnostic panel is important to identify FH/FH-phenocopies and personalize each patient’s treatment accordingly to reduce their </span></span><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">increased risk of CAD.</span></span></p>
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