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Functional Studies in LDLR to Improve Genetic Diagnosis in Familial Hypercholesterolemia
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Resumo(s)
Familial hypercholesterolemia (FH) is the most common inherited disorder of lipid metabolism, affecting approximately 1 in 300 individuals. FH is an autosomal semidominant disorder and was the first genetic lipid metabolism disorder to be molecularly characterized. Individuals with FH present elevated blood cholesterol levels from birth, leading to a high cumulative risk of developing cardiovascular disease. Pathogenic variants in the low-density lipoprotein receptor (LDLR) gene are the primary cause of FH, with more than 4,000 variants identified to date. However, only 15% of these have been functionally characterized in vitro, demonstrating their impact (or lack of) on LDL receptor function.
This study highlights the role of functional studies in genetic diagnosis and personalized medicine, using the Portuguese Familial hypercholesterolemia Study (EPHF) as an example of how these studies have clinical impact. Functional studies of LDLR are crucial for understanding how this receptor activity regulates cholesterol clearance.
In a cohort of 1088 individuals (1073 heterozygotes and 15 homozygotes) with a clinical diagnosis of FH, 164 different LDLR variants were identified. To date, 70 of these variants have been functionally studied within the EPHF and 38 have been characterized by other labs. This functional characterization contributed to obtain a definitive genetic diagnosis for 847 individuals, marking a significant step towards personalized medicine and the effective management of FH.
These studies not only improve the classification of LDLR variants but also directly influence treatment decisions and patient outcomes. By advancing the functional characterization of these variants, we contribute to more specialized and precise diagnostics, leading to more tailored therapeutic approaches for cholesterol-related disorders.
Descrição
Palavras-chave
Familial Hypercholesterolemia Cholesterol LDLR Genetic Diagnosis Doenças Cardio e Cérebro-vasculares