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Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: The SAFEHEART registry

  • Mafalda Bourbon
    Correspondence
    Corresponding author. Unidade I&D, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal.
    Affiliations
    Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal

    BioISI – Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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  • Ana Catarina Alves
    Affiliations
    Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal

    BioISI – Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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  • Rodrigo Alonso
    Affiliations
    Fundación Hipercolesterolemia Familiar, Madrid, Spain

    Clínica las Condes, Santiago de Chile, Chile
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  • Nelva Mata
    Affiliations
    Fundación Hipercolesterolemia Familiar, Madrid, Spain

    Department of Epidemiology, Madrid Health Authority, Madrid, Spain
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  • Pedro Aguiar
    Affiliations
    Centro de Investigação de Saúde Pública, Escola Nacional de Saúde Pública, Universidade Nova de Lisboa, Portugal
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  • Teresa Padró
    Affiliations
    Instituto Catalán Ciencias Cardiovasculares, IIB-Sant Pau, Barcelona, Spain
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  • Pedro Mata
    Affiliations
    Fundación Hipercolesterolemia Familiar, Madrid, Spain
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      Highlights

      • The majority of the genetic variants in the SAFEHEART registry are considered to be pathogenic or likely pathogenic.
      • A total of 194 variants have been detected in the SAFEHEART registry, 24 not described previously.
      • Patients with null allele variants have a more severe phenotype than carriers of defective variants.
      • More than 12% of the variants in the SAFEHEART registry are novel.
      • The genetic characterization of this registry is relevant for a better interpretation of follow-up data.

      Abstract

      Background and aims

      Familial hypercholesterolemia (FH) is an autosomal dominant disease of cholesterol metabolism that confers an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Therefore, early identification and treatment of these patients can improve prognosis and reduce the burden of cardiovascular mortality. The aim of this work was to perform the mutational analysis of the SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) registry.

      Methods

      The study recruited 2938 individuals with genetic diagnosis of FH belonging to 775 families. Statistical analysis was performed using SPSS v23.

      Results

      A total of 194 variants have been detected in this study, 24 of them were never described before. About 88% of the patients have a pathogenic or likely pathogenic variant. Patients with null variants have a more severe phenotype than patients with defective variants, presenting with significantly higher levels of atherogenic particles (total cholesterol, LDL-cholesterol and apolipoprotein B).

      Conclusions

      This study shows the molecular characteristics of the FH patients included in the SAFEHEART registry and the relationship with the phenotypic expression. The majority of the genetic variants are considered to be pathogenic or likely pathogenic, which confers a high level of confidence to the entry and follow-up data analysis performed with this registry concerning FH patients' prognosis, treatment and survival.

      Keywords

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