title: Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.
abstract: OBJECTIVE
  Familial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism caused by mutations in LDLR, APOB, and PCSK9. To fulfill the World Health Organization recommendation, the Portuguese FH Study was established. Here, we report the results of the past 15 years and present practical considerations concerning the genetic diagnosis of FH based on our experience.
  
  
  METHODS
  Our approach comprises a biochemical and molecular study and is divided into five phases, including the study of whole APOB and functional assays.
  
  
  RESULTS
  A total of 2,122 individuals were enrolled. A putative pathogenic variant was identified in 660 heterozygous patients: LDLR (623), APOB (33), and PCSK9 (4); 8 patients presented with homozygous FH. A detection rate of 41.5% was observed. A stricter biochemical criteria was shown to improve patient identification. Overall, we have identified 3.4% and 80% of all heterozygous and homozygous patients, respectively, estimated to exist in our country.
  
  
  CONCLUSIONS
  The Portuguese FH Study has established the genetic diagnosis of FH in Portugal and is committed to continue the investigation of the genetic complexity of FH. Genetic diagnosis of FH should be expanded to include the study of all coding/flanking regions of APOB and functional in vitro studies, to improve the correct patient identification, and to avoid misdiagnosis.Genet Med 18 4, 316-324.
authors.affiliation: 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, Lisbon, Portugal.|BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
authors.forename: Ana Margarida
authors.identifier: http://orcid.org/0000-0003-2972-0872
authors.initials: AM
authors.lastname: Medeiros
authors.affiliation: 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, Lisbon, Portugal.|BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
authors.forename: Ana Catarina
authors.initials: AC
authors.lastname: Alves
authors.affiliation: 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, Lisbon, Portugal.|BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
authors.forename: Mafalda
authors.identifier: http://orcid.org/0000-0001-8843-3799
authors.initials: M
authors.lastname: Bourbon
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011174:Portugal; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D015415:Biomarkers; C573412:LDLR protein, human; D008055:Lipids; D011973:Receptors, LDL