The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia.
OBJECTIVE
Familial hypercholesterolemia (FH) is one of the most common monogenic disorders, and the high concentrations of low-density lipoprotein (LDL) cholesterol presented since birth confers on these patients an increased cardiovascular risk. More than 1,600 alterations have been described in the LDL receptor gene (LDLR), but a large number need to be validated as mutations causing disease to establish a diagnosis of FH. This study aims to characterize, both at the phenotypic and genotypic levels, families with a clinical diagnosis of FH and present evidence for the importance of the integration of clinical, molecular, and functional data for the correct diagnosis of patients with FH.


METHODS
A detailed analysis of the phenotype and genotype presented by 55 families with 13 different alterations in the LDLR was conducted. For eight of these, an extensive functional characterization was performed by flow cytometry, confocal microscopy, and reverse transcriptase polymerase chain reaction.


RESULTS
Carriers of neutral alterations presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75(th) percentile. presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75th percentile However, the functional study was essential to determine the pathogenicity of variants.


CONCLUSIONS
The data collected illustrate the importance of this integrated analysis for the correct assessment of patients with FH who can otherwise be misdiagnosed.
Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Bilbao, Spain.
Asier
A
Benito-Vicente
Grupo de Investigação Cardiovascular, Unidade I&D, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal.|BioISI - Biosystems & Integrative Sciences Institute, University of Lisbon, Faculty of Sciences, Lisbon, Portugal.
Ana Catarina
AC
Alves
Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Bilbao, Spain.
Aitor
A
Etxebarria
Grupo de Investigação Cardiovascular, Unidade I&D, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal.|BioISI - Biosystems & Integrative Sciences Institute, University of Lisbon, Faculty of Sciences, Lisbon, Portugal.
Ana Medeiros
AM
Medeiros
Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Bilbao, Spain.
Cesar
C
Martin
Grupo de Investigação Cardiovascular, Unidade I&D, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal.|BioISI - Biosystems & Integrative Sciences Institute, University of Lisbon, Faculty of Sciences, Lisbon, Portugal.
Mafalda
M
Bourbon
D000328:Adult; D002318:Cardiovascular Diseases / Q000209:etiology; D008078:Cholesterol, LDL / Q000032:analysis* / Q000097:blood / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011174:Portugal; D012307:Risk Factors
D008078:Cholesterol, LDL