The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia

Benito-Vicente, A.; Alves, A.C; Etxebarria, A.; Medeiros, A.M.; Martin, C.; Bourbon, M.

http://hdl.handle.net/10400.18/3092

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Abstract(s)

Purpose: 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 75th 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.Conclusion:The data collected illustrate the importance of this integrated analysis for the correct assessment of patients with FH who can otherwise be misdiagnosed.

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The authors thank Rocío Alonso for excellent technical assistance. They are also grateful to A. Gómez-Muñoz for making flow cytometry facilities available and SGIker (Analytical and High-Resolution Microscopy in Biomedicine Service of the UPV/ EHU) and Monty Krieger for kindly providing CHO-ldlA7 cells. Capillary sequencing was performed at Unidade de Tecnologia e Inovação (Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge).