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Familial Hypercholesterolaemia (FH) is a monogenic disorder characterised by high LDL-C concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Methods and Results Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by PCR amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management. This article is protected by copyright. All rights reserved.

Aim: The correct identification of the dyslipidaemia is of great importance in order to implement specific interventions, especially for cardiovascular disease (CVD) prevention. The Global Lipids Genetics Consortium (GLGC) reported 158 loci associated with lipid traits, by genome-wide association studies (GWAS), although practical value of GWAS approach is still a subject of debate, half of these loci are previously known to influence serum lipid concentrations. Previous studies (Talmud et al., 2013; Futema et al., 2015) have demonstrated that the co-inheritance of low-density lipoprotein (LDLC)-raising alleles from 6 of these SNPs is associated with the Familial Hypercholesterolaemia (FH) phenotype. Here we investigated the applicability of the LDL-C genetic risk score in the Portuguese FH population. Cibelle Mariano is grateful for the EAS for support in the form of a Young Investigator Fellowship to present her work. Cibelle Mariano was funded by SFRH/BD/52494/2014. N/A

Projects grants: Portuguese Cardiology Society [D13123], Science and Technology Foundation [project grant PIC/IC/83333/2007]; AM Medeiros was funded by BRJ-DPS/2012; Cibelle Mariano was funded by SFRH/BD/52494/2014

AM Medeiros was funded by BRJ-DPS/2012; C Mariano was funded by SFRH/BD/52494/2014. Project funding was obtained from Synageva BioPharma (which was acquired by Alexion Pharmaceuticals, Inc. June 2015).