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The present work aims to determine the genetic cause (monogenic or polygenic) of hypercholesterolemia in clinical FH patients. N/A

Aims and study samples: Estimate cardiovascular disease (CVD) risk; What are the lipid-lowering therapy (LLT) strategies; How many are reaching LDL-C targets … in Familial Hypercholesterolemia (FH) patients and in the Portuguese general population. N/A

The American College of Medical Genetics and Genomics guidelines for variant classification are composed of several evidence criteria that, when combined, lead to a 5-tier pathogenicity variant classification. Several criteria rely on case-level data from patients, relatives, or controls with or without a particular variant of interest. (...) N/A

n.a. FCT SFRH/BD/108503/2015 N/A

Familial Hypercholesterolemia (FH): - Lipid metabolism autosomal dominant condition; - Elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since childhood → increased risk of atherosclerotic cardiovascular disease; - High heterozygote prevalence (1/250-1/500); Homozygous rare (1/ 300 000- 1/ 1 000 000); - Caused by pathogenic variants in LDLR (>90%), APOB (5- 10%) and PCSK9 (1-3%) genes; -Marked increase in FH variants submitted to ClinVar; -45% of variants were classified with more than one method and 466 variants submitted with potential clinical significance had conflicting or no classifications. N/A

Prémio do melhor caso clínico Aim: To determine the prevalence of statin pharmacogenetic relevant genotypes in the Portuguese population. N/A

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. Cibelle Mariano was supported by a PhD student grant [SFRH/BD/52494/2014]. Marta Futema is supported by the Fondation Leducq Transatlantic Networks of Excellence Program grant (no 14 CVD03). The work of Marilia Antunes is partially funded by UID/MAT/000016/2019. SEH acknowledges funding from the British Heart Foundation grant (BHF PG08/008) and from the NIHR UCLH BRC. MB acknowledges funding from Science and Technology Foundation (PIC/IC/83020/2007) (PIC/IC/83333/2007) for the e_COR and Portuguese FH Study and from Portuguese Cardiology Society for the Portuguese FH Study. info:eu-repo/semantics/publishedVersion

Familial Hypercholesterolaemia (FH) is a monogenic lipid disorder caused by mutations in LDLR, APOB, and PCSK9 genes. However, 50% of individuals with clinical diagnosis of FH do not have a mutation in one of these three genes, so other causes for their phenotype must exist. The FH phenotype has been associated recently to other monogenic disorders as lysosomal acid lipase deficiency (LALD) and sitosterolaemia or can have a polygenic origin. The aim of this work was to characterize the origin of the FH phenotype in a cohort of patients with clinical diagnosis of FH. Cibelle Mariano was funded by SFRH/BD/52494/2014. N/A

PurposeFamilial hypercholesterolemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. Although more than 1,700 variants have been associated with FH, the great majority have not been functionally proved to affect the low-density lipoprotein receptor cycle. We aimed to classify all described variants associated with FH and to establish the proportion of variants that lack evidence to support their pathogenicity.MethodsWe followed American College of Medical Genetics and Genomics (ACMG) guidelines for the classification, and collected information from a variety of databases and individual reports. A worldwide overview of publicly available FH variants was also performed.ResultsA total of 2,104 unique variants were identified as being associated with FH, but only 166 variants have been proven by complete in vitro functional studies to be causative of disease. Additionally, applying the ACMG guidelines, 1,097 variants were considered pathogenic or likely pathogenic. Only seven variants were found in all five continents.ConclusionThe lack of functional evidence for about 85% of all variants found in FH patients can compromise FH diagnosis and patient prognosis. ACMG classification improves variant interpretation, but functional studies are necessary to understand the effect of about 40% of all variants reported. Nevertheless, ACMG guidelines need to be adapted to FH for a better diagnosis. This work was partly supported by a grant from Genediag. J.R.C. and A.M.M. acknowledge their PhD fellowships funded by the Science and Technology Foundation (SFRH/BD/108503/2015 and SFRH/BD/113017/2015, respectively). info:eu-repo/semantics/publishedVersion

The Iberoamerican Familial Hypercholesterolemia network (IBAFH_N) was created in 2013 to promote awareness for Familial Hypercholesterolemia (FH) in these countries – Argentina, Brazil, Chile, Mexico, Portugal, Spain, Uruguay and more recently Colombia – that share a past and history. The aim of this work was to perform a molecular analysis of FH mutations in Iberoamerica. JR Chora was funded by FCT: SFRH/BD/108503/2015; AM Medeiros was funded by FCT: SFRH/BD/113017/2015.

Aims: Familial hypercholesterolemia (FH) is an autosomal dominant disorder with increased cardiovascular risk, caused by mutations in LDLR, APOB and PCSK 9 genes. Although it is described that over 1700 variants have been found, none of the existing databases are completely updated. The aim of this work is to construct a FH database in order to provide a unique source of verified information about variants associated with FH for a more accurate genetic diagnosis. JR Chora was funded by FCT: SFRH/BD/108503/2015; AM Medeiros was funded by FCT: SFRH/BD/113017/2015. This project was funded by Gendiag.