FH phenotype: monogenic, polygenic and other causes

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/publishedVersio

Classification of genetic variants for clinical use – the case of Familial Hypercholesterolemia (Part 2): How to classify LDLR variants

Lecture about FH LDLR variants - classification of genetic variants for clinical use.N/

LDLR variant interpretation guidelines by the Clinical Genome Resource’s Familial Hypercholesterolemia Expert Panel

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

Pharmacogenomics of dyslipidaemia drugs in Portugal

Background/Aim: Statins are the standard treatment for dyslipidaemia disorders, but there is a wide (10-70%) variation in patient response to statin treatment and several documented serious adverse effects. Studies of variants in genes regulating drug absorption, metabolism, pharmacodynamics and excretion mechanisms, have been implicated as reasons for this variability. The aim of this study is to determine the prevalence of pharmacogenetic relevant genotypes in the Portuguese population and in a sample of high cardiovascular risk patients: familial hypercholesterolemia subjects.N/

Prevalence of statin pharmacogenomic SNPs in Portugal

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

Familial hypercholesterolemia in Portugal - lipid-lowering strategies and cardiovascular disease risk

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/

Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis

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/publishedVersio

Systematic review of LDLR mutations associated to Familial hypercholesterolaemia evidence of functional studies and application of ACMG guidelines for FH diagnosis

Familial hypercholesterolaemia (FH) is an autosomal dominant disorder caused by functional mutations in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%). An accurate genetic diagnosis is essential for a correct diagnosis. However it is known that only a small part of the variants identified have been characterized by in vitro functional assays. To overcome this lack of functional data the American College of Medical Genetics and Genomics (ACMG) published recently a guideline for variant interpretation in clinical settings. The propose of this review was to analyze the number of total variants in LDLR associated with FH worldwide and classify these variants’ pathogenicity by the application of ACMG variant interpretation guidelines with a special focus on functional evidence.JR Chora was funded by SFRH/BD/108503/2015; AM Medeiros was funded by SFRH/BD/113017/2015. This work was partly supported by a grant from Genediag, Exe. With thanks to the EAS for support in the form of a Young Investigator Fellowship.N/

LDLR, APOB and PCSK9 variants associated with Familial hypercholesterolaemia application of ACMG guidelines for variant interpretation

Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of lipid metabolism presenting with increased cardiovascular risk. It is caused by functional mutations in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%). Although more than 1700 variants have been associated with FH, the great majority have not been proved functionally to affect the LDL receptor cycle. The American College of Medical Genetics and Genomics (ACMG) recently published a guideline for variant interpretation in clinical settings. We aimed to classify, following ACMG guidelines, all published variants associated with FH in different databases and individual reports to establish the proportion of variants that lack evidence to support their pathogenicity. A worldwide overview of FH variants has also been performed.This work was partly supported by a grant from Genediag, Exe. JR Chora and AM Medeiros each have a PhD fellowship funded by FCT (SFRH/BD/108503/2015 and SFRH/BD/113017/2015, respectively). AC Alves is funded by Genediag, Exe (“FH genetic diagnosis” - 2015DPS1165).N/

Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis

Familial Hypercholesterolemia (FH): Lipid metabolism autosomal dominant condition; Patients present elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since birth - elevated cardiovascular risk.FCT: SFRH/BD/108503/2015N/