Browsing by Author "Freiberger, Tomáš"
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- ClinVar database of global familial hypercholesterolemia-associated DNA variantsPublication . Iacocca, Michael A.; Chora, Joana R.; Carrié, Alain; Freiberger, Tomáš; Leigh, Sarah E.; Defesche, Joep C.; Kurtz, C. Lisa; DiStefano, Marina T.; Santos, Raul D.; Humphries, Steve E.; Mata, Pedro; Jannes, Cinthia E.; Hooper, Amanda J.; Wilemon, Katherine A.; Benlian, Pascale; O'Connor, Robert; Garcia, John; Wand, Hannah; Tichy, Lukáš; Sijbrands, Eric J.; Hegele, Robert A.; Bourbon, Mafalda; Knowles, Joshua W.; on behalf of the ClinGen FH Variant Curation Expert PanelAccurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.
- Familial hypercholesterolemiaassociated variants in ClinVarPublication . Chora, Joana R.; Iacocca, Michael A.; Carrié, Alain; Freiberger, Tomáš; Leigh, Sarah E.; Defesche, Joep C.; Kurtz, C. Lisa; DiStefano, Marina T.; Santos, Raul D.; Humphries, Steve E.; Mata, Pedro; Jannes, Cinthia E.; Hooper, Amanda J.; Wilemon, Katherine A.; Benlian, Pascale; O'Connor, Robert; Garcia, John; Wand, Hannah; Tichý, Lukáš; Sijbrands, Eric J.; Hegele, Robert A.; Bourbon, Mafalda; Knowles, Joshua W.; On behalf of the ClinGen FH Variant Curation Expert PanelFamilial 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 if untreated; High heterozygote prevalence (1/250-500); Homozygous rare (1/300 000-1 000 000); Caused by pathogenic variants in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%) genes.
- Functional characterization of 16 variants found in the LDL receptor genePublication . Konečná, Kateřina; Přerovská, Tereza; Loja, Tomáš; Fajkusová, Lenka; Koutná, Jana; Kramárek, Michal; Alves, Ana Catarina; Bourbon, Mafalda; Freiberger, Tomáš; Tichý, LukášFamilial hypercholesterolemia (FH) is a disorder of cholesterol metabolism characterized by elevated LDL-cholesterol levels. The most common cause of FH is pathogenic variants in the LDL receptor (LDLR) gene. To shed light on the functional impact of selected LDLR variants, we functionally characterized 16 LDLR genetic variants alongside 10 control variants. We performed in vitro assays based on transient expression of WT and mutant LDLRs in LDLR-deficient Chinese hamster ovary cells. We used flow cytometry to analyze the relative amount of LDLRs expressed on the cell surface and the relative amount of internalized LDL. In addition, we analyzed the expression and maturation of LDLR protein by Western blotting. Of the 16 studied variants, two variants (p.(Asn272Thr) and p.(Arg574Leu)) did not exhibit a defect in LDLR function, one variant (p.(Ala540Thr)) exhibited a defect in LDL binding and/or internalization despite normal LDLR cell surface expression, and the remaining 13 variants had a detrimental effect on both LDLR cell surface expression and LDL internalization. The information presented in this study contributes to the clinical classification of LDLR variants and a more precise diagnosis of FH patients, highlighting the type of defect each variant produces.
- The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classificationPublication . Chora, Joana R.; Iacocca, Michael A.; Tichý, Lukáš; Wand, Hannah; Kurtz, C. Lisa; Zimmermann, Heather; Leon, Annette; Williams, Maggie; Humphries, Steve E.; Hooper, Amanda J.; Trinder, Mark; Brunham, Liam R.; Costa Pereira, Alexandre; Jannes, Cinthia E.; Chen, Margaret; Chonis, Jessica; Wang, Jian; Kim, Serra; Johnston, Tami; Soucek, Premysl; Kramarek, Michal; Leigh, Sarah E.; Carrié, Alain; Sijbrands, Eric J.; Hegele, Robert A.; Freiberger, Tomáš; Knowles, Joshua W.; Bourbon, Mafalda; ClinGen Familial Hypercholesterolemia Expert PanelPurpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. Methods: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. Results: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. Conclusion: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.
- The time is now: Achieving FH paediatric screening across Europe – The Prague DeclarationPublication . Bedlington, Nicole; Abifadel, Marianne; Beger, Birgit; Bourbon, Mafalda; Bueno, Héctor; Ceska, Richard; Cillíková, Kristýna; Cimická, Zdenka; Daccord, Magdalena; Beaufort, Carine de; Dharmayat, Kanika I.; Ference, Brian A.; Freiberger, Tomáš; Geanta, Marius; Gidding, Samuel S.; Grošelj, Urh; Halle, Martin; Johnson, Neil; Novakovic, Tanja; Májek, Ondrej; Pallidis, Athanasios; Peretti, Noel; Pinto, Fausto J.; Ray, Kausik Kosh; Rees, Bleddyn; Reeve, John; Reiner, Željko; Santos, Raul D.; Schunkert, Heribert; Šikonja, Jaka; Sokolovic, Milka; Tokgözoglu, Lale; Vrablík, Michal; Wiegman, Albert; Gutiérrez-Ibarluzea, IñakiFamilial Hypercholesterolaemia (FH) is severely under-recognized, under-diagnosed and under-treated in Europe, leading to a significantly higher risk of premature cardiovascular diseases in those affected. FH stands for inherited, very high cholesterol and affects 1:300 individuals regardless of their age, race, sex, and lifestyle, making it the most common inherited metabolic disorder and a non-modifiable cardiovascular disease risk factor in the world.