Browsing by Author "Hegele, Robert A."
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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 hypercholesterolemia-associated variants submitted to ClinVar: a ClinGen FH effortPublication . Rita Chora, Joana; Iacocca, Michael A.; DiStefano, Marina T.; Carrie, Alain; Freiberger, Tomas; Leigh, Sarah E.; Kurtz, C. Lisa; Defesche, Joep; Sijbrands, Eric J.; Hegele, Robert A.; Knowles, Joshua W.; Bourbon, Mafalda; on behalf of the ClinGen FH Variant Curation CommitteeFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism characterized by elevated levels of LDL-C and increased cardiovascular risk. A vast number of potentially pathogenic variants have been identified in FH patients in LDLR, APOB, and PCSK9 genes. We sought to encourage FH researchers/clinicians worldwide to submit their variant findings to the centralized ClinVar database, with the ultimate goal of achieving accurate and consistent variant classification through data sharing and eventual development of FH-specific variant interpretation guidelines.
- 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.
- The Functional Landscape Of Coding Variation In The Familial Hypercholesterolemia Gene LDLRPublication . Tabet, Daniel R.; Coté, Atina G.; Lancaster, Megan C.; Weile, Jochen; Rayhan, Ashyad; Fotiadou, Iosifina; Kishore, Nishka; Li, Roujia; Kuang, Da; Knapp, Jennifer J.; Carrero, Carmela Serio; Taverniti, Olivia; Axakova, Anna; Castelli, Jack M. P.; Islam, Mohammad Majharul; Sowlati-Hashjin, Shahin; Gandhi, Aanshi; Maaieh, Ranim; Garton, Michael; Matreyek, Kenneth; Fowler, Douglas M.; Bourbon, Mafalda; Pfisterer, Simon G.; Glazer, Andrew M.; Kroncke, Brett M.; Parikh, Victoria N.; Ashley, Euan A.; Knowles, Joshua W.; Claussnitzer, Melina; Cirulli, Elizabeth T.; Hegele, Robert A.; Roden, Dan M.; MacRae, Calum A.; Roth, Frederick P.Variants in the familial hypercholesterolemia gene -the most important genetic driver of cardiovascular disease-can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis. Definitive classifications are lacking for nearly half of clinically encountered missense variants, limiting interventions that reduce disease burden. Here, we tested the impact of ~17,000 (nearly all possible) missense coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence-function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants. Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.
- Progress in ACMG/AMP-adapted guidelines for standardized variant curation in familial hypercholesterolemiaPublication . Iacocca, Michael A.; Chora, Joana; Rivera, E. Andy; DiStefano, Marina T.; Carrie, Alain; Sijbrands, Eric J.; Defesche, Joep; Freiberger, Tomas; Knowles, Joshua W.; Hegele, Robert A.; Bourbon, MafaldaBackground: - The successes of clinical genetics rely on accurate variant interpretation for the purpose of informing diagnosis and treatment: - However, this practice is often rudimentary and differs among diagnostic laboratories, leading to inconsistencies in pathogenicity classification; - In response, the Clinical Genome Resources (ClinGen) consortium approves expert panels to recommend disease-specific guidelines to achieve evidence-based, standardized variant curation practice. Familial Hypercholesterolemia (FH) Working Group: - FH is a prevalent monogenic disorder, affecting ~1/250 individuals; - It is characterized by extreme LDL cholesterol levels and premature atherosclerosis causing cardiovascular disease; - Genetic testing is increasingly offered worldwide as a central part of diagnosis.
- Specification of ACMG AMP Guidelines for Variant Interpretation in Familial HypercholesterolemiaPublication . Chora, Joana R.; Lacocca, Michael A.; Carrié, Alain; Leigh, Sarah E.; Tichý, Lukáš; Kurtz, C. Lisa; Freiberger, Tomas; Sijbrands, Eric J.; Hegele, Robert A.; Knowles, Joshua W.; Bourbon, MafaldaBackground and Aims: the general ACMG/AMP guidelines for standardized variant interpretation in Mendelian disorders are a great asset in determining variants’ pathogenicity, but need to be adapted to each specific gene and disease.
- 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.
- Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort studyPublication . Tromp, Tycho R.; Hartgers, Merel L.; Hovingh, G Kees; Vallejo-Vaz, Antonio J.; Ray, Kausik K.; Soran, Handrean; Freiberger, Tomas; Bertolini, Stefano; Harada-Shiba, Mariko; Blom, Dirk J.; Raal, Frederick J.; Cuchel, Marina; Tromp, Tycho R.; Hartgers, Merel L.; Hovingh, G. Kees; Vallejo-Vaz, Antonio J.; Ray, Kausik K.; Soran, Handrean; Freiberger, Tomas; Bertolini, Stefano A.; Harada-Shiba, Mariko; Pang, Jing; Watts, Gerald F.; Greber-Platzer, Susanne; Mäser, Martin; Stulnig, Thomas M.; Ebenbichler, Christoph F.; Bin Thani, Khalid; Cassiman, David; Descamps, Olivier S.; Rymen, Daisy; Witters, Peter; Santos, Raul D.; Brunham, Liam R.; Francis, Gordon A.; Genest, Jacques; Hegele, Robert A.; Kennedy, Brooke A.; Ruel, Isabelle; Sherman, Mark H.; Jiang, Long; Wang, Luya; Reiner, Željko; Blaha, Vladimir; Ceska, Richard; Dvorakova, Jana; Dlouhy, Lubomir; Horak, Pavel; Soska, Vladimir; Tichy, Lukas; Urbanek, Robin; Vaverkova, Helena; Vrablik, Michal; Zemek, Stanislav; Zlatohlavek, Lukas; Emil, Sameh; Naguib, Tarek; Reda, Ashraf; Béliard, Sophie; Bruckert, Eric; Gallo, Antonio; Elisaf, Moses S.; Kolovou, Genovefa; Cohen, Hofit; Durst, Ronen; Dann, Eldad J.; Elis, Avishay; Hussein, Osama; Leitersdorf, Eran; Schurr, Daniel; Setia, Nitika; Verma, Ishwar C.; Alareedh, Mohammed D.; Al-Khnifsawi, Mutaz; Abdalsahib Al-Zamili, Ali F.; Rhadi, Sabah H.; Shaghee, Foaad K.; Arca, Marcello; Averna, Maurizio; Bartuli, Andrea; Bucci, Marco; Buonuomo, Paola S.; Calabrò, Paolo; Calandra, Sebastiano; Casula, Manuela; Catapano, Alberico L.; Cefalù, Angelo B.; Cicero, Arrigo F.G.; D'Addato, Sergio; D'Erasmo, Laura; Di Costanzo, Alessia; Fasano, Tommaso; Gazzotti, Marta; Giammanco, Antonina; Iannuzzo, Gabriella; Ibba, Anastasia; Negri, Emanuele A.; Pasta, Andrea; Pavanello, Chiara; Pisciotta, Livia; Rabacchi, Claudio; Ripoli, Carlo; Sampietro, Tiziana; Sbrana, Francesco; Sileo, Fulvio; Suppressa, Patrizia; Tarugi, Patrizia; Trenti, Chiara; Zenti, Maria G.; Hori, Mika; Ayesh, Mahmoud H.; Azar, Sami T.; Bitar, Fadi F.; Fahed, Akl C.; Moubarak, Elie M.; Nemer, Georges; Nawawi, Hapizah M.; Madriz, Ramón; Mehta, Roopa; Cupido, Arjen J.; Defesche, Joep C.; Reijman, M. Doortje; Roeters-van Lennep, Jeanine E.; Stroes, Erik S.G.; Wiegman, Albert; Zuurbier, Linda; Al-Waili, Khalid; Sadiq, Fouzia; Chlebus, Krzysztof; Bourbon, Mafalda; Gaspar, Isabel M.; Lalic, Katarina S.; Ezhov, Marat V.; Susekov, Andrey V.; Groselj, Urh; Charng, Min-Ji; Khovidhunkit, Weerapan; Aktan, Melih; Altunkeser, Bulent B.; Demircioglu, Sinan; Kose, Melis; Gokce, Cumali; Ilhan, Osman; Kayikcioglu, Meral; Kaynar, Leyla G.; Kuku, Irfan; Kurtoglu, Erdal; Okutan, Harika; Ozcebe, Osman I.; Pekkolay, Zafer; Sag, Saim; Salcioglu, Osman Z.; Temizhan, Ahmet; Yenercag, Mustafa; Yilmaz, Mehmet; Yilmaz Yasar, Hamiyet; Mitchenko, Olena; Lyons, Alexander R.M.; Stevens, Christophe A.T.; Brothers, Julie A.; Hudgins, Lisa C.; Nguyen, Christina; Alieva, Rano; Shek, Aleksandr; Do, Doan-Loi; Kim, Ngoc-Thanh; Le, Hong-An; Le, Thanh-Tung; Nguyen, Mai-Ngoc T.; Truong, Thanh-Huong; Blom, Dirk J.; Raal, Frederick J.; Cuchel, MarinaBackground: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38). Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH.