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Browsing by Author "Defesche, Joep C."

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  • Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel
    Publication . Sturm, Amy C.; Knowles, Joshua W.; Gidding, Samuel S.; Ahmad, Zahid S.; Ahmed, Catherine D.; Ballantyne, Christie M.; Baum, Seth J.; Bourbon, Mafalda; Carrié, Alain; Cuchel, Marina; de Ferranti, Sarah D.; Defesche, Joep C.; Freiberger, Tomas; Hershberger, Ray E.; Hovingh, G. Kees; Karayan, Lala; Kastelein, Johannes Jacob Pieter; Kindt, Iris; Lane, Stacey R.; Leigh, Sarah E.; Linton, MacRae F.; Mata, Pedro; Neal, William A.; Nordestgaard, Børge G.; Santos, Raul D.; Harada-Shiba, Mariko; Sijbrands, Eric J.; Stitziel, Nathan O.; Yamashita, Shizuya; Wilemon, Katherine A.; Ledbetter, David H.; Rader, Daniel J.; convened by the Familial Hypercholesterolemia Foundation
    Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
    2018-08-07Journal article Restricted access Show more
  • ClinVar database of global familial hypercholesterolemia-associated DNA variants
    Publication . 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 Panel
    Accurate 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.
    2018-11Journal article Restricted access Show more
  • Familial hypercholesterolemiaassociated variants in ClinVar
    Publication . 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 Panel
    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 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.
    2018-10Conference object Restricted access Show more
  • Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study
    Publication . 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, Marina
    Background: 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.
    2022-02-19Journal article Restricted access Show more