Browsing by Author "Tichy, Lukas"
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- Adaptation of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemiaPublication . Iacocca, Michael A.; Chora, Joana R.; Freiberger, Tomas; Carrie, Alain; Leigh, Sarah E.; Kurtz, C. Lisa; Tichy, Lukas; DiStefano, Marina T.; Wand, Hannah; Defesche, Joep; Sijbrands, Eric J.; Hegele, Robert A; Knowles, Joshua W.; Bourbon, Mafalda; On behalf of the ClinGen FH Variant Curation Expert PanelBackground: The successes of clinical genetics rely on accurate DNA 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 (ClinGen) Resource consortium approves expert panels to recommend disease-specific guidelines to achieve evidence-based, standardized variant curation practice.
- Adaptation of ACMG/AMP guidelines for variant interpretation in familial hypercholesterolemia – a ClinGen FH Expert Panel pilot studyPublication . Chora, Joana; A. Iacocca, Michael; Lisa Kurtz, C; Carrie, Alain; Tichy, Lukas; E. Leigh, Sarah; T. DiStefano, Marina; Defesche, Joep; J. Sijbrands, Eric; Freiberger, Tomas; A. Hegele, Robert; W. Knowles, Joshua; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism associated with premature atherosclerosis and increased cardiovascular risk. Over 3,000 variants in LDLR, APOB, and PCSK9 have been identified in FH patients; however, <10% of these have been functionally proven to cause disease. The recent ACMG/AMP guidelines for standardized variant interpretation in Mendelian disorders are being used to help further classify FH-associated variants. Despite such efforts, these existing ACMG/AMP guidelines need to be modified to become more disease-specific for FH. In 2016, the Clinical Genome Resource (ClinGen) consortium FH Expert Panel was created with the goal to develop FH-specific variant interpretation guidelines
- Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countriesPublication . Futema, Marta; Ramaswami, Uma; Tichy, Lukas; Bogsrud, Martin P.; Holven, Kirsten B.; Roeters van Lennep, Jeanine; Wiegman, Albert; Descamps, Olivier S.; De Leener, Anne; Fastre, Elodie; Vrablik, Michal; Freiberger, Tomas; Esterbauer, Harald; Dieplinger, Hans; Greber-Platzer, Susanne; Medeiros, Ana M.; Bourbon, Mafalda; Mollaki, Vasiliki; Drogari, Euridiki; Humphries, Steve E.Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.
- Specification of ACMG/AMP variant classification guidelines for Familial Hypercholesterolemia – a ClinGen FH Variant Curation Committee Pilot StudyPublication . Kurtz, C. Lisa; Carrie, Alain; Chora, Joana R.; Iacocca, Michael; Leigh, Sarah; Freiberger, Tomas; Tichy, Lukas; Defesche, Joep; Hegele, Robert; Sijbrands, Eric; Knowles, Josh; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is a common autosomal dominant disorder (~1:250 individuals affected) of lipid metabolism, associated with an increased risk of cardiovascular disease. Individuals with FH characteristically present with severely elevated blood cholesterol levels, which leads to atherosclerotic plaque formation and subsequently, myocardial infarction due to premature coronary artery disease. Three main causative genes have been associated with FH: LDLR, APOB and PCSK9. Diagnosis is critical for early intervention and treatment, and it is imperative that family members of affected individuals be identified as early as possible.
- 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.