Browsing by Author "Freiberger, Tomas"
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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
- Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert PanelPublication . 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 FoundationAlthough 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.
- Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countriesPublication . Ramaswami, Uma; Futema, Marta; Bogsrud, Martin P.; Holven, Kirsten B.; Roeters van Lennep, Jeanine; Wiegman, Albert; Descamps, Olivier S.; Vrablik, Michal; Freiberger, Tomas; Dieplinger, Hans; Greber-Platzer, Susanne; Hanauer-Mader, Gabriele; Bourbon, Mafalda; Drogari, Euridiki; Humphries, Steve E.Background and aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8-10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3-11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations.
- 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.
- 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.
- Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)Publication . EAS Familial Hypercholesterolaemia Studies Collaboration; Vallejo-Vaz, Antonio J.; De Marco, Martina; Stevens, Christophe A.T.; Akram, Asif; Freiberger, Tomas; Hovingh, G. Kees; Kastelein, John J.P.; Mata, Pedro; Raal, Frederick J.; Santos, Raul D.; Soran, Handrean; Watts, Gerald F.; Abifadel, Marianne; Aguilar-Salinas, Carlos A.; Al-Khnifsawi, Mutaz; AlKindi, Fahad A.; Alnouri, Fahad; Alonso, Rodrigo; Al-Rasadi, Khalid; Al-Sarraf, Ahmad; Ashavaid, Tester F.; Binder, Christoph J.; Bogsrud, Martin P.; Bourbon, Mafalda; Bruckert, Eric; Chlebus, Krzysztof; Corral, Pablo; Descamps, Olivier; Durst, Ronen; Ezhov, Marat; Fras, Zlatko; Genest, Jacques; Groselj, Urh; Harada-Shiba, Mariko; Kayikcioglu, Meral; Lalic, Katarina; Lam, Carolyn S.P.; Latkovskis, Gustavs; Laufs, Ulrich; Liberopoulos, Evangelos; Lin, Jie; Maher, Vincent; Majano, Nelson; Marais, A. David; März, Winfried; Mirrakhimov, Erkin; Miserez, André R.; Mitchenko, Olena; Nawawi, Hapizah M.; Nordestgaard, Børge G.; Paragh, György; Petrulioniene, Zaneta; Pojskic, Belma; Postadzhiyan, Arman; Reda, Ashraf; Reiner, Željko; Sadoh, Wilson E.; Sahebkar, Amirhossein; Shehab, Abdullah; Shek, Aleksander B.; Stoll, Mario; Su, Ta-Chen; Subramaniam, Tavintharan; Susekov, Andrey V.; Symeonides, Phivos; Tilney, Myra; Tomlinson, Brian; Truong, Thanh-Huong; Tselepis, Alexandros D.; Tybjærg-Hansen, Anne; Vázquez-Cárdenas, Alejandra; Viigimaa, Margus; Vohnout, Branislav; Widén, Elisabeth; Yamashita, Shizuya; Banach, Maciej; Gaita, Dan; Jiang, Lixin; Nilsson, Lennart; Santos, Lourdes E.; Schunkert, Heribert; Tokgözoğlu, Lale; Car, Josip; Catapano, Alberico L.; Ray, Kausik K.; Hypercholesterolaemia Studies Collaboration (FHSC) InvestigatorsManagement of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries.
- Overweight, Obesity, And Cardiovascular Disease In Heterozygous Familial Hypercholesterolaemia: The EAS FH Studies Collaboration RegistryPublication . Elshorbagy, Amany; Vallejo-Vaz, Antonio J.; Barkas, Fotios; Lyons, Alexander R.M.; Stevens, Christophe A.T.; Dharmayat, Kanika I.; Catapano, Alberico L.; Freiberger, Tomas; Hovingh, G. Kees; Mata, Pedro; Raal, Frederick J.; Santos, Raul D.; Soran, Handrean; Watts, Gerald F.; Abifadel, Marianne; Aguilar-Salinas, Carlos A.; Alhabib, Khalid F.; Alkhnifsawi, Mutaz; Almahmeed, Wael; Alnouri, Fahad; Alonso, Rodrigo; Al-Rasadi, Khalid; Al-Sarraf, Ahmad; Arca, Marcello; Ashavaid, Tester F.; Averna, Maurizio; Banach, Maciej; Becker, Marianne; Binder, Christoph J.; Bourbon, Mafalda; Brunham, Liam R.; Chlebus, Krzysztof; Corral, Pablo; Cruz, Diogo; Davletov, Kairat; Descamps, Olivier S.; Dwiputra, Bambang; Ezhov, Marat; Groselj, Urh; Harada-Shiba, Mariko; Holven, Kirsten B.; Humphries, Steve E.; Kayikcioglu, Meral; Khovidhunkit, Weerapan; Lalic, Katarina; Latkovskis, Gustavs; Laufs, Ulrich; Liberopoulos, Evangelos; Lima-Martinez, Marcos M.; Maher, Vincent; Marais, A David; März, Winfried; Mirrakhimov, Erkin; Miserez, André R.; Mitchenko, Olena; Nawawi, Hapizah; Nordestgaard, Børge G.; Panayiotou, Andrie G.; Paragh, György; Petrulioniene, Zaneta; Pojskic, Belma; Postadzhiyan, Arman; Reda, Ashraf; Reiner, Željko; Reyes, Ximena; Sadiq, Fouzia; Sadoh, Wilson Ehidiamen; Schunkert, Heribert; Shek, Aleksandr B.; Stroes, Erik; Su, Ta-Chen; Subramaniam, Tavintharan; Susekov, Andrey V.; Tilney, Myra; Tomlinson, Brian; Truong, Thanh Huong; Tselepis, Alexandros D.; Tybjærg-Hansen, Anne; Vázquez-Cárdenas, Alejandra; Viigimaa, Margus; Vohnout, Branislav; Yamashita, Shizuya; Ray, Kausik K.; EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)Background and aims: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear. Methods: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD. Results: Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations. Conclusions: Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.
- 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.
- Proposal of a Familial Hypercholesterolemia Pediatric Diagnostic Score (FH-PeDS)Publication . Kafol, Jan; Miranda, Beatriz; Sikonja, Rok; Sikonja, Jaka; Wiegman, Albert; Medeiros, Ana Margarida; Alves, Ana Catarina; Freiberger, Tomas; Hutten, Barbara A.; Mlinaric, Matej; Battelino, Tadej; Humphries, Steve E.; Bourbon, Mafalda; Groselj, UrhBackground and aims: Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing pediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods: Five established FH diagnostic criteria were assesed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N=1,360) and Portuguese (N=340) pediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Results: Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; p<0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; p<0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; p<0.01) despite population differences. Conclusions: Current FH diagnostic criteria perform suboptimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.