Global survey of genetic testing methods for familial hypercholesterolaemia: a study and recommendations from the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration registry
Joana Rita ChoraBiosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon , Campo Grande, 1749-016 Lisbon ,Irene KarungiImperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London , London ,Amany ElshorbagyDepartment of Physiology, Faculty of Medicine, University of Alexandria , Alexandria ,Christophe A T StevensImperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London , London ,Antonio J Vallejo-VazCentro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública, Instituto de Salud Carlos III , Madrid ,Kanika DharmayatImperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London , London ,Marianne AbifadelLaboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Saint Joseph University , Beirut ,CA Aguilar-SalinasTecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud , Monterrey ,Khalid F. AlHabibDepartment of Cardiac Sciences, King Fahad Cardiac Centre, College of Medicine, King Saud University Medical City, King Saud University , Riyadh ,Wael AlmahmeedCleveland Clinic Abu Dhabi, Heart and Vascular Institute , Abu Dhabi ,Fahad AlnouriCardiovascular Prevention Unit, Adult Cardiology Department, Prince Sultan Cardiac Centre , Riyadh ,Rodrigo AlonsoKhalid Al-RasadiDepartment of Biochemistry, College of Medicine and Health Science and Medical Research Centre, Sultan Qaboos University , Muscat ,Ahmad Al-SarrafSabah Al Ahmad Cardiac Centre , Kuwait City ,Marcello ArcaDepartment of Medicina Interna e Specialità Mediche, AO Policlinico Umberto I , Rome ,Engy A. AshaatClinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre , Cairo ,Tester F AshavaidDepartment of Laboratory Medicine, P.D. Hinduja Hospital and Medical Research Centre Mahim , Mumbai ,Maurizio AvernaDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Università degli Studi di Palermo , Palermo ,Maciej BanachCollegium Medicum, John Paul II Catholic University of Lublin , Lublin ,Marianne BeckerDepartment of Pediatric Endocrinology and Diabetology, Centre Hospitalier de Luxembourg , Luxembourg City ,Christoph J. BinderDepartment of Laboratory Medicine, Medical University of Vienna , Vienna ,Liam R. BrunhamDepartments of Medicine and Medical Genetics, Centre for Heart Lung Innovation, The University of British Columbia , Vancouver ,Alberico L CatapanoDepartment of Pharmacological and Biomolecular Sciences, University of Milan , Milan ,Pablo CorralPharmacology Department, FASTA University, School of Medicine , Mar del Plata ,Olivier DescampsDepartment of Internal Medicine, Centres Hospitaliers Universitaires HELORA at La Louvière and University of Mons , Mons ,Euridiki DrogariFirst Department of Pediatrics, Unit of Inherited Metabolic Disorders and Inherited Dyslipidaemias, Choremio Research Institute, National and Kapodistrian University of Athens , Athens ,R.Y. DurstCardiology Department and Centre for Treatment and Prevention of Atherosclerosis, Hadassah Hebrew University Medical Centre , Jerusalem ,Marat EzhovNational Medical Research Centre of Cardiology n.a. Acad. E.I. Chazov, Ministry of Health of the Russian Federation , Moscow ,Urh GrošeljDepartment of Endocrinology, Diabetes and Metabolism, University Medical Centre, University Children’s Hospital Ljubljana , Ljubljana ,Mariko Harada-ShibaOsaka Medical and Pharmaceutical University , Takatsuki ,Kirsten B. HolvenDepartment of Nutrition, Medical Faculty, University of Oslo , Oslo ,G Kees HovinghDepartment of Vascular Medicine, Amsterdam UMC, University of Amsterdam , Amsterdam ,Weerapan KhovidhunkitDepartment of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital , Bangkok ,Katarina LalicFaculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University of Belgrade , Belgrade ,G LatkovskisFaculty of Medicine and Life Sciences, Research Institute of Cardiology and Regenerative Medicine, University of Latvia, Pauls Stradins Clinical University Hospital , Riga ,U LaufsKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig , Leipzig ,E LiberopoulosFirst Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistian University of Athens , Athens ,Jie LinBeijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing ,Winfried MärzClinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz , Graz ,Pedro MataFundación Hipercolesterolemia Familiar , Madrid ,Anne Thushara MatthiasDepartment of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura , Nugegoda ,André R. MiserezDiagene Research Institute , Breitenbach, Reinach ,Olena MitchenkoDepartment of Dyslipidaemia, Institute of Cardiology, National Academy of Medical Sciences , Kiev ,Hapizah Mohd NawawiSpecialist Lipid Clinics, Hospital Al-Sultan Abdullah (HASA), Universiti Teknologi MARA (UiTM) Teaching Hospital, Puncak Alam, and Management & Science University (MSU) , Shah Alam, Selangor ,B G NordestgaardCopenhagen University Hospital—Herlev and Gentofte, University of Copenhagen , Copenhagen ,Andrie G. PanayiotouDepartment of Rehabilitation Sciences, School of Health Sciences, Cyprus University of Technology , Limassol ,G ParaghDivision of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen , Debrecen ,Žaneta PetrulionienėVilnius University Faculty of Medicine and Vilnius University Hospital Santaros Klinikos , Vilnius ,Arman PostadzhiyanMedical University of Sofia , Sofia ,Ximena ReyesGENYCO Program, Comisión Honoraria Para la Salud Cardiovascular , Montevideo ,Fouzia SadiqDirectorate of Research, Shifa Tameer-e-Millat University , Islamabad ,A F G SahebkarBiotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad ,R D SantosHeart Institute (InCor), University of São Paulo and Hospital Israelita Albert Einstein , São Paulo ,J P S SawhneyDepartment of Cardiology, Sir Ganga Ram Hospital , New Delhi ,Heribert SchunkertClinic for Heart and Circulatory Diseases, German Heart Centre Munich, Technical University Munich , Munich ,Swarup A V ShahDepartment of Laboratory Medicine, PD Hinduja Hospital and Medical Research Centre Mahim , Mumbai ,Aleksandr B. ShekDepartment of Coronary Heart Disease and Atherosclerosis, Republican Specialized Centre of Cardiology, Ministry of Health of Republic Uzbekistan , Tashkent ,Handrean SoranNIHR/Wellcome Trust Clinical Research Facility, Manchester University NHS Foundation Trust , Manchester ,Ta‐Chen SuDivision of Cardiology, Department of Internal Medicine, Tungs’ Taichung MetroHarbor Hospital , Taichung ,Tavintharan SubramaniamAdmiralty Medical Centre and Khoo Teck Puat Hospital, Yishun Health , Yishun Central ,Myra TilneyLipid Clinic, Department of Medicine, Mater Dei Hospital, University of Malta , Msida ,Brian TomlinsonFaculty of Medicine, Macau University of Science and Technology , Macau ,Thanh Huong TruongFaculty of Medicine, Phenikaa University, and Cardiovascular Center, Phenikaa University Hospital , Hanoi ,Anne Tybjærg-HansenDepartment of Clinical Biochemistry, Copenhagen University Hospital—Rigshospitalet , Copenhagen ,Margus ViigimaaNorth Estonia Medical Centre, Tallinn University of Technology , Tallinn ,Branislav VohnoutDepartment of Diabetology, LF SZU, Institute of Nutrition, FOaZOS, Coordination Centre for Familial Hyperlipidemias, Slovak Medical University in Bratislava , Bratislava ,Gerald F WattsLipid Disorders Clinic, Cardiometabolic Service, Department of Cardiology, Royal Perth Hospital , Perth, WA ,Shizuya YamashitaKausik K. RayImperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London , London ,Frederick J RaalCarbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand , Johannesburg ,Steve E HumphriesInstitute of Cardiovascular Science, Faculty of Population Health, University College London , London ,Tomáš FreibergerCarDia—National Institute for Metabolic and Cardiovascular Disease Research ,Mafalda BourbonBiosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon , Campo Grande, 1749-016 Lisbon ,
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Annotatsiya
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL-C and increased cardiovascular risk. Genetic testing offers the definitive diagnosis, yet global approaches to FH genetic testing remain unstandardized. We investigate current testing practices worldwide and provide relevant recommendations. METHODS: A survey was distributed to national lead-investigators (NLIs) of 68 countries in the FH-Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. RESULTS: NLIs from centres in 55/68 countries (81%) responded, spanning Africa (N=2), Americas (N=6), Asia (N=20), Europe (N=26), and Oceania (N=1). DLCN scores were the most common reason for referral to genetic testing (adults:72%; children:57%). Simon Broome and MEDPED criteria were reported only by centres from high-income countries (adults: 7% and 2%; children: 12% and 2%). Methods for testing in index versus non-index cases were significantly different (p <0.001). Next-generation sequencing (NGS) was the predominant assay method for index cases (62%), while Sanger sequencing was favoured for non-index (71%). However, these testing techniques did not differ between centres from high- and non-high-income countries for index cases (p=0.74) and non-index cases (p=0.49). Copy-number variants (CNVs) were assessed by 65% of centres, with most integrating CNV analysis into NGS platforms (86%) and others (14%) using multiplex ligation-dependent probe-amplification (MLPA) or microarrays. Screening encompassed LDLR (100%), APOB (97%), PCSK9 (95%), and other genes. Most centres (96%) incorporated pathogenicity interpretation into their reports, adhering largely to American College of Medical Genetics and Genomics guidelines. CONCLUSIONS: FH genetic testing practices vary widely across countries surveyed, emphasizing the need for global standardization to enhance accuracy and comparability of FH diagnoses worldwide. We suggest that genetic testing should include the three FH-causing genes and ideally the five associated/phenocopy genes.
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