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Orientador(es)
Resumo(s)
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.
Lay Summary: This was a global survey from centres within 55 countries within the Familial Hypercholesterolemia Studies Collaboration (FHSC). The study evaluated the current practice of genetic testing for familial hypercholesterolemia (FH), an inherited condition characterized by high cholesterol levels and increased cardiovascular risk, since a definitive diagnosis is a key determinant of patient-centred care. The study found that while most centres screen for the three main FH genes and incorporate interpretation on whether a genetic change is disease-causing, notable differences existed in the reasons for referring for a test and laboratory testing techniques among and within centres from high and non-high income countries. Among testing techniques, next-generation sequencing was the predominant method for testing index cases, while Sanger sequencing was commonly used for relatives. The study also found that about one-third of centres did not test for other important genetic changes called copy-number variants (CNVs).To ensure patients receive accurate diagnoses regardless of where they live, the authors recommend creating a global standard where testing always includes the three primary genes responsible for the condition, ideally alongside five other associated genes.
Lay Summary: This was a global survey from centres within 55 countries within the Familial Hypercholesterolemia Studies Collaboration (FHSC). The study evaluated the current practice of genetic testing for familial hypercholesterolemia (FH), an inherited condition characterized by high cholesterol levels and increased cardiovascular risk, since a definitive diagnosis is a key determinant of patient-centred care. The study found that while most centres screen for the three main FH genes and incorporate interpretation on whether a genetic change is disease-causing, notable differences existed in the reasons for referring for a test and laboratory testing techniques among and within centres from high and non-high income countries. Among testing techniques, next-generation sequencing was the predominant method for testing index cases, while Sanger sequencing was commonly used for relatives. The study also found that about one-third of centres did not test for other important genetic changes called copy-number variants (CNVs).To ensure patients receive accurate diagnoses regardless of where they live, the authors recommend creating a global standard where testing always includes the three primary genes responsible for the condition, ideally alongside five other associated genes.
Descrição
Contributors to Country Data for Current Study - PORTUGAL: Ana Margarida Medeiros (Instituto Nacional de Saúde Doutor Ricardo Jorge, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis Unidade de I&D, Grupo de Investigação Cardiovascular, Lisboa), Ana Catarina Alves (Instituto Nacional de Saúde Doutor Ricardo Jorge, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis Unidade de I&D, Grupo de Investigação Cardiovascular, Lisboa), Beatriz Miranda (Instituto Nacional de Saúde Doutor Ricardo Jorge, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis Unidade de I&D, Grupo de Investigação Cardiovascular, Lisboa).
Palavras-chave
Familial Hypercholesterolemia Genetic Testing Genetics Global Standardization Pathogenicity Interpretation Doenças Cardio e Cérebro-vasculares Doenças Genéticas
Contexto Educativo
Citação
Eur J Prev Cardiol. 2026 May 14:zwag198. doi: 10.1093/eurjpc/zwag198. Online ahead of print
Editora
Oxford University Press