Global Survey of Genetic Testing Methods for Familial Hypercholesterolaemia: a Study and Recommendations from the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration Registry

Aims Familial hypercholesterolaemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL cholesterol 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 and results A survey was distributed to national lead investigators of 68 countries in the Familial Hypercholesterolaemia Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. National lead investigators 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). Dutch Lipid Clinic Network (DLCN) scores were the most common reason for referral to genetic testing (adults, 72%; children, 57%). Simon-Broome and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria were reported only by centres from high-income countries (adults, 7% and 2%; children, 12% and 2%). Methods for testing in index vs. 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. Conclusion Familial hypercholesterolaemia 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.