Genetic Diagnosis and Family Cascade Screening for Familial Hypercholesterolaemia in Patients with Premature Coronary Artery Disease: A Prospective Cohort Study from Vietnam

Background: Familial hypercholesterolaemia (FH) is a prevalent monogenic disorder where genetic diagnosis enables risk re-stratification and management for entire families, serving as a paradigm for personalized medicine. Data on FH in South-East Asia are limited, and family cascade screening has not previously been documented in Vietnam. Objectives: To identify the prevalence of pathogenic variants in FH-associated genes and evaluate the feasibility of cascade screening in a Vietnamese cohort. Materials and methods: We conducted a prospective single-centre cohort study involving 500 consecutive patients with premature coronary artery disease (CAD) at a Vietnamese tertiary centre between March 2023 and September 2025. Patients underwent next-generation sequencing of LDLR, APOB, and PCSK9 genes, with variants classified according to American College of Medical Genetics and Genomics criteria. First-degree relatives of patients who tested positive for a variant were offered genetic counselling and cascade sequencing. Results: A pathogenic or likely pathogenic variant was identified in 18 of 500 patients (3.6%; 95% CI 2.1–5.4%), primarily within the LDLR gene. Variant carriers were younger, exhibited significantly higher LDL-cholesterol levels, and presented with more extensive coronary disease compared to non-carriers (all p < 0.001). Cascade screening completed in 13 families identified the family-specific variant in 46 of 105 first-degree relatives (43.8%; 95% CI 34.7–53.4%), many of whom were young and asymptomatic. Conclusions: Precise genetic diagnosis in a small number of index patients facilitated the identification of a large group of high-risk relatives who would otherwise have remained undiagnosed. This approach underscores the potential of personalized medicine in managing inherited cardiovascular disorders in Vietnam.