Implementing genetics-based cascade testing for familial hypercholesterolemia in Colombia: results from a pilot study and implications for national screening strategies

Background Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder mainly caused by pathogenic variants in the LDLR gene, leading to elevated low-density lipoprotein cholesterol levels and an increased risk of premature cardiovascular disease. In Colombia, FH remains largely underdiagnosed because of the absence of systematic screening programs and structured cascade screening strategies. Objective To evaluate the applicability of a genetic cascade screening strategy in Colombian families carrying pathogenic variants in LDLR in order to identify new cases and describe genotype-phenotype correlations. Methods A descriptive pilot study was conducted in 5 families of index cases with a previous clinical and molecular diagnosis of FH. Cases were analyzed by Sanger sequencing targeting the previously identified variants c.11G>A (p.Trp4*), c.1246C>T (p.Arg416Trp), and c.1187-1_1187delinsTA. Clinical classification was performed using the Dutch Lipid Clinic Network (DLCN) score. Results Twenty-five individuals from 5 families were evaluated, including 5 index cases and 20 relatives. Molecular testing confirmed FH in 12 of 20 relatives (60%) newly identified as carriers through cascade screening. Carriers of the same pathogenic variant tended to exhibit similar clinical and biochemical characteristics, suggesting a relatively homogeneous phenotype within individual families. Conclusion This pilot study supports the feasibility and diagnostic utility of genetic cascade screening for FH in Colombian families. The identification of 12 previously undiagnosed carriers among 20 relatives (60%), including relatives with low DLCN scores, highlights the limitations of relying solely on clinical criteria and underscores the value of molecular diagnosis as part of a family-based detection strategy.