Genetic Heterogeneity of Familial Dyslipidemia: Real-World Evidence from a Large Colombian Cohort

Background Familial dyslipidemia (FD) comprises a heterogeneous group of genetic disorders of lipoprotein metabolism associated with premature cardiovascular disease, with familial hypercholesterolemia being the most extensively characterized. Despite their clinical relevance, the genetic architecture of FD remains poorly described in Latin American populations, limiting risk stratification and genetic counseling in the region. Methods A retrospective and pragmatic cohort study (September 2020–July 2025) was conducted on 860 Colombian patients referred for whole-exome sequencing (WES) with a clinical suspicion of FD. Patients were recruited from a national reference laboratory serving the EPS Sanitas healthcare network. While all patients underwent WES, analysis strategies included 616 targeted exomes (filtered through a gene panel); additionally, 198 singleton exomes, 42 trio exomes, and 4 duo exomes. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results The overall positivity rate was 14.88% (128/860). This rate varied according to age and clinical phenotype and was highest in young adults (21.83%) and in patients with hypercholesterolemia (17.39%). The LDLR gene accounted for the majority of the positive findings (94 variants), followed to a lesser extent by APOB and LPL ; fourteen large deletions (CNVs) in LDLR completed the molecular landscape. The geographic distribution was heterogeneous: the highest positivity rates were recorded in Magdalena (42.86%) and Sucre (37.50%), while the lowest were recorded in Bogotá (~ 11%) and Antioquia (< 10%), with specific variants clustering by region (e.g., LDLR c.11G > A in Cesar and Bogotá; c.1246C > T in Tolima–Caldas–Valle del Cauca). Notable findings included the first Colombian case of the Lebanese allele ( LDLR c.2043C > A), a novel LDLR variant (c.1955T > G) segregating in two sisters, and 0.58% of cases presenting with homozygous dyslipidemia. Additionally, our results demonstrated that a larger panel size does not increase the positivity rate of the genetic test; specifically, 25 of the 37 genes (67.6%) yielded no diagnostic findings of the genetic test. Conclusions This study represents the most extensive genomic characterization of FD in a Colombian cohort to date to our knowledge. The findings reveal marked genetic heterogeneity without a single dominant founder allele, reflecting the ancestral admixture of the Colombian population. These results support the need for more selective, clinically impact-driven criteria when genetic testing is requested. Furthermore, they underscore the urgent need for national cascade screening programs to make precision medicine for FD accessible throughout the Colombian territory.