Clinical and genetic characterization of homozygous LDLR variants in familial hypercholesterolaemia: insights from two case reports

Familial hypercholesterolaemia (FH) is an inherited lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and increased risk of atherosclerotic cardiovascular disease. Despite its high prevalence, FH remains underdiagnosed and undertreated in many regions, particularly in low- and middle-income countries.

We describe two patients with homozygous FH (HoFH) diagnosed at a tertiary care centre using the Dutch Lipid Clinic Network diagnostic criteria, both presented with severe hypercholesterolaemia (LDL-C > 340 mg/dL) and tendon xanthomas, whereas early cardiovascular complications were evident only in Case 1. Genetic analysis confirmed pathogenic variants in LDLR: c.1060+2T>G (rs774069731) in Case 1 and c.530C>T (rs121908026) in Case 2. The patients were managed with high-intensity statins, ezetimibe, PCSK9 inhibitors, inclisiran, and lipoprotein apheresis, which resulted in partial LDL-C reduction.

These cases highlight the genotypic and phenotypic heterogeneity of FH, with the c.1060+2T>G variant being reported for the first time in this region, thus expanding the known genetic spectrum of FH.

This case series reinforces the importance of comprehensive clinical and genetic evaluation in patients with severe hypercholesterolaemia. Early diagnosis, intensified lipid-lowering strategies, and equitable access to advanced therapies are essential to improve outcomes in resource-constrained settings.