Key result
In a 75-year-old female with severe phenotypic familial hypercholesterolemia and statin intolerance, evolocumab therapy successfully reduced LDL-C to 0.9 mmol/L.
Why the study?
Many clinical cases of familial hypercholesterolemia remain genetically unexplained by canonical genes, highlighting the need to identify novel variants in non-canonical genes to understand lipid disorders.
Case Report (n=1)
This case highlights the diagnostic challenge of clinically definite familial hypercholesterolemia lacking canonical mutations, identifying a rare CELSR2 variant of uncertain significance.
FH diagnosis may rely on clinical criteria despite negative genetics; case report leaves open roles of VUS and Lp(a).
Familial hypercholesterolemia (FH) is a genetic disorder characterized by severely elevated cholesterol levels and increased cardiovascular risk. While typically associated with mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, many clinical cases remain genetically unexplained. Identifying novel variants in non-canonical genes is essential for understanding the complex genetic architecture of lipid disorders. A 75-year-old female patient presented with severe hyperlipidemia, multifocal atherosclerosis, and multiple comorbidities. Her native low-density lipoprotein cholesterol (LDL-C) was 6.7 mmol/L. Based on a Dutch Lipid Clinic Network (DLCN) score of 9 (5 points for LDL-C level, 2 points for personal premature coronary artery disease (CAD), and 2 points for a first-degree relative - specifically the patient's father - with xanthomata of the Achilles tendons area, with personal tendon xanthomata and corneal arcus being absent), a clinical diagnosis of definite familial hypercholesterolemia was established. Furthermore, an elevated lipoprotein(a) level of 407.5 nmol/L was identified as an independent cardiovascular risk factor. Comprehensive genetic testing revealed no pathogenic mutations in the LDLR, APOB, or PCSK9 genes. However, molecular analysis identified a heterozygous variant of uncertain significance (VUS), c.7031G>T p.(Arg2344Leu), in the Cadherin EGF LAG Seven-Pass G-Type Receptor 2 (CELSR2) gene. This case demonstrates the diagnostic challenges in patients who fulfill the clinical criteria for familial hypercholesterolemia but lack mutations in primary candidate genes. Genetic testing revealed a rare missense VUS in the CELSR2 gene. However, this finding should be interpreted as an incidental VUS of unproven clinical relevance, as no mechanistic link between this specific coding variant and the patient’s severe hyperlipidemic phenotype has been established. Further functional studies are required to determine the clinical significance of this specific CELSR2 variant in the context of cardiovascular risk.
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Buczyński et al. (2026) conducted a case report in Severe Hyperlipidemia and Multifocal Atherosclerosis (n=1). Evolocumab was evaluated on Achieved low-density lipoprotein cholesterol (LDL-C). In a 75-year-old female with severe phenotypic familial hypercholesterolemia and statin intolerance, evolocumab therapy successfully reduced LDL-C to 0.9 mmol/L.
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