Posters
Presenting Author Academic/Professional Position
Resident
Academic Level (Author 1)
Resident
Discipline/Specialty (Author 1)
Internal Medicine
Academic Level (Author 2)
Faculty
Discipline/Specialty (Author 2)
Internal Medicine
Presentation Type
Poster
Discipline Track
Clinical Science
Abstract Type
Case Report
Abstract
Background: Severe hypercholesterolemia, defined as a low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dL, is most often attributed to familial hypercholesterolemia (FH), a monogenic autosomal dominant disorder caused by pathogenic variants in genes essential for LDL-C catabolism, including the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1). Clinically, FH is characterized by markedly elevated LDL-C levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Homozygous individuals typically present in childhood, while heterozygous individuals are more commonly diagnosed in adulthood. However, a substantial proportion of patients with an FH phenotype lack identifiable monogenic mutations and instead demonstrate a polygenic accumulation of common LDL-C–raising alleles, referred to as polygenic hypercholesterolemia (PH).
Case Presentation: A 38-year-old Hispanic female with no significant comorbidities presented for routine evaluation and was found to have severe hypercholesterolemia, with an LDL-C of 272 mg/dL and total cholesterol of 346 mg/dL. Triglyceride levels were normal at 95 mg/dL, and lipoprotein(a) was mildly elevated at 34 mg/dL. Evaluation for secondary causes, including hemoglobin A1c, thyroid-stimulating hormone, hepatic and renal function tests, and assessment for proteinuria, was unremarkable. Additional risk factors, including cigarette smoking, excessive alcohol consumption, dietary contributors, and medication use, were excluded. The patient reported a history of elevated cholesterol since childhood with inconsistent treatment but denied any personal or first-degree family history of premature coronary, cerebrovascular, or peripheral arterial disease. Physical examination revealed no evidence of tendon xanthomas or xanthelasma. Given diagnostic uncertainty based on clinical criteria and the need to identify a pathogenic variant to guide cascade screening, a comprehensive familial hypercholesterolemia gene panel (LDLR, APOB, LDLRAP1, and PCSK9) was obtained and returned negative for pathogenic variants. In the absence of secondary causes and monogenic mutations, PH was considered the most likely diagnosis The patient was initiated on high-intensity statin therapy with atorvastatin 80 mg daily and ezetimibe 10 mg daily to achieve aggressive LDL-C reduction given her elevated ASCVD risk. At 5-week follow-up, she reported alternate-day statin dosing due to intolerance while continuing ezetimibe daily, with LDL-C improving to 206 mg/dL. She was advised to continue therapy as tolerated and return in 8 weeks for repeat lipid assessment, with plans to consider additional lipid-lowering therapies, including bempedoic acid or PCSK9 inhibitors, to achieve an LDL-C target < 70 mg/dL.
Conclusion: Most patients with markedly elevated LDL-C levels (≥190 mg/dL) do not harbor monogenic FH mutations and instead have PH. This condition is typically characterized by elevated LDL-C with normal triglyceride levels and absence of tendon xanthomas. Although polygenic risk scores may aid diagnosis, their performance varies by ancestry and explains only a portion of LDL-C variability, resulting in different implications for cascade screening compared with monogenic FH and should be carefully discussed with affected families. PH is associated with a clinically meaningful increase in ASCVD risk, intermediate between non-genetic hypercholesterolemia and monogenic FH. With advancing age, cardiovascular risk approaches that of monogenic FH, underscoring the importance of early recognition and aggressive lipid-lowering therapy.
Recommended Citation
Singh, Ripudaman and Hernandez, Daniela, "Severe LDL-C Elevation with Negative Monogenic Familial Hypercholesterolemia Testing: A Case of Polygenic Hypercholesterolemia" (2026). Research Symposium. 2.
https://scholarworks.utrgv.edu/somrs/2026/posters/2
Included in
Severe LDL-C Elevation with Negative Monogenic Familial Hypercholesterolemia Testing: A Case of Polygenic Hypercholesterolemia
Background: Severe hypercholesterolemia, defined as a low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dL, is most often attributed to familial hypercholesterolemia (FH), a monogenic autosomal dominant disorder caused by pathogenic variants in genes essential for LDL-C catabolism, including the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1). Clinically, FH is characterized by markedly elevated LDL-C levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Homozygous individuals typically present in childhood, while heterozygous individuals are more commonly diagnosed in adulthood. However, a substantial proportion of patients with an FH phenotype lack identifiable monogenic mutations and instead demonstrate a polygenic accumulation of common LDL-C–raising alleles, referred to as polygenic hypercholesterolemia (PH).
Case Presentation: A 38-year-old Hispanic female with no significant comorbidities presented for routine evaluation and was found to have severe hypercholesterolemia, with an LDL-C of 272 mg/dL and total cholesterol of 346 mg/dL. Triglyceride levels were normal at 95 mg/dL, and lipoprotein(a) was mildly elevated at 34 mg/dL. Evaluation for secondary causes, including hemoglobin A1c, thyroid-stimulating hormone, hepatic and renal function tests, and assessment for proteinuria, was unremarkable. Additional risk factors, including cigarette smoking, excessive alcohol consumption, dietary contributors, and medication use, were excluded. The patient reported a history of elevated cholesterol since childhood with inconsistent treatment but denied any personal or first-degree family history of premature coronary, cerebrovascular, or peripheral arterial disease. Physical examination revealed no evidence of tendon xanthomas or xanthelasma. Given diagnostic uncertainty based on clinical criteria and the need to identify a pathogenic variant to guide cascade screening, a comprehensive familial hypercholesterolemia gene panel (LDLR, APOB, LDLRAP1, and PCSK9) was obtained and returned negative for pathogenic variants. In the absence of secondary causes and monogenic mutations, PH was considered the most likely diagnosis The patient was initiated on high-intensity statin therapy with atorvastatin 80 mg daily and ezetimibe 10 mg daily to achieve aggressive LDL-C reduction given her elevated ASCVD risk. At 5-week follow-up, she reported alternate-day statin dosing due to intolerance while continuing ezetimibe daily, with LDL-C improving to 206 mg/dL. She was advised to continue therapy as tolerated and return in 8 weeks for repeat lipid assessment, with plans to consider additional lipid-lowering therapies, including bempedoic acid or PCSK9 inhibitors, to achieve an LDL-C target < 70 mg/dL.
Conclusion: Most patients with markedly elevated LDL-C levels (≥190 mg/dL) do not harbor monogenic FH mutations and instead have PH. This condition is typically characterized by elevated LDL-C with normal triglyceride levels and absence of tendon xanthomas. Although polygenic risk scores may aid diagnosis, their performance varies by ancestry and explains only a portion of LDL-C variability, resulting in different implications for cascade screening compared with monogenic FH and should be carefully discussed with affected families. PH is associated with a clinically meaningful increase in ASCVD risk, intermediate between non-genetic hypercholesterolemia and monogenic FH. With advancing age, cardiovascular risk approaches that of monogenic FH, underscoring the importance of early recognition and aggressive lipid-lowering therapy.
