Key result
Genetic evaluation of three patients with extremely low HDL-C identified pathogenic mutations in ABCA1, LCAT, and APOA1, each associated with distinct clinical phenotypes including premature cardiovascular disease.
Why the study?
Extremely low HDL-C levels (<20 mg/dl) are rare and can stem from rare genetic mutations in genes like LCAT, APOA1, and ABCA1 that cause profound alterations in lipid metabolism.
Case Report (n=3)
No
Exome sequencing in patients with extremely low HDL-C (<20 mg/dl) can identify rare pathogenic mutations in genes such as ABCA1, LCAT, and APOA1, which have profound implications for patient care and risk stratification.
May inform genetic testing in extreme low HDL-C; leaves open impact on care and outcomes.
Introduction High-Density Lipoprotein Cholesterol (HDL-C) plays a pivotal role in cardiovascular health, acting as a key component in lipid transport and atheroprotection. While low HDL-C levels in the general population are often the result of multifactorial causes, extremely low HDL-C levels (<20 mg/dl) are rare and may be attributed to underlying genetic defects. Mutations in genes such as LCAT , APOA1 , and ABCA1 —although exceedingly rare—have been linked to profound alterations in lipid metabolism, often resulting in significant morbidity and increased cardiovascular risk. Methods In this study, we used exome sequencing on patients with very low HDL-C. Results We identified three patients with pathogenic mutations associated with genetic low HDL-C syndrome, including ABCA1 [NM_005502.4(ABCA1):c.4175 + 1G > T, chr:9 91757308° C > A, rs375247413], LCAT [NM_000229.2(LCAT):c.349G > A p.Ala117Thr, rs28940886], and APOA1 [NM_000039.3(APOA1):c.388A > T, p.Lys130*]. Discussion Each case presented a unique spectrum of clinical phenotypes, systemic complications, and biochemical abnormalities, illustrating the diverse impact of these genetic mutations. We provide a detailed analysis of the clinical and biochemical profiles of these patients, highlighting key aspects of disease manifestation and progression. This report underscores the importance of recognizing and characterizing rare genetic causes of low HDL-C, which may have profound implications for patient care and risk stratification.
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Sphitzen et al. (2025) conducted a case report in Extremely low HDL-C (n=3). Genetic mutations in ABCA1, LCAT, and APOA1 was evaluated on Identification of pathogenic mutations and clinical phenotypes. Genetic evaluation of three patients with extremely low HDL-C identified pathogenic mutations in ABCA1, LCAT, and APOA1, each associated with distinct clinical phenotypes including premature cardiovascular disease.
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