Monogenic and polygenic causes of low and extremely low LDL-C levels in patients referred to specialty lipid clinics: Genetics of low LDL-C

Brandon Jakubowski, Yanqiu Shao, Catherine McNeal, Chao Xing, Zahid Ahmad

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: In clinical setting, current standard-of-care does not include genetic testing for patients with low (<50 mg/dL) and extremely low (<20 mg/dL) levels of serum low-density lipoprotein-cholesterol (LDL-C). Objective: We aimed identify the underlying molecular cause – both monogenic and polygenic - of low and extremely low LDL-C levels in a cohort of patients presenting to specialty lipid clinics. Methods: Whole exome sequencing was done in patients with low or extremely low LDL-C not due to any secondary causes. Results: Nine patients (4 women), ranging in age from 25 to 63 years old, with low or extremely low LDL-C levels were evaluated. Median LDL-C was 16 mg/dL (range undetectable - 43), total cholesterol 82 mg/dL (42 – 101), triglycerides 35 mg/dL (19–239), and high-density lipoprotein-cholesterol 45 mg/dL (24–81). Of nine patients, two carried known pathogenic variants in APOB (one stop-gain, one deletion; LDL-C range undetectable -10 mg/dL); three patients had novel APOB heterozygous mutations (two frameshift deletions and one splice site; LDL-C range undectable-13 mg/dL); two had heterozygous APOB frameshift deletions previously reported as variants of unknown significance (LDL-C 18 mg/dL in both patients); one (LDL-C 43 mg/dL) had two heterozygous mutations in PCSK9, both previously reported to be benign; and one patient (LDL-C 16 mg/dL) had the APO E2/E2 genotype along with several variants of unknown significance in genes associated with triglycerides. No patients had an LDL-C polygenic risk score below the 5th percentile (range 26th percentile to 93rd percentile). Conclusion: We found APOB mutations to be the most common molecular defect in patients presenting to lipid clinics with low or extremely low LDL-C . Whether clinical genetic testing and LDL-C polygenic risk scores have any utility - other than diagnostic purposes - for such patients remains unclear. In addition, further efforts may be needed to better reclassify pathogenicity of variants of unknown significance.

Original languageEnglish (US)
Pages (from-to)658-664
Number of pages7
JournalJournal of Clinical Lipidology
Issue number5
StatePublished - Sep 1 2021


  • APOB
  • Cholesterol
  • Hypobetalipoproteinemia
  • Hypocholesterolemia
  • LDL-C
  • PCSK9

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics
  • Cardiology and Cardiovascular Medicine


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