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

Abstract

In clinical setting, current standard-of-care does not include genetic testing for patients with low (<50mg/dL) and extremely low (<20mg/dL) levels of serum low-density lipoprotein-cholesterol (LDL-C). 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. Whole exome sequencing was done in patients with low or extremely low LDL-C not due to any secondary causes. 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 45mg/dL (24-81). Of nine patients, two carried known pathogenic variants in APOB (one stop-gain, one deletion; LDL-C range undetectable -10mg/dL); three patients had novel APOB heterozygous mutations (two frameshift deletions and one splice site; LDL-C range undectable-13mg/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 43mg/dL) had two heterozygous mutations in PCSK9, both previously reported to be benign; and one patient (LDL-C 16mg/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). 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.