The following is a summary of “A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia,” published in the February 2023 issue of Endocrinology & Metabolism by Hori, et al.

Heterozygous familial hypercholesterolemia (HeFH) is a rare genetic disorder caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. However, in about 40% of HeFH patients, the causative variants in these genes remain unidentified. Therefore, for a study, researchers sought to identify novel or additional genes/variants that contribute to HeFH.

The study involved whole-exome sequencing of 215 family members from 122 families with HeFH who did not have pathogenic variants in the LDLR or PCSK9 genes. However, the family analysis revealed no novel familial hypercholesterolemia (FH) genes/variants.

Researchers then examined all APOB variants and identified 24 non-synonymous variants. One variant, the c.2863C > T:p.(Pro955Ser), had allele frequencies of 0.15 in HeFH probands and 0.034 in the general Japanese population [odds ratio 4.9 (95% CI 3.4-7.1); P = 6.9 × 10⁻¹³]. The c.2863C > T:p.(Pro955Ser) variant was present in 9.8% (n = 63) of unrelated HeFH patients (n = 645). The penetrance of the variant was low in pedigree-based genetic analysis. In vitro assays showed patients with the homozygous c.2863C > T:p.(Pro955Ser) the variant had 44% of the LDL uptake from control subjects, similar to patients with the known pathogenic heterozygous p.(Arg3527Gln) variant.

The findings suggested that while the low-frequency APOB c.2863C > T:p.(Pro955Ser) a variant is not an FH-causative variant; it has a moderate effect size in HeFH. The combination of this variant and other factors such as age, environmental factors, or other genetic factors may contribute to the severity or variability of the HeFH phenotype.

Reference: academic.oup.com/jcem/article-abstract/108/2/422/6747529?redirect