**3. Genetics**

True HoFH is caused by two identical mutations that are inherited in an autosomal dominant pattern [16]. Two mutant alleles of the *LDLR* gene (*MIM 606945*) cause the majority (85–95%)

of cases [7, 10, 17]. Mutations in this gene cause a reduction in LDLR activity and are associated with decreased clearance of LDL particles and increased LDL‐C levels.

Secondary genes associated with HoFH include *APOB* (*MIM107730*), *PCSK9* (*MIM 607786*), and *LDLR‐adaptor protein 1* (*LDLRAP1*; *MIM 605747*) [8, 10, 17]. In addition to "true" HoFH, patients with HoFH can have compound heterozygous mutations (different mutations in each allele of the same gene) or double heterozygous mutations (mutations in two different genes affecting LDLR function) [7, 10]. The severity of the HoFH depends on residual LDLR activity. Irrespective of the underlying genetic defect, patients with HoFH are classified as either receptor negative (i.e., <2% residual activity) or receptor defective (i.e., 2–25% residual activity) [10]. The effect on LDL‐C concentrations is also related to genotype. Homozygous *LDLR*‐defective mutations are generally associated with the highest LDL‐C levels, followed by compound heterozygous *LDLR*‐defective + *LDLR‐*negative mutations, homozygous *LDLRAP1* or *LDLR*‐defective mutations, homozygous *APOB* or *PCKS9* gain‐of‐function mutation, and double heterozygous mutation [5, 10]. Metabolic defects include impaired LDL uptake (the most common functional defect), hepatic oversecretion of apo B, decreased catabolism of triglyceride‐rich lipoproteins, increased plasma levels of lipoprotein(a) (Lp(a)), and low levels of HDL‐C [10].
