Can We Clarify the Causative Gene/Variants Underlying Familial Hypercholesterolemia and Improve Genetic Diagnosis Rate?

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein-cholesterol (LDL-C) levels, skin and tendon xanthomas, and premature coronary artery disease. FH is caused by pathogenic gene variants of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB), an LDL ligand, and proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR. Worldwide, ＞95% of the variants that cause FH are in LDLR, 2%–11% are in APOB, and ＜1% are in PCSK9 [1) ] . However, FH varies genetically across geography, so it is necessary to assess FH-causing variants in each population/country.

In the issue of the journal, Huang et al. investigated the spectrum of pathogenic variants of LDLR, APOB, PCSK9, LDLRAP1, ABCG5, and ABCG8 in patients who were clinically diagnosed with FH in Taiwan [2) ] . Of the 750 index cases, 443 pathogenic variants of LDLR and APOB but not of PCSK9 were identified in approximately 60% of the unrelated patients with FH. Of FH-causing variants, 86% were variants of LDLR and 13% were of APOB. This is consistent with the global rate of FH-causing variants. The most common variant was APOB c.10579C＞T (p.Arg352Trp) (12.6%), which has been reported in Chinese patients with FH [3) ] . Huang et al. also discussed the regional difference in FH-related variants found in East Asia.

We reported that pathogenic variants of LDLR and PCSK9 were found in 46% and 7.8% of unrelated Japanese patients with FH (n=650), respectively [4) ] . Of FH-causing variants, 85% were variants of LDLR and 15% were of PCSK9. The c.94G＞A (p.Glu32Lys) variant comprised 88% of the pathogenic variants of PCSK9. Worldwide, this variant has only been reported in one patient with FH in Korea [5) ] . Mabuchi et al. and we have reported that patients with FH harboring the c.94G＞A (p.Glu32Lys) variant have mild phenotypes compared with patients with FH harboring LDLR pathogenic variants . The c.94G＞A (p.Glu32Lys) variant shows a mild FH phenotype compared with gain-of-function (GOF) variants of PCSK9 detected in countries other than Japan. Thus, the c.94G＞A (p.Glu32Lys) variant of PCSK9 is unique to Japan. We recently found the first Japanese family with FH due to the c.10580G＞A: p.(Arg3527Gln) variant of APOB although the frequency was low [7) ] . The phenotype of APOB pathogenic variant carriers has been reported to be mild compared with that of LDLR pathogenic variant carriers [8) ] . The LDLR pathogenic variants and PCSK9 GOF variants are definite FH-causing variants, but the phenotype of FH caused by variants of APOB and PCSK9 other than these variants is mild. Thus, the second type of FH-causing gene/variant varies by country and population.

Patients with FH harboring no pathogenic variants of LDLR, APOB, or PCSK9 comprised approximately 40% of the total unrelated patients with FH . Recently, rare variants of ABCG5 and ABCG8 have been reported in patients with FH . Tada et al. reported that rare and deleterious mutations of ABCG5 or ABCG8 were found in 8% in the 487 patients who were clinically diagnosed with FH in Japan [9) ] . Reeskamp et al. reported that 2.4% of subjects in Netherlands’s FH cohort carried putative pathogenic variants of ABCG5 and ABCG8 but had lower LDL-C levels compared with FH patients with an LDLR variant [10) ] . They concluded that these genes can partly explain the FH phenotype in some individuals but they might not cause FH inheritance patterns. In recent years, whole-exome/genome sequencing has been increasingly implemented in genetic analysis for FH. It may be useful to search for novel FH-related genes/variants from LDL-C-associated single-nucleotide polymorphisms from genome-wide association studies in the FH cohort of each country [11) ] . The variants of ABCG5/ABCG8 and other FH-related genes may reveal the FH phenotype by the presence of other genetic or environmental factors that affect cholesterol metabolism.

In conclusion, a cohort of larger size is needed to clarify the causative gene/variant underlying FH and improve genetic diagnosis rate. The regional or national FH registries, including genome information, could serve for detection and management of FH in each country/population.

Conflicts of Interest

None.