TABLE 4.

Genetic diagnosis of familial hypercholesterolemia in Japan.

Case numbers	Age	Male	Diagnosis criteria	Genotyping	Main Findings	References
350	45	197 (56.3%)	Clinically diagnosed HeFH	Genetic analysis of APOB 3500 mutation	APOB 3500 mutation was not detected.	Nohara et al., 1995
200	45	90 (45.0%)	Clinically diagnosed HeFH	Denaturing gradient-gel electrophoresis, DNA sequencing and Southern blotting analysis	LDLR mutations were detected in 125 patients (62.5%). APOB mutation was not detected in this cohort.	Yu et al., 2002
25	32 (1–73)	12 (48.0%)	Clinically or genetically diagnosed HoFH	LDLR mutations were identified using the Invader assay method. Mutations in PCSK9 were detected by PCR- single-strand conformational polymorphism followed by direct sequence analysis.	There were 15 true homozygotes and 10 compound heterozygotes for LDLR mutations. Thirteen LDLR mutations were detected. Five of these patients had PCSK9 mutation, including 2 patients with true homozygotes and 3 patients with compound heterozygotes. Three types of double heterozygotes for LDLR and PCSK9 were detected.	Mabuchi et al., 2011
269	NM	NM	Clinically diagnosed HeFH	A direct sequence analysis for all 18 exons of LDLR and 12 exons of PCSK9 gene	There were 11 PCSK9 variants detected. PCSK9 c.10 G > A (p.V4I) variant was linked to increased risk of coronary artery disease in patients aged ≥30 years and having LDLR mutations.	Ohta et al., 2016
801	NM	NM	The patients having at least two of the following factors: LDL-C ≥ 180 mg/dL, tendon/skin xanthomas, and familial history of FH or premature coronary artery disease within the second degree of kinship.	All coding regions and the exon-intron boundary sequence of the LDLR and PCSK9 genes were examined.	Pathogenic variants in the LDLR and PCSK9 genes were found in 296 (46%) and 51 (7.8%) of unrelated FH patients (n = 650), respectively.	Hori et al., 2019

APOB, apolipoprotein B; DNA, deoxyribonucleic acid; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; NM, not mention;PCSK9, proprotein convertase subtilisin/kexin type 9.