Familial hypercholesterolemia (FH) is an autosomal dominant (rarely autosomal recessive) hereditary disease caused by mutations in genes related to the low-density lipoprotein (LDL) receptor. The main characteristics of FH are high LDL cholesterol (LDL-C) levels, skin and tendon xanthomas, and early-onset coronary atherosclerosis.

The prevalence of heterozygous FH patients is over 1 in 300 people, while homozygous FH patients occur at a frequency of more than 1 in 360,000 to 1 million people. FH is the most common hereditary metabolic disease, often encountered in routine clinical practice. The total number of FH patients in Japan is estimated to exceed 250,000.

Thus, FH is not rare; approximately 8.5% of high LDL-C patients receiving treatment for lipid abnormalities with or other drugs are reported to have FH. Compared to hypercholesterolemia without a genetic basis, the increase in LDL-C levels in FH is remarkably high, with faster progression of atherosclerosis and a higher risk of developing coronary artery disease. Early detection and aggressive LDL-C lowering therapy are therefore desirable.

FH occurs when abnormalities arise in the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) is also known to cause autosomal recessive FH. Gene mutations causing FH exist across a broad spectrum of these genes, with over 2,000 mutations already reported in the LDLR genes alone1.

Analysis of causative gene mutations is a suitable diagnostic method for hereditary diseases. As FH has multiple causative genes spanning various regions requiring analysis, until recently, it was difficult to comprehensively analyze FH gene mutations as a laboratory test due to the cost and labor involved. However, advancements in next-generation sequencing (NGS) have made testing for FH causative gene mutations with comprehensive gene mutation analysis possible.

BML has developed and provides genetic testing using NGS to analyze the entire regions of four FH causative genes: LDLR, APOB, PCSK9, and LDLRAP1 [Test name: FH Gene Mutation Analysis].

We also offer genetic testing using Multiplex Ligation-dependent Probe Amplification (MLPA) to detect LDLR gene structural variants (large exon deletions and duplications) that are difficult to detect even with NGS [Test name: LDLR Gene Mutation Analysis Test (MLPA Method)].

In some patients presenting with high LDL-C levels and tendon/skin xanthomas, the cause may be sitosterolemia. This recessive hereditary disease appears due to decreased excretion of sterols into the intestine resulting from ATP binding cassette transporter G5/G8 (ABCG5/ABCG8) gene mutations. Since patients with sitosterolemia have elevated serum plant sterol levels, measuring blood levels of plant sterols such as sitosterol and campesterol is useful to differentiate familial hypercholesterolemia from sitosterolemia2. BML has developed a method to measure serum sitosterol and campesterol concentrations using liquid chromatography with tandem mass spectrometry (LC-MS/MS).