Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia

Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan. Methods: Patients with LDL-C＞190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative. Results: The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows:LDLR (n=395),APOB (n=58),PCSK9 (n=0), andABCG5 (n=3). The most common mutations wereAPOB c.10579 C＞T (p.R3527W) (12.6%),LDLR c.986 G＞A (p.C329Y) (11.5%), andLDLR c.1747 C＞T (p.H583Y) (10.8%).LDLR c.1187-10 G＞A (IVS 8-10) andAPOB c.10580 G＞A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, includingLDLR c.1060＋2 T＞C (IVS 7＋2),LDLR c.1139 A＞C (p.E380A),LDLR c.1322 T＞C (p.A431T)＋c.1867 A＞G (p.I623V), and ABCG5 c.1337 G＞A (p.R447Q). Conclusion: LDLR andAPOB, but notPCSK9, mutations were the major genetic causes of FH. Four novel mutations inLDLR orABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.