Complex LDLR mutations in Taiwanese familial hypercholesterolemia

Abstract

Aim: Familial hypercholesterolemia (FH) is a rare autosomal dominant lipid disorder, usually caused by LDLR (low-density lipoprotein receptor) mutations and strongly associated with premature coronary heart disease (CHD). Despite its clinical impact, FH remains underdiagnosed, and data on complex mutations in Asian populations are scarce. This study aimed to determine the prevalence and clinical significance of complex LDLR mutations in Taiwanese patients with heterozygous FH (HeFH), to evaluate the diagnostic utility of a two-step genetic strategy [FHChip plus MLPA (multiplex ligation-dependent probe amplification)], and to explore therapeutic implications for intensive lipid-lowering regimens and orphan drugs.

Methods: We recruited 100 index patients with phenotypic FH from National Taiwan University Hospital. Genetic testing included FHChip (Vita Genomics, Taiwan) for LDLR, apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and known InDels, followed by multiplex ligation-dependent probe amplification (MLPA) for mutation-negative cases. Complex mutations were defined as compound heterozygous, double mutations in one allele, or large LDLR rearrangements. Clinical and biochemical features were compared between patients with complex and single mutations.

Results: Pathogenic variants were detected in 76% of patients, with 12 (18.2%) harboring complex mutations. Compared with single mutations, complex mutations were associated with higher Low-density lipoprotein cholesterol (LDL-C) (319 vs. 210 mg/dL), more premature CHD (34.8% vs. 6.5%), and tendon xanthomas (69.6% vs. 1.1%). Intensive lipid-lowering therapy (statin-ezetimibe ± additional agents) achieved ~60% LDL-C reduction.

Conclusion: Complex mutations are not rare in Taiwanese HeFH and predict severe outcomes. Timely detection with FHChip-MLPA and aggressive therapy, including orphan drugs, is critical to lowering premature CHD risk in rare dyslipidemia.

Keywords

Familial hypercholesterolemia / LDLR complex mutations / founder effect / genetic testing (FHChip / MLPA) / orphan drugs

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