From Phenotype to Genotype and Beyond: Insights into Familial Hypercholesterolemia and Familial Hypertriglyceridemia

作者：Cozma D, Lighezan DF, Tudoran C, Voinescu OR, Mornos C · 发表于：Medicina (Kaunas, Lithuania) · 年份：2026 · DOI：10.3390/medicina62071257

Familial hypercholesterolemia (FH) and familial hypertriglyceridemia (FHTG) represent a spectrum of inherited conditions with profoundly different etiologies, risk profiles, and therapeutic implications. Despite decades of clinical experience, their formal diagnostic definitions remain rooted in frameworks developed before the genomic era (the Dutch Lipid Clinic Network (DLCN) score), leading to substantial gaps in diagnostic accuracy. This review traces the historical evolution of diagnostic criteria for FH and FHTG from early phenotypic observation to contemporary genomic and biomarker-driven models. It systematically evaluates the major limitations of current criteria, including the (DLCN) score, and integrates evidence from landmark Mendelian randomization (MR) studies to identify persistent gaps. A narrative synthesis of landmark clinical, epidemiological, and genetic studies was performed, encompassing the original discovery of the low-density lipoprotein cholesterol (LDL-C) receptor pathway, the development of international diagnostic criteria, and contemporary mendelian randomization (MR) evidence on the causal roles of LDL-C, lipoprotein (a) [Lp(a)], triglyceride-rich lipoprotein remnants, and apolipoprotein B (ApoB). Current diagnostic frameworks suffer from age-dependent confounding of LDL-C measurements, failure to account for Lp(a)-mediated phenocopies, inadequate discrimination between monogenic and polygenic etiologies, sex differences, ethnicity, and inapplica...