Foster, Emily¹, Turner, Jacob², Mitchell, Grace³, Clark, Oliver⁴, Bennett, Ava⁵, Parker, Leo⁶, Hughes, Mia⁷, Reed, Benjamin⁸
ABSTRACT:
Familial hypercholesterolemia (FH) represents a paradigm for precision medicine in cardiovascular disease. This review examines: (1) diagnostic yield of next-generation sequencing (NGS) panels covering LDLR, APOB, PCSK9 and novel genes (LDLRAP1, APOE); (2) epigenetic modifications (DNA methylation at LDLR promoter, circulating miR-148a) correlating with phenotypic variability among mutation carriers; and (3) pharmacogenomic markers (PCSK9 variants, miR-27b) predicting response to statins, ezetimibe and PCSK9 inhibitors. We evaluate the clinical utility of integrating genetic and epigenetic data into: (a) modified diagnostic criteria (Dutch Lipid Clinic Network), (b) atherosclerosis progression models (SAFEHEART algorithm), and (c) treatment algorithms (precision dosing of PCSK9 inhibitors). Challenges in variant interpretation (ACMG guidelines) and cost-effective implementation of comprehensive biomarker panels are discussed, along with emerging technologies like CRISPR-based diagnostics and epigenetic editing.