Abstract

Familial hypercholesterolemia (FH) is a common inherited lipid disorder associated with markedly elevated 
cholesterol levels and a substantially increased risk of premature cardiovascular disease. Advances in population 
genomics, including biobank sequencing, newborn screening initiatives, and genotype-first approaches, have 
created new opportunities for early identification of individuals with pathogenic FH variants and for systematic 
cascade testing of at-risk relatives. This narrative review synthesizes current evidence on three critical domains 
shaping the implementation of population genomics for FH: return of genomic results, cascade testing processes, 
and health-system readiness. The literature indicates that returning genomic results can enhance early diagnosis 
and preventive treatment, yet practices vary widely regarding disclosure methods, patient engagement, and 
integration with cardiovascular risk assessment. Cascade testing remains the most effective and cost-efficient 
strategy for identifying affected relatives, but uptake is consistently low due to communication barriers, limited 
digital infrastructure, and insufficient clinical coordination. Ethical, legal, and social considerations, including 
informed consent, privacy, potential stigma, and equitable access to testing, further complicate implementation. 
Evidence on health-system readiness highlights important gaps in laboratory capacity, workforce training, 
interoperability of genomic and clinical data systems, reimbursement models, and long-term sustainability 
planning. Overall, population genomics offers substantial promise for improving FH detection and prevention of 
cardiovascular disease at scale. However, successful implementation will require standardized return-of-results 
frameworks, strengthened cascade-testing pathways, equity-focused policies, and coordinated health-system 
investments. Future research should prioritize longitudinal outcome studies, evaluation of digital and patient
centered communication tools, and cross-jurisdictional implementation frameworks to ensure that population 
genomic screening for FH translates into measurable public-health benefits.