Abstract Body (Do not enter title and authors here): Background: Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-cholesterol (LDL-C) and high risk of early-onset cardiovascular disease. Population genomic screening can identify FH-associated pathogenic variants, but its impact on subsequent lipid management remains unclear.

Objective: Assess the impact of population genomic screening for FH on clinical outcomes.

Methods: Participants across 9 U.S. health systems underwent clinical-grade exome sequencing and were offered genetic counseling if positive for FH. Using longitudinal EHR data, FH-positive patients were propensity score-matched (1:4) with FH-negative controls who also enrolled in the screening program and had similar baseline LDL-C and risk factors at the time of screening. Weighted Cox proportional hazards models assessed associations with lipid management outcomes.

Results: Among 228,602 adults screened from 2017-2025, 1,155 (~1 in 198) had a pathogenic FH variant in LDLR (74%), APOB (25%), or PCSK9 (1%). For this outcome-based analysis, 304 individuals with baseline LDL-C ≥100 mg/dL and with ≥12 months retrospective and ≥6 months prospective EHR data were included. All characteristics were well-balanced between positive vs negative groups, including baseline statin use (37% vs 38%) and LDL-C (mean of 153 vs 155 mg/dL). FH-positive patients were 2.95 times more likely than FH-negative patients to receive new/modified lipid-lowering therapies within 1 year after screening (p<0.0001). This was more pronounced in patients with baseline LDL-C 100-129 mg/dL (HR=3.25; p<0.0001) or 130-189 mg/dL (HR=2.82; p<0.0001) compared to those with LDL-C ≥190 mg/dL (HR=1.53; p=0.14). FH-positive patients on statins were more likely to be on high-intensity statins (68.9% vs 55.3%; p=0.014) or dual therapy with another lipid-lowering agent (32.8% vs 13.7%; p=0.0002). Additionally, FH-positive patients were more likely to achieve LDL-C <100 mg/dL (HR=1.35; p=0.013) or LDL-C <70 mg/dL (HR=1.82; p=0.0032) within 2 years.

Conclusion: Identification of patients with pathogenic FH variants through population genomic screening is associated with improvements in lipid management and control compared to similar FH-negative individuals. FH-positive patients received more timely and aggressive lipid-lowering therapies, likely contributing to superior LDL-C outcomes. These findings suggest clinical utility when population genomics programs are integrated with clinical management for patients with FH.