Population Genomic Screening and Improved Lipid Management in Patients With Familial Hypercholesterolemia

The Helix Research Network program is a large population genomics initiative that screens an all-comers population of patients for Centers for Disease Control and Prevention Tier 1 genetic conditions, including familial hypercholesterolemia (FH). We evaluated changes in clinical management and low-density lipoprotein cholesterol (LDL-C) levels among patients we identified to have FH.

Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels.

Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in LDLR (74%), APOB (25%), or PCSK9 (1%). Of the 622 with retrospective and prospective electronic health record data available (mean of 11.8 and 2.1 years, respectively), 84% lacked a prior clinical FH diagnosis. Overall, 33% received new/modified lipid-lowering therapy within the first year, but this proportion was higher in those with a newly documented FH diagnosis code (57% versus 17% for those without documentation; P<0.001). Patients with new/modified therapies had a mean LDL-C reduction of 52 mg/dL, compared with 20 mg/dL in patients with no therapeutic change (difference=32 mg/dL; P<0.001).

Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH.