Familial hypercholesterolemia cascade testing: Insights from the Dutch Program

Familial hypercholesterolemia (FH) is a prevalent genetic disorder causing lifelong elevated LDL-cholesterol and premature cardiovascular disease. After the Dutch national FH testing program ended in 2014, the Landelijk Expertisecentrum Familiaire Hypercholesterolemie (LEEFH) foundation continued testing with an 80% reduction in funding and a leaner model. This study evaluates the first 10 years of FH testing via LEEFH as a model for global FH testing initiatives.

Cross-sectional study of retrospective data from the Dutch FH cascade testing program (LEEFH, 2014-2024). Outcomes included the number of individuals tested, diagnostic yield, relatives identified per index patient, temporal trends, and referral patterns. Geographic coverage was assessed by mapping testing data to postal codes and comparing detected cases with estimated FH prevalence.

31,487 individuals underwent genetic FH-testing. Annual testing increased from 1416 in 2014 to 4356 in 2024, while the annual yield of cascade testing increased from 165 to 541 FH-positive relatives. Diagnostic yield among index patients declined from 20.9% (236/1128) in 2014 10.0% (304/3044) in 2024 (P < .001), while yield among relatives remained close to 50% (56.9%-48.7%, P = .013). Cascade testing efficiency improved, from 0.69 to 1.78 FH-positive relatives per index case. The proportion of individuals aged <18 years identified through cascade testing was 41.4% in 2014 and 48.1% in 2024 (P = .138; P for trend = .006).

The LEEFH cascade testing program effectively detects new FH cases through family cascade testing, with substantial public health impact. Updated insights into outcomes and efficiency may guide international FH testing efforts.