Key result
Genotype-positive pediatric FH is linked to ~62% higher premature CAD in first-degree relatives.
Observational (n=230)
Absolute Event Rate: 60% vs 37%
Reverse cascade screening effectively identifies pediatric familial hypercholesterolemia and highlights a substantial burden of premature coronary artery disease in affected families.
Background and aims Familial hypercholesterolemia (FH) is associated with lifelong exposure to elevated LDL-cholesterol and a markedly increased risk of atherosclerotic cardiovascular disease (ASCVD). The EPIRUS FH Reverse Cascade Project applies targeted family-based screening in Northwestern Greece, enabling pediatric identification and assessment of vascular risk, including cerebrovascular events. Methods Children aged 4 to 16 years were enrolled if they met at least one of the following: LDL-cholesterol >160 mg/dL or >130 mg/dL plus family history of hyperlipidemia and/or premature ASCVD or current lipid-lowering therapy. All participants (n=230) underwent standardized clinical evaluation, detailed lipid profiling and next generation sequencing. Stroke and coronary artery disease (CAD) history was recorded in children, parents, and grandparents. Results Children were classified as genotype positive FH (GP, n=123). Median age was 9.0 years and 119 children (51.7%) were female. Compared with genotype-negative (GN), GP children had significantly higher levels of total and LDL-cholesterol, triglycerides, and apolipoprotein B, and lower HDL-cholesterol and apolipoprotein AI. Premature CAD in first-degree relatives was more frequent in GP families (60% vs 37%). “Cryptogenic” ischemic stroke was recorded in 1 genotype-positive child. Stroke history was reported in 3 parents and 8 grandparents of GP children, compared with 0 parents and 2 grandparents in GN families. Conclusions Reverse cascade screening efficiently identifies pediatric FH and reveals a substantial burden of premature CAD within affected families. In contrast, stroke was uncommon and markedly less frequent than CAD, supporting the concept that cerebrovascular manifestations tend to occur later in life, even in FH. (ClinicalTrials.gov ID NCT05825612) Conflict of interest None
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Milionis et al. (2026) conducted an observational in Familial hypercholesterolemia (n=230). Genotype positive familial hypercholesterolemia vs. Genotype-negative was evaluated on Premature CAD in first-degree relatives. Genotype-positive familial hypercholesterolemia in children was associated with a higher frequency of premature CAD in first-degree relatives compared to genotype-negative families (60% vs 37%).
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