Abstract
<title>Abstract</title> <p>Familial hypercholesterolaemia (FH) remains substantially underdiagnosed despite being a major preventable cause of premature atherosclerotic cardiovascular disease. We evaluated a real-world regional FH detection pathway integrating Dutch Lipid Clinic Network (DLCN)-based clinical pre-selection, targeted next-generation sequencing and family cascade screening. Between 2017 and 2024, 197 index cases with DLCN ≥ 6 underwent genetic testing, and relatives of genetically confirmed cases were offered targeted testing for the familial variant. A conclusive molecular diagnosis was established in 81/197 index cases (41.1%). Although molecular yield increased with clinical probability, 51.6% of clinically definite FH index cases (DLCN ≥ 8) did not have a conclusive molecular diagnosis. Cascade screening was initiated in 51 genetically confirmed families and led to testing of 195 relatives, of whom 133 (68.2%) carried the familial variant. This corresponded to 2.6 newly identified carrier relatives per index case with cascade screening performed. Carrier relatives were identified approximately 9 years earlier than genetically confirmed index cases, and one quarter were identified before adulthood. These findings show that clinically guided genetic testing is most impactful when embedded in family-based cascade prevention pathways.</p>