Performance of LDL-C only compared to the Dutch Lipid Clinic Network Score for screening of familial hypercholesterolaemia: the Austrian experience and literature review.

Aims: Familial hypercholesterolaemia (FH) is a severely underdiagnosed, inherited disease, causing dyslipidaemia and premature atherosclerotic cardiovascular disease. In order to facilitate screening in a broad clinical spectrum, we aimed to analyse the current yield of routine genetic diagnostics for FH and to evaluate the performance of the Dutch Lipid Clinic Network Score (DLCNS) compared to a single value, the off-treatment LDL-cholesterol exceeding 190 mg/dL.

Methods and results: We investigated all patients that underwent molecular genotyping routinely performed for FH over a 4-year period in two Austrian specialist lipid clinics. Variants reported in FH-causing genes including LDLR, APOB, PCSK9, LDLRAP, and APOE were collected and classified. For clinical classification, the DLCNS was calculated retrospectively and compared to the original scores documented in patient charts. Additionally, a literature review on comparisons of DLCNS to LDL-C was performed. Of 469 patients tested, 21.3% had a disease-causing variant. A median of 3 out of 8 (excluding genotyping results and LDL-C) DLCNS criteria were unavailable. DLCNS was documented in 48% of cases, with significant discrepancies compared to retrospective scoring (P < 0.001). DLCNS did not outperform off-treatment LDL-C alone (Δ = 0.006; P = 0.660), analogously to several reports identified in the literature. A single cut-off of 190 mg/dL LDL-C compared to DLCNS ≥ 6 showed excellent sensitivity (84.9% vs. 53.8%) and acceptable specificity (39.0% vs. 84.1%).

Conclusion: Missing criteria and severe discrepancies observed between retrospective and on-site scoring by treating physicians were highly prevalent, confirming limited utility of DLCNS in clinical routine and warranting a single off-treatment LDL-C cut-off of 190 mg/dL for enhanced index-case identification.