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.
Keywords: Austria; DLCNS; Familial Hypercholesterolaemia; Performance; Spectrum; Yield.
Familial hypercholesterolaemia as a genetic disorder driving the development of premature atherosclerotic cardiovascular disease needs intensified and reliable screening as it is severely underdiagnosed and undertreated. Definite diagnosis of Familial Hypercholesterolaemia is facilitated via genetic confirmation of an underlying variant. Genetic diagnostics however is costly and therefore dependent on the correct identification of patients at risk, using clinical tools such as the commonly used Dutch Lipid Clinic Network Score. In our study, however, its utility has been demonstrated to be severely limited by the highly prevalent lack of availability of critical information for the score in clinical routine.Furthermore, we found significant inconsistencies in scoring results between the treating physician and the retrospective evaluation by the study team, indicative of unreliable results produced by the score in clinical routine. Therefore, we propose to promote the utilization of a more time-effective approach, which is the use of a single LDL-C value, allowing for the urgently needed surge in referrals to tertiary care centres for index-case identification through a low-threshold access.
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.