Endocrine Abstracts

JOINT960

Background: Familial hypercholesterolemia (FH) is a common inherited disorder that significantly contributes to atherosclerotic cardiovascular disease (ASCVD). In Asia, limited access to genetic testing often necessitates the use of clinical criteria, such as the Simon-Broome (SB) or Dutch Lipid Clinic Network (DLCN) criteria, to identify FH. Younger adults, who typically have fewer metabolic comorbidities, are more likely to be diagnosed with FH. However, the accuracy of these criteria compared to genetic testing in younger adults remains unclear. This study assessed the performance of SB and DLCN criteria against genetic testing for FH in individuals under 25 years.

Methods: Between May 2021 and June 2024, 40 individuals under 25 years who underwent genetic testing for FH at a single institution were included. Retrospective data collection covered demographic (age, gender), anthropometric (BMI), clinical (physical stigmata of FH, family history of premature ASCVD), and biochemical (lipid profiles) parameters. Genetic testing results were classified as "positive" (pathogenic/likely pathogenic variants) or "negative" (VUS, benign, likely benign, no mutation). The diagnostic performance of SB, DLCN, total cholesterol (TChol), and LDL-C criteria was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Nineteen individuals (47.5%) tested positive for FH, with all carrying heterozygous mutations; 17 had LDLR gene variants. There were an additional 7 individuals with variants of uncertain significance (VUS). No significant differences were observed in age, gender, BMI, or comorbidities between test-positive and test-negative groups. While a higher proportion of test-positive individuals had a family history of premature ASCVD (36.8% vs 14.3%), this was not statistically significant (P = 0.100). Test-positive individuals had significantly higher median TChol (8.30 mmol/l vs 7.55 mmol/l, P = 0.012) and LDL-C (6.53 mmol/l vs 5.43 mmol/l, P = 0.002). ROC analysis showed AUCs of 0.866 for DLCN, 0.818 for SB, 0.791 for LDL-C, and 0.733 for TChol. DLCN >5 points achieved 94.7% sensitivity and 71.4% specificity, whilst raising the cut-off to >7 points improved specificity to 76.2% without changing sensitivity. SB “possible FH” had 89.5% sensitivity but lower specificity (57.1%). An LDL-C cutoff of >5.45 mmol/l provided the same sensitivity and specificity as SB.

Discussion: In our cohort of young adults, traditional FH criteria performed well but offered limited advantages over lipid levels alone. The low prevalence of physical signs and family history in this age group reduces the utility of SB and DLCN criteria. LDL-C thresholds alone may serve as a simpler and effective tool for FH detection in young Asian populations.