EP3 - ECE_3361 - Accuracy and clinical utility of founder mutation testing for familial hypercholesterolemia in Finnish population

Background In Finland, due to a founder effect, seven pathogenic variants are estimated to account for approximately 80% of the genetic spectrum of Familial Hypercholesterolemia (FH). National current care guidelines recommend these founder variants be tested in patients with probable or definite FH according to the Dutch Lipid Clinic Network Criteria (DLCNC). If testing is negative but clinical suspicion remains high, broader genetic testing is advised. However, the clinical characteristics of patients referred for founder mutation testing and its diagnostic yield are not well defined. With the increasing availability of next-generation sequencing (NGS), the optimal testing strategy should be reassessed to improve variant detection and guide best practice. Aims To evaluate clinical characteristics, family history, and FH probability (based on DLCNC) of patients referred for FH founder mutation testing in the Pirkanmaa Health Services region, Finland (2000–2024); to assess the proportion of positive founder-mutation results; and to determine the proportion of patients with negative founder testing underwent broader genetic evaluation and were diagnosed with a pathogenic FH variant. Methods and Results We performed a retrospective analysis of 1126 patients referred for FH founder variant testing between 2000 and 2024. Clinical and genetic data were collected from electronic health records. Testing was conducted as cascade screening in 37 patients with a known familial FH founder mutation and in 1089 unrelated patients. A positive FH variant was detected in 67.6% of those with a known familial mutation and 1.5% of those without. Out of founder mutation–negative patients, 121 underwent extended genetic testing, revealing an FH variant in 9.9%. Based on DLCNC clinical classification, FH variant prevalence was 64.3% in patients with definite FH, 10.7% in probable FH, 2.7% in possible FH, and 1.2% in unlikely FH categories. Overall, 137 patients had premature atherosclerotic cardiovascular disease (ASCVD) and 989 did not; FH prevalence was similar in both groups (5.1% vs 4.8%). Conclusions Founder mutation testing remains an effective first-line genetic screening approach for patients with definite FH or family history of FH in Finland. However, its diagnostic yield is low among unrelated individuals without known familial variants. Broader genetic testing after a negative founder result identified additional FH cases in 10% of patients, highlighting the need to combine targeted founder screening with comprehensive sequencing for optimal FH detection.