Expanded Genetic Analysis Facilitates the Definitive Diagnosis of Familial Hypercholesterolemia in Patients with Very Early-Onset Coronary Artery Disease

Abstract

Background: Familial hypercholesterolemia (FH) is the one of major cause of coronary artery disease (CAD), especially for young patients. A recent FH Expert Panel suggested that FH was underdiagnosed and undertreated which needs early diagnosis. Methods: One hundred and five patients with age ≤35 years and LDL-C ≥ 3·4 mmol/L were evaluated for 9 genes (LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8). Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria for FH were also performed. Findings: The prevalence of genetically confirmed FH was 38·1% in 105 patients (LDLR, APOB, PCSK9, STAP1, homozygote and two mutations in 15, 7, 2, 1, 4, and 11 patients respectively). DLCN categorized 26·7% patients to probable and definite FH while SB identified 17·1% of patients with possible to definite FH. Twenty-five (62·5%) and seventeen (42·5%) patients with pathogenic mutations were undiagnosed according to SB and DLCN criteria. FH variant carriers, especially homozygote, had significantly higher plasma LDL-C levels. The best LDL-C threshold for genetically confirmed FH was 4·56 mmol/L in the present study. Interpretation: FH is really a common cause for very young CAD patients (≤ 35 years) with a 38·1% of causative mutations in China and best LDL-C threshold for predicting mutations was 4·56 mmol/L. The underdiagnostic rate of clinical criteria was around 42·5%-62·5%, suggesting that the expanded genetic testing could indeed promote the diagnosis of FH. Funding: This work was supported by the Capital Health Development Fund (201614035) and CAMS Major Collaborative Innovation Project (2016-I2M-1-011). Declaration of Interest: The authors declared no conflict of interest. Ethical Approval: The study protocol complied with the Declaration of Helsinki and was approved by hospital’s ethical review board (FuWai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Informed written consents were obtained from all patients enrolled in this analysis.