Abstract 12689: Targeted Exon Sequencing of Lipid-related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia

Abstract

Background: Familial hypercholesterolemia (FH) is at high risk of premature coronary artery disease (CAD). Japan Atherosclerosis Society (JAS) has published original criteria for FH. Patients are diagnosed clinical FH if at least 2 of the following criteria are satisfied: i) LDL-C ≥ 180 mg/dL, ii) Tendon/ skin xanthomas, iii) History of FH or premature CAD within 2nd degree blood relatives. Although it is easy to apply these criteria for FH-suspected patients, in fact, we are not sure whether other lipid-related genes may be overlapped in addition to those of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Methods and Results: Ninety-one heterozygous FH (HeFH) patients in Osaka University Hospital, who met the clinical FH criteria of JAS were enrolled after obtaining informed consent. Genomic DNA for each patient was extracted from peripheral blood cells. Targeted exon sequencing was performed to investigate 36 lipid-related genes including conventional FH genes. We have defined pathogenic variants if they fulfilled i) rare protein truncating variants, ii) rare damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 91 HeFH patients (52.9 ± 14.7 years), 41 patients (45.1%) were males. We have identified LDLR pathogenic variants in 61 patients (67.0%) and PCSK9 variants in 1 patient (1.1%). Among these 62 patients, 22 patients (35.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 1 patient, apolipoprotein E4 (APOE4) in 10 patients, ATP-binding cassette subfamily G member 5 (ABCG5) in 2 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 10 patients. As for remaining 29 patients without conventional FH gene variants, 13 patients (44.8%) have pathogenic variants of other lipid-related genes, which include APOE4 in 11 patients, apolipoprotein E5 (APOE5) in 1 patient, and variants of ABCG5 in 1 patient. Conclusion: We have identified several variants of lipid-related genes in addition to conventional FH genes in HeFH patients diagnosed according to JAS criteria. These variants may affect the atherogenicity of patients and selection of medication.