Abstract 11850: Targeted Next-Generation Sequencing of 36 Lipid-Related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia

Abstract

Background: Familial hypercholesterolemia (FH) is characterized by elevated serum low-density lipoprotein cholesterol (LDL-C) levels and premature coronary artery disease. This condition is considered to be caused by mutations of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). However, it is not fully elucidated whether other lipid-related gene variants may be overlapped in addition to these FH genes. Methods and Results: One hundred twenty-five heterozygous FH (HeFH) patients in Osaka University Hospital and Rinku General Medical Center, who met the clinical FH criteria of Japan Atherosclerosis Society were enrolled. 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. Among variants with a minor allele frequency of <5% in 1000 Genomes Project of East-Asian population, we have defined pathogenic variants if they fulfilled i) protein truncating variants, ii) damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 125 HeFH patients, we have identified LDLR pathogenic variants in 89 patients (71.2%), PCSK9 variants in 6 patients (4.8%), and APOB variants in 1 patient (0.8%). Among these 96 patients, 37 patients (38.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 3 patients, apolipoprotein E4 (APOE4) in 19 patients, variants of ATP-binding cassette subfamily G member 5 (ABCG5) in 3 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 11 patients. As for remaining 29 patients without conventional FH gene variants, 17 patients (58.6%) have pathogenic variants of other lipid-related genes, which include APOE4 in 13 patients, apolipoprotein E5 (APOE5) in 1 patient, variants of ABCG5 in 1 patient, and CD36 in 2 patients. Conclusion: Approximately 40% clinically diagnosed HeFH patients have pathogenic variants of other lipid-related genes in addition to those of conventional FH genes. These overlapping variants may affect the atherogenicity of patients and selection of medication.