Approximately 40% of clinically diagnosed patients with heterozygous familial hypercholesterolemia (HeFH) have pathogenic variants of other lipid-related genes in addition to those of conventional FH genes, according to a study. “These overlapping variants may affect the atherogenicity of patients and selection of medication,” a study co-author said. A total of 125 patients with HeFH were enrolled in the study. 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 less than 5% in 1000 Genomes Project of East-Asian population, researchers defined pathogenic variants if they fulfilled protein truncating variants, damaging missense variants, and ClinVar-registered pathogenic or likely pathogenic variants. Among total patients with HeFH, researchers identified low-density lipoprotein receptor (LDLR) pathogenic variants in 89 patients, proprotein convertase subtilisin/kexin type 9 (PCSK9) variants in six patients, and apolipoprotein B (APOB) variants in one patient. Among these 96 patients, 37 additionally had pathogenic variants of other lipid-related genes, which include apolipoprotein E2 in three patients, apolipoprotein E4 in 19 patients, variants of ATP-binding cassette subfamily G member 5 in three patients, apolipoprotein C3 in one patient, and CD36 in 11 patients. As for the remaining 29 patients without conventional FH gene variants, 17 patients had pathogenic variants of other lipid-related genes, which include APOE4 in 13 patients, apolipoprotein E5 in one patient, variants of ABCG5 in one patient, and CD36 in two patients.
