Abstract
Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.
Highlights
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease
We found that 23 of 69 patients harbored FH-linked mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9)
Next-generation sequencing (NGS) has been applied in studies on FH and demonstrated as an efficient tool to identify causing mutations in known and novel genes. [10, 24] The current study utilized whole-exome sequencing (WES) to identify FH-causing mutations in Korean FH cases and presented the values of WES in the diagnosis of FH
Summary
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease. It is commonly caused by loss-of-function mutations in LDLR, mutations in APOB, or less-frequent gain-of-function mutations within PCSK9. To this date, several genetic techniques are available for the diagnosis of FH. [3] genetic screening through conventional molecular diagnostic techniques has limitations for effective FH diagnosis due to the wide variety of types and locations of mutations in known genes [4], as well as the existence of undiscovered or potential FH-causing genes. Several studies have demonstrated the utility of NGS in the diagnosis of FH. [8,9,10]
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