Genetic Testing of Korean Familial Hypercholesterolemia Using Whole-Exome Sequencing

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.

Characteristics and Vascular Complications of Familial Hypercholesterolemia in Korea

“…In the study, LDLR point mutations were most frequent on exons 4 and 14 ( Fig. 1) 5, 18) . Point mutations of LDLR have been previously reported in a variety of gene locations in Koreans 19) .…”

“…Point mutations of LDLR have been previously reported in a variety of gene locations in Koreans 19) . Large deletions [20][21][22][23] and copy number variation 18) in LDLR associated with FH have also been identified. Although not common, mutations in APOB and PCSK9 are reported in Korean FH patients 5,18) .…”

“…Large deletions [20][21][22][23] and copy number variation 18) in LDLR associated with FH have also been identified. Although not common, mutations in APOB and PCSK9 are reported in Korean FH patients 5,18) . On the basis of the data reported thus far, it is difficult to determine whether there are any hot spots of mutations in Koreans.…”

Management of Familial Hypercholesterolemia in Hong Kong

“…Recent data from 97 Korean FH patients revealed conventional clinical criteria (Simon Broome or Dutch Lipid Clinic) showed limited mutation detection power (35% -37%), but the mutation detection rate by MEDPED criteria was as high as 67% -75%, and the best LDL-C threshold for putative mutations in LDLR, APOB or PCSK9 genes was 225 mg/dl (5.8 mmol/L) in this group of patients 30) . However, whole-exome sequencing analysis did not identify any other novel genes accounting for the genetic cause of FH 31) . Our initial genetic testing was only performed in those probands with severe phenotypes and their family members and this may contribute to the high detection rate (100% after excluding the case with sitosterolemia).…”

The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia

“…first used whole-genome resequencing to perform a genetic diagnosis in an 11-month-old female with severe hypercholesterolemia and found that the patient carried two nonsense mutations in the ABCG5 gene14. Since then, whole exome sequencing has been used to detect mutations in FH patients, but this technology has not yet found any FH-causing mutations in genes other than LDLR, APOB or PCSK91516. Target exome sequencing in combination with clinical criteria now has a high success rate in the genetic diagnosis of FH patients with hyperlipidemia8171819.…”