Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia

Abstract

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients. Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9. Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G A, c.1747C T, c.313 1G A, c.400T C, and APOB c.10579C T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants. Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients. as 1 in 200-500 3) , with even higher frequencies in populations with founder effects 4). FH is also the first genetic disorder shown to cause myocardial infarction 5) , leading to premature heart disease and death in affected individuals. If untreated, men have a 50% chance of coronary heart disease before the age of 50 years, and women have a 30% risk by the age of 60 years 6, 7). Most FH cases are caused by mutations in three Copyright©2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia

“…Recently, there were some case reports of sitosterolemia from China 28,29) . In a recent study from China, 2 cases of sitosterolemia were identified from 208 unrelated Chinese with possible/probable or definite FH probands by a targeted genetic panel 30) . In Taiwan, five cases of sitosterolemia Two novel LDLR mutations were identified by targeted NGS in this series.…”

Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020

“…It is interesting that P685L, the most common PV in our study, was not infrequently found in Japanese FH patients. In contrast, a recent Chinese report revealed that c.1879G A, c.1747C T, and c313+1G A were highly prevalent among PV carriers 14) . These findings highlight that the characteristics of LDLR variants in each East Asian country are distinctive.…”

“…The optimal threshold levels identified based on the sensitivity and specificity are indicated. substantially lower than those of patients with FH in the Netherlands 19) and other Asian countries 14,20) . The underlying reasons for these differences, including the effects of distinct genetic backgrounds, remain to be clarified.…”

“…Although several studies have focused on Asian patients with FH 9,14) , including ours 8,12,15) , it is clear that more data are needed for a better understanding of the disease and for better patient management in this region. In Korea, a registry of patients with FH started several years ago; however, the final phenotypic and genetic results only became available in 2020.…”

Universal Screening for Familial Hypercholesterolemia in Children in Kagawa, Japan

“…Hayato Tada; Bayer Yakuhin, Ltd, and Sanofi K.K. sequencing can identify pediatric FH patients, genetic testing may be a powerful method for diagnosing FH 21) in children whenever family history is not available.…”