Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis

Ye-Xuan Cao; Di Sun; Hui-Hui Liu; Jing-Lu Jin; Sha Li; Yuan-Lin Guo; Na-Qiong Wu; Cheng-Gang Zhu; Geng Liu; Qian Dong; Jing Sun; Xie-Hui Chen; Jian-Jun Li

doi:10.1016/j.jacasi.2021.04.001

Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis

JACC Asia. 2021 Apr 21;1(1):82-89. doi: 10.1016/j.jacasi.2021.04.001. eCollection 2021 Jun.

Authors

Ye-Xuan Cao^{1

2}, Di Sun¹, Hui-Hui Liu¹, Jing-Lu Jin¹, Sha Li¹, Yuan-Lin Guo¹, Na-Qiong Wu¹, Cheng-Gang Zhu¹, Geng Liu¹, Qian Dong¹, Jing Sun¹, Xie-Hui Chen¹, Jian-Jun Li¹

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Cardiology, Beijing Chaoyang Hospital Affiliated to Capital University of Medical Science, Beijing, China.

Abstract

Background: The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice.

Objectives: The present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance.

Methods: A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs).

Results: Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non-LDLR CNVs detected in the present study.

Conclusions: LDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH.

Keywords: APOB, apolipoprotein B; CNV, copy number variant; CVD, cardiovascular disease; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein-cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; copy number variant; familial hypercholesterolemia; genetic testing; variant.