Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis
Ye-Xuan Cao, PhD,
Di Sun, PhD,
Hui-Hui Liu, MD,
Jing-Lu Jin, PhD,
Sha Li, PhD,
Yuan-Lin Guo, MD,
Na-Qiong Wu, MD,
Cheng-Gang Zhu, MD,
Geng Liu, MD,
Qian Dong, BS,
Jing Sun, BS,
Xie-Hui Chen, MD,
Jian-Jun Li, PhD, MD
Affiliations
Ye-Xuan Cao, PhD
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; Department of Cardiology, Beijing Chaoyang Hospital Affiliated to Capital University of Medical Science, Beijing, China
Di Sun, PhD
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
Hui-Hui Liu, MD
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
Jing-Lu Jin, PhD
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
Sha Li, PhD
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
Yuan-Lin Guo, MD
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
Na-Qiong Wu, MD
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
Cheng-Gang Zhu, MD
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
Geng Liu, MD
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
Qian Dong, BS
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
Jing Sun, BS
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
Xie-Hui Chen, MD
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
Jian-Jun Li, PhD, MD
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; Address for correspondence: Prof. Jian-Jun Li, 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 100037, China.
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.
